U.S. patent application number 16/940610 was filed with the patent office on 2021-07-08 for highly active polypeptides and methods of making and using the same.
The applicant listed for this patent is Longevity Biotech, Inc.. Invention is credited to Samuel H. Gellman, Scott J. Shandler.
Application Number | 20210205415 16/940610 |
Document ID | / |
Family ID | 1000005433086 |
Filed Date | 2021-07-08 |
United States Patent
Application |
20210205415 |
Kind Code |
A1 |
Shandler; Scott J. ; et
al. |
July 8, 2021 |
HIGHLY ACTIVE POLYPEPTIDES AND METHODS OF MAKING AND USING THE
SAME
Abstract
This invention relates to novel compositions comprising analogs
of naturally occurring polypeptides, wherein the analog comprises
an .alpha.-amino acid and at least one .beta.-amino acid.
Administration of the compositions may be used for effecting
treatment or prevention of a plurality of disease states caused by
dysfunctional biochemical or biological pathways. The compositions
and methods of this invention are particularly useful to identify
novel therapeutic modulators of in-vivo receptor activity with
extended half-lives and relevant bioactivity as compared to the
naturally translated polypeptides upon which the analogs are
derived.
Inventors: |
Shandler; Scott J.;
(Philadelphia, PA) ; Gellman; Samuel H.; (Madison,
WI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Longevity Biotech, Inc. |
Philadelphia |
PA |
US |
|
|
Family ID: |
1000005433086 |
Appl. No.: |
16/940610 |
Filed: |
July 28, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15691811 |
Aug 31, 2017 |
10772934 |
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16940610 |
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13642757 |
Jan 2, 2013 |
9782454 |
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PCT/US11/33684 |
Apr 22, 2011 |
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15691811 |
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61445468 |
Feb 22, 2011 |
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61405560 |
Oct 21, 2010 |
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61364359 |
Jul 14, 2010 |
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61327098 |
Apr 22, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 14/57563 20130101;
A61K 38/2278 20130101 |
International
Class: |
A61K 38/22 20060101
A61K038/22; C07K 14/575 20060101 C07K014/575 |
Claims
1. A composition comprising a vasoactive intestinal peptide (VIP)
analog, wherein said analog comprises an .alpha.-amino acid and at
least one .beta.-amino acid.
2.-52. (canceled)
53. A composition comprising a peptide or a pharmaceutical salt
thereof comprising a repetitive pattern of .alpha. and .beta. amino
acids from the amino-terminus to the carboxy-terminus chosen from:
.beta..beta..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..beta..beta.;
.beta..alpha..beta..beta..alpha..alpha..alpha..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..beta..beta.;
.beta..alpha..alpha..beta..beta..alpha..alpha..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..beta..alpha..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..beta..beta.;
.beta..alpha..alpha..beta..alpha..alpha..beta..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..beta..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..beta..alpha..beta..-
alpha..alpha..alpha..beta..alpha..beta..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..beta..beta..-
alpha..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.beta..alpha..alpha..beta..alpha..beta..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..beta..alpha..beta..alpha..beta..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..beta..beta..alpha..beta..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..alpha..beta.; and
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..alpha..beta..beta.; wherein the peptide
comprises between about 7% to about 50% .beta. amino acids.
54. The composition of claim 53, wherein the peptide or
pharmaceutical salt thereof comprises between about 10 and about
100 residues.
55. The composition of claim 53, wherein at least one .beta. amino
acid is a cyclic .beta. amino acid.
56. The composition of claim 55, wherein the cyclic .beta. amino
acid is APC or ACPC.
57. The composition of claim 53, wherein the pattern of .alpha. and
.beta. amino acids repeats at least once.
58. The composition of claim 53, wherein the peptide or
pharmaceutical salt thereof comprises an amino acid sequence from
the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3,
SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO:
8, SEQ ID NO: 9, and SEQ ID NO: 10.
59. The composition of claim 53, further comprising at least one
other active agent.
60. A method of manufacturing the composition of claim 53 or a
pharmaceutical salt derived therefrom comprising catalyzing a
reaction between at least one .alpha.-amino acid with at least one
.beta.-amino acid.
61. A kit comprising the composition of claim 53.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/691,811, filed Aug. 31, 2017, now issued as
U.S. Pat. No. 10/772,934, which is a continuation of U.S. patent
application Ser. No. 13/642,757, filed Jan. 2, 2013, now issued as
U.S. Pat. No. 9,782,454, which is a National Stage entry of
International Application No. PCT/US11/33684, filed on Apr. 22,
2011, which claims priority to U.S. Provisional Ser. No.
61/364,098, filed on Apr. 22, 2010; U.S. Provisional Ser. No.
61/364,359, filed on Jul. 14, 2010; U.S. Provisional Ser. No.
61/405,560, filed on Oct. 21, 2010; and U.S. Provisional Ser. No.
61/445,468, filed on Feb. 22, 2011, all of which are herein
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates generally to compositions comprising
modified polypeptide sequences with greater resistance to
degradation and equivalent and/or increased bioactivity as compared
to naturally encoded, unmodified polypeptide sequences, and to
methods of making the compositions and methods of using the
compositions as pharmaceutically active agents to treat disease in
animals, including humans.
BACKGROUND OF THE INVENTION
[0003] The secretin family is a family of well-conserved animal
proteins with a variety of biological functions. Biologically
active members of the secretin family are generally from about 26
to about 65 amino acids in length and are thought to have
relatively simple alpha-helical secondary structures. Many members
are originally produced in vivo as larger pro-peptides, which are
eventually converted in the active forms. Members of the secretin
family include the following proteins: GHRF, GIP, GLP-1, Glucagon,
PACAP-27, PACAP-38, PHM, PrP, and secretin. The q25 region of
chromosome 6 on the human genome encodes another secretin family
member that is 170 amino acids long which becomes
post-translationally cleaved to form vasoactive intestinal peptide
(VIP). The active form of the VIP polypeptide is a 28 amino acid
protein that functions, among other ways, to reduce arterial blood
pressure, to increase vasodilation of blood vessel walls, to relax
smooth muscle in the respiratory system and gastrointestinal
tissues, reduce inflammatory responses through both promotion of
Th2 differentiation as well as the reduction of Th1 responses,
modulate both the innate and adaptive immune response, and to
stimulate secretion of electrolytes in the gut. VIP has also been
shown to be active in the central nervous system as a
neurotransmitter and in communication with lymphocytes. Bioactivity
of VIP is transmuted through three known receptor subtypes:
VIP.sub.1R, VIP.sub.2R, and PAC.sub.1R. These receptors are known
to induce cAMP concentration as well as stimulate the production of
intracellular calcium. Their affinities for secretins such as VIP
vary depending upon the subtype and the amino acid sequence of the
ligand.
[0004] Secretin family members have short half-lives. For instance,
VIP has a half-life of about two minutes in the blood stream. It is
desirable to identify polypeptides that mimic the function of
secretins such as VIP, but have increased half-life and equivalent
or more bioactivity than the naturally occurring VIP amino acid
sequence. It is also desirable to identify another peptidomimetic
of VIP to have association to one receptor subtype over another
secretin receptor.
[0005] HDL cholesterol level is inversely related to the incidence
of coronary heart disease and recently received increasing
attention as a novel target in lipid management of treating
atherosclerotic vascular disease. Direct vascular protective
effects of HDL have been attributed to apolipoprotein (apo) A-I or
apoA-I-associated molecules in HDL using direct intravenous
injections of homologous HDL, 3 recombinant mutant apoA-Imilano or
apoA-I gene therapy, or use of transgenic animals overexpressing
apoA-I or apoAI-related molecules such as paraoxonase. A recent
phase II randomized trial showed that 5 weekly intravenous
injections of recombinant apoA-1milano induced rapid regression of
coronary atherosclerotic lesions in humans. It is desirable to
identify polypeptides that mimic the function of apoA-1 such as
paraoxonase, but have increased half-life and equivalent or more
bioactivity than the naturally occurring paraoxonase amino acid
sequence. It is also desirable to identify another peptidomimetic
of apoA-1 to have association to a natural ligand for apoA-1 as
compared to wild-type sequences.
[0006] Cytokines mediate cellular activities in a number of ways.
Cytokines support the proliferation, growth, and differentiation of
pluripotential hematopoietic stem cells into vast numbers of
progenitors comprising diverse cellular lineages making up a
complex immune system. Proper and balanced interactions between the
cellular components are necessary for a healthy immune response.
The different cellular lineages often respond in a different manner
when cytokines are administered in conjunction with other
agents.
[0007] Cytokines mediate communication between cells of the immune
system, e.g., antigen presenting cells (APCs) and T lymphocytes.
Dendritic cells (DCs) are the most potent of antigen presenting
cells. See, e.g., Paul (ed.) (1993) Fundamental Immunology 3d ed.,
Raven Press, NY. Antigen presentation refers to the cellular events
in which a proteinaceous antigen is taken up, processed by antigen
presenting cells (APC), and then recognized to initiate an immune
response. The most active antigen presenting cells have been
characterized as the macrophages (which are direct developmental
products from monocytes), dendritic cells, and certain B cells. DCs
are highly responsive to inflammatory stimuli such as bacterial
lipopolysaccharides (LPS), and cytokines such as tumor necrosis
factor alpha (TNFalpha). Cytokines or stimuli, such as LPS, can
induce a series of phenotypic and functional changes in DC that are
collectively referred to as maturation. See, e.g., Banchereau and
Schmitt (eds.) (1995) Dendritic Cells in Fundamental and Clinical
Immunoloy, Plenum Press, NY. It is desirable to identify
polypeptides that mimic the function of cytokine families such as
IL-10, IL-2, IL-4, IL-12, and IL-17, but have increased half-life
and equivalent or more bioactivity than the naturally occurring
IL-10, IL-2, IL-4, IL-12, and IL-17 representative amino acid
sequences. It is also desirable to identify another peptidomimetic
of a cytokine such as IL-17 to have association to a natural
receptor for IL-17 as compared to wild-type sequences.
[0008] Chemists have long sought to extrapolate the power of
biological catalysis and recognition to synthetic systems. These
efforts have focused largely on low-molecular weight catalysts and
receptors. Most biological systems, however, rely almost
exclusively on large polymers such as proteins and RNA to perform
complex biochemical and/or biological functions. There is a
long-felt need to identify synthetic polymers of amino acids which
display discrete and predictable folding propensities to mimic
natural biological systems. Such polypeptides are designed to
provide a molecular equivalent or improved functionality as
compared to naturally occurring protein-protein interactions
specifically because of their ability to mimic natural interactions
in addition to their resistance to natural degradative enzymes in a
subject. Whereas a naturally occurring probe, comprised entirely of
.alpha.-amino acid residues, will be readily degraded by any number
of proteases and peptidases, the secretin analogs of the present
invention comprising a mixture of .alpha.- and .beta.-amino acid
residues are not degraded in the same manner
[0009] There is a need for secretin analogs that exhibit increased
conformational constraints or increased conformational flexibility
and greater half-lives. Increased conformational constraints may
lock the active domain of the polypeptides into their active state.
Increased conformational flexibility of the polypeptide may yield a
high affinity selectivity for the naturally occurring polypeptide's
natural biological target. There is a need for use of such analogs,
compositions comprising such analogs, and methods of using the
compositions as pharmaceutically active agents to treat disease in
animals. New polypeptide analogs are disclosed that may provide one
of more increased half-life, reduced degradation upon
administration, reduced degradation upon solubilization, increased
conformational constraints and that produce the same or greater
biological effect as compared to naturally occurring secretin
family members. The present invention addresses these and other
needs associated with treatment and prevention of disease that
implicate dysfunction of biological systems involving naturally
occurring polypeptides.
SUMMARY OF THE INVENTION
[0010] In some embodiments, the invention relates to compositions
comprising a helical polypeptide synthesized with a repeated
pattern of .beta.-amino acids at positions along the entire length
of a polypeptide chain. For any of the peptides described herein,
there may embodiments in which there are no .beta.-amino acids
within the peptide. The selected pattern of synthetic amino acids
along the helical polypeptide decreases the rate at which the
polypeptide may degrade when administered to a subject or when
reconstituted or placed in solution. Selected side chains of the
amino acids increase the conformational rigidity of the polypeptide
in order to constrain the polypeptide in its active state. The
selected pattern of synthetic amino acids along the helical
polypeptide increases the half-life of the polypeptide as compared
to naturally encoded polypeptides with the same .alpha.-amino acid
sequence. In some embodiments, the polypeptide comprises
.beta.-amino acids that spatially aligned along a longitudinal axis
of the analog in order to confer degradation resistance to the
composition while preserving the native binding interface. In some
embodiments, the composition comprises a secretin analog. In some
embodiments, the composition comprises a vasoactive intestinal
peptide (VIP) analog, wherein said analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid.
[0011] In some embodiments, the composition comprises a secretin
analog wherein the total number of .beta.-amino acids in the analog
is from about 10 percent to about 60 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a secretin analog wherein the total number of
.beta.-amino acids in the analog is from about 12 percent to about
50 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a secretin analog
wherein the total number of .beta.-amino acids in the analog is
from about 14 percent to about 50 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a secretin analog wherein the total number of
.beta.-amino acids in the analog is from about 16 percent to about
50 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a secretin analog
wherein the total number of .beta.-amino acids in the analog is
from about 18 percent to about 50 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a secretin analog wherein the total number of
.beta.-amino acids in the analog is from about 20 percent to about
50 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a secretin analog
wherein the total number of .beta.-amino acids in the analog is
from about 30 percent to about 50 percent of the total number of
amino acids of the analog.
[0012] In some embodiments, the composition comprises a secretin
analog wherein the total number of .beta.-amino acids in the analog
is from about 40 percent to about 50 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a secretin analog wherein the total number of
.beta.-amino acids in the analog is from about 45 percent to about
50 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a secretin analog
wherein the total number of .beta.-amino acids in the analog is
from about 40 percent to about 45 percent of the total number of
amino acids of the analog.
[0013] In some embodiments, the composition comprises a secretin
analog wherein the total number of .beta.-amino acids in the analog
is from about 30 percent to about 40 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a secretin analog wherein the total number of
.beta.-amino acids in the analog is from about 35 percent to about
40 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a secretin analog
wherein the total number of .beta.-amino acids in the analog is
from about 20 percent to about 30 percent of the total number of
amino acids of the analog.
[0014] In some embodiments, the composition comprises a secretin
analog wherein the total number of .beta.-amino acids in the analog
is from about 10 percent to about 20 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a secretin analog wherein the total number of
.beta.-amino acids in the analog is from about 15 percent to about
20 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a secretin analog
wherein the total number of .beta.-amino acids in the analog is
from about 20 percent to about 25 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a secretin analog wherein the total number of
.beta.-amino acids in the analog is from about 25 percent to about
30 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a secretin analog
wherein the total number of .beta.-amino acids in the analog is
from about 30 percent to about 35 percent of the total number of
amino acids of the analog.
[0015] In some embodiments, the invention relates to analogs of
various protein targets. In some embodiments, the amino acid
sequences upon which the analogs are based or derived include
biologically active polypeptides chosen from the group of
transcription factors, ligands for cellular receptors, hormones and
extracellular binding peptides. In some embodiments, the invention
comprises analogs of derived from amino acid sequences chosen from
human and non-human enkephlin, LHRH, neuropeptides, glycoincretins,
integrin, glucagons and glucagon-like peptides, antithrombotic
peptides, cytokines and interleukins, transferrins, interferons,
endothelins, natriuretic hormones, extracellular kinase ligands,
angiotensin enzyme inhibitors, peptide antiviral compounds,
thrombin, substance P, substance G, somatotropin, somatostatin,
GnRH, bradykinin, vasopressin, insulin, and growth factors. The
amino acid sequences of these proteins or peptides are known to the
skilled artisan and can be obtained by numerous means. The amino
acid sequences are incorporated herein by reference from databases
such as, for example, GenBank.
[0016] As used herein, "glucagon-like peptide-1" or "GLP-1" shall
include those polypeptides and proteins that have at least one
biological activity of human GLP-1, including but not limited to
those described in U.S. Patent Publication No. 20040127412, EP
0699686-A2 and EP0733,644, U.S. Pat. Nos. 5,545,618; 5,118,666;
5,512,549; WO 91/11457; WO 90/11296; WO 87/06941 which are
incorporated by reference herein, as well as GLP-1 analogs, GLP-1
isoforms, GLP-1 mimetics, GLP-1 fragments, hybrid GLP-1 proteins,
fusion proteins, oligomers and multimers, homologues, glycosylation
pattern variants, and muteins, thereof, regardless of the
biological activity of same, and further regardless of the method
of synthesis or manufacture thereof including synthetic,
transgenic, and gene activated methods. Numerous GLP-1 analogs and
derivatives are known and are referred to herein as "GLP-1
compounds." These GLP-1 analogs include the Exendins which are
peptides found in the venom of the GILA-monster. Specific examples
of GLP-1 include, but are not limited to, GLP-1(3-36), GLP-1(3-37),
GLP-1(1-45), and Exendins 1 through 4. Further, it is possible to
obtain GLP-1 through the use of recombinant DNA technology, as
disclosed by Maniatis, T., et al., Molecular Biology: A Laboratory
Manual, Cold Spring Harbor, N.Y. (1982), and produce GLP-1 in host
cells by methods known to one of ordinary skill in the art.
[0017] The term "human GLP-1 (GLP-1)" or "GLP-1 polypeptide" refers
to GLP-1 as described herein, as well as a polypeptide that retains
at least one biological activity of a naturally-occurring GLP-1.
GLP-1 polypeptides also include the pharmaceutically acceptable
salts and prodrugs, and prodrugs of the salts, polymorphs,
hydrates, solvates, biologically-active fragments, biologically
active variants and stereoisomers of the naturally-occurring human
GLP-1 as well as agonist, mimetic, and antagonist variants of the
naturally-occurring human GLP-1, the family of exendins including
exendins 1 through 4, and polypeptide fusions thereof. Examples of
GLP-1 polypeptides include, but are not limited to, those described
in U.S. Pat. No. 5,118,666; which is incorporated by reference
herein. Fusions comprising additional amino acids at the amino
terminus, carboxyl terminus, or both, are encompassed by the term
"GLP-1 polypeptide." Exemplary fusions include, but are not limited
to, e.g., fusions for the purpose of purification (including, but
not limited to, to poly-histidine or affinity epitopes), fusions
with serum albumin binding peptides; fusions with serum proteins
such as serum albumin; fusions with constant regions of
immunoglobulin molecules such as Fc; and fusions with fatty acids.
The naturally-occurring GLP-1 nucleic acid and amino acid sequences
for various forms are known, as are variants such as single amino
acid variants or splice variants.
[0018] The term "GLP-1 polypeptide" encompasses GLP-1 polypeptides
comprising one or more amino acid substitutions, additions or
deletions. Exemplary substitutions in a wide variety of amino acid
positions in naturally-occurring GLP-1 have been described,
including but not limited to, substitutions that modulate one or
more of the biological activities of GLP-1, such as but not limited
to, increase agonist activity, increase solubility of the
polypeptide, convert the polypeptide into an antagonist, decrease
peptidase or protease susceptibility, etc. and are encompassed by
the term "GLP-1 polypeptide."
[0019] Human GLP-1 antagonists include, but are not limited to,
those with a substitutions at: 7, 8, 9, 22, 18, 29, 25, 32, 21, 28,
17, 24, 31, and 20 (other GLP-1 sequence of U.S. Patent Application
Publication 2010-0048871). In some embodiments, the GLP-1
antagonist comprises a non-naturally encoded amino acid linked to a
water soluble polymer that is present in a receptor binding region
of the GLP-1 molecule. In some embodiments the water soluble
polymer is coupled to the GLP-1 polypeptide at one or more of the
amino acid positions: 7, 8, 9, 22, 18, 29, 25, 32, 21, 28, 17, 24,
31, and 20 (U.S. Patent Application Publication 2010-0048871).
[0020] For the GLP-1 amino acid sequence as well as the exendin-4
and exendin-3 amino acid sequence, {His Ala Glu Gly Thr Phe Thr Ser
Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp
Leu Val Lys Gly Arg} (GLP-1(7-36), SEQ ID NO: 1330); {His Ala Glu
Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys
Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly} (GLP-1(7-37), SEQ ID
NO:1331); {His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GIn Met
Glu Glu Glu Ala Val Arg Leu Phe lIe Glu Trp Leu Lys Asn Gly Gly Pro
Ser Ser Gly Ala Pro Pro Pro Ser} (exendin-4, SEQ ID NO:1332); and
{His Ser Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
Glu Ala Val Arg Leu Phe He Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser
Gly Ala Pro Pro Pro Ser} (exendin-3, SEQ ID NO:724). In some
embodiments, GLP-1 polypeptides of the invention are substantially
identical to the sequences above, or any other sequence of a GLP-1
polypeptide (see, U.S. Patent Application Publication
2010-0048871). Nucleic acid molecules encoding GLP-1 mutants and
mutant GLP-1 polypeptides are well known. Examples of GLP-1 mutants
include those disclosed in U.S. Patent Publication No.
20040127412A1; which is incorporated by reference herein.
[0021] A number of GLP-1 products are in preclinical and clinical
development, including GLP-1 peptide analogs, conjugates, fusion
proteins, and drug delivery or combination therapies. Some of the
products in development are Exenatide (AC2993, Amylin/Eli Lilly),
AVE-0010 (ZP10, Zealand Pharm/Aventis), BIM-51077 (Ipsen/Roche),
Liraglutide (NN2211, Novo Nordisk), CJC-1131 (Conjuchem), Albugon
(Human Genome Sciences/Glaxo Smith Kline), GLP-1 transferrin
(Biorexis), AC2993 LAR (Amylin/Alkermes), GLP-1 nasal (Suntory) and
GLP-1-INT (Transition Therapeutics).
[0022] The biological activities of GLP-1 have been disclosed and
are known in the art, and can be found, for example, in U.S. Patent
Publication No: 20040082507A1 and 20040232754A1 which are
incorporated by reference herein.
[0023] Variants of GLP-1(7-37) and analogs thereof, also have been
disclosed. These variants and analogs include, for example,
Gln.sup.9-GLP-1(7-37), D-Gln.sup.9-GLP-1(7-37),
acetyl-Lys.sup.9-GLP-1(7-37), Thr.sup.16-Lys.sup.18-GLP-1(7-37),
Lys.sup.18-GLP-1(7-37) and the like, and derivatives thereof
including, for example, acid addition salts, carboxylate salts,
lower alkyl esters, and amides (see, e.g., WO 91/11457; EP0733,644
(1996); and U.S. Pat. No. 5,512,549 (1996), which are incorporated
by reference). Generally, the various disclosed forms of GLP-1 are
known to stimulate insulin secretion (insulinotropic action) and
cAMP formation (see, e.g., Mojsov, S., Int. J. Peptide Protein
Research, 40:333-343 (1992)).
[0024] As used herein, "T-20" or "DP-178" shall include those
polypeptides and proteins that have at least one biological
activity of human DP-178, as well as DP-178 analogs, DP-178
isoforms, DP-178 mimetics, DP-178 fragments, hybrid DP-178
proteins, fusion proteins, oligomers and multimers, homologues,
glycosylation pattern variants, and muteins, thereof, regardless of
the biological activity of same, and further regardless of the
method of synthesis or manufacture thereof including, but not
limited to, recombinant (whether produced from cDNA, genomic DNA,
synthetic DNA or other form of nucleic acid), synthetic,
transgenic, and gene activated methods. Hyphenated and
non-hyphenated forms (T20, DP178) of the terms are equivalent.
[0025] The term "human DP-178" or "DP-178 polypeptide" refers to
DP-178 or T-20 as described herein, as well as a polypeptide that
retains at least one biological activity of a naturally-occurring
DP-178. "DP-178" includes portions, analogs, and homologs of
DP-178, all of which exhibit antiviral activity. Antiviral activity
includes, but is not limited to, the inhibition of HIV transmission
to uninfected CD-4+ cells. Further, the invention relates to the
use of DP-178 and DP-178 fragments and/or analogs or homologs as
inhibitors of retroviral transmission, in particular HIV, to
uninfected cells, in both humans and non-humans. Non retroviral
viruses whose transmission may be inhibited by the peptides of the
invention include, but are not limited to enveloped viruses, human
respiratory syncytial virus, canine distemper virus, Newcastle
disease virus, human parainfluenza virus, and influenza
viruses.
[0026] DP-178 polypeptides also include the pharmaceutically
acceptable salts and prodrugs, and prodrugs of the salts,
polymorphs, hydrates, solvates, biologically-active fragments,
biologically active variants and stereoisomers of the
naturally-occurring human DP-178 as well as agonist, mimetic, and
antagonist variants of the naturally-occurring human DP-178, and
polypeptide fusions thereof. Fusions comprising additional amino
acids at the amino terminus, carboxyl terminus, or both, are
encompassed by the term "DP-178 polypeptide." Exemplary fusions
include, but are not limited to, e.g., methionyl DP-178 in which a
methionine is linked to the N-terminus of DP-178 resulting from the
recombinant expression of DP-178, fusions for the purpose of
purification (including, but not limited to, to poly-histidine or
affinity epitopes), T-20 extended at the N-terminus, fusions with
serum albumin binding peptides; fusions with serum proteins such as
serum albumin; fusions with constant regions of immunoglobulin
molecules such as Fc; and fusions with fatty acids. The
naturally-occurring DP-178 nucleic acid and amino acid sequences
are known, as are variants such as single amino acid variants or
splice variants.
[0027] The term "DP-178 polypeptide" encompasses DP-178
polypeptides comprising one or more amino acid substitutions,
additions or deletions. Exemplary substitutions in a wide variety
of amino acid positions in naturally-occurring DP-178 have been
described, including but not limited to, substitutions that
modulate one or more of the biological activities of DP-178, such
as but not limited to, increase agonist activity, increase
solubility of the polypeptide, convert the polypeptide into an
antagonist, decrease peptidase or protease susceptibility, etc. and
are encompassed by the term "DP-178 polypeptide," the DP-178 amino
acid sequence, (Tyr Thr Ser Leu He His Ser Leu lIe Glu Glu Ser GIn
Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala
Ser Leu Trp Asn Trp Phe) (SEQ ID NO:1333). In some embodiments,
DP-178 polypeptides of the invention are substantially identical to
the following sequences or functional fragments thereof: (Tyr Thr
Ser Leu He His Ser Leu Ile Glu Glu Ser GIn Asn Gln Gln Glu Lys Asn
Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp
Phe); Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser
Leu Ile Glu Glu Ser Gln Asn GIn Gln Glu Lys Asn Glu GIn Glu Leu Leu
Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe (SEQ ID NO:1334);
or any other sequence of a DP-178 polypeptide. Nucleic acid
molecules encoding DP-178 mutants and mutant DP-178 polypeptides
are well known.
[0028] A commercially available form of DP-178 is Fuzeon.RTM..
(enfuvirtide. Roche Laboratories Inc. and Trimeris, Inc.).
Fuzeon.RTM. has an acetylated N terminus and a carboxamide as the
C-terminus. It is used in combination with other antivirals in
HIV-1 patients that show HIV-1 replication despite ongoing
antiretroviral therapy.
[0029] As used herein, "PYY" and "peptide YY" shall include those
polypeptides and proteins that have at least one biological
activity of human PYY, as well as PYY analogs, PYY isoforms, PYY
mimetics, PYY fragments, hybrid PYY proteins, fusion proteins,
oligomers and multimers, homologues, glycosylation pattern
variants, and muteins, thereof, regardless of the biological
activity of same, and further regardless of the method of synthesis
or manufacture thereof including, but not limited to, recombinant
(whether produced from cDNA, genomic DNA, synthetic DNA or other
form of nucleic acid), synthetic, transgenic, and gene activated
methods.
[0030] The term "PYY" or "PYY polypeptide" refers to PYY as
described herein, as well as a polypeptide that retains at least
one biological activity of a naturally-occurring PYY. "PYY"
includes portions, analogs, and homologs of PYY including, but not
limited to, PYY(3-36), full-length PYY, PYY(22-36), and DPPIV
resistant variants of PYY. The term "PYY" includes the human full
length: Tyr Pro Ile Lys Pro Glu Ala Pro Gly Glu ASp Ala Ser Pro Glu
Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr
Arg Gln Arg Tyr (SEQ ID NO: 561), which is disclosed in
International Publication No. WO 02/47712 (which is the PCT
counterpart to U.S. patent Publication No. 2002/0141985, which is
hereby incorporated by reference) and the following amino acid
sequences from Tatemoto, Proc Natl Acad Sci U.S.A. 79:2514-8, 1982,
which are incorporated by reference herein: [0031] 1.
Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly (SEQ ID NO: 1375) [0032] 2.
Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-
-Leu-Ser-Arg (SEQ ID NO: 1376) [0033] 3. Tyr-Tyr-Ala-Ser-Leu-Arg
(SEQ ID NO: 1377) [0034] 4. His-Tyr-Leu-Asn-Leu-Val-Thr-Arg (SEQ ID
NO: 1378) [0035] 5.
Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-
-Leu-Ser-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-A-
rg-Tyr-NH.sub.2 (SEQ ID NO: 1379)
[0036] PYY agonists are also included in the term "PYY". PYY
agonists include any compound which elicits an effect of PYY to
reduce nutrient availability, for example a compound (1) having
activity in the food intake, gastric emptying, pancreatic
secretion, or weight loss assays described in Examples 1, 2, 5, or
6 of WO 02/47712 and U.S. patent Publication No. 2002/0141985, and
(2) which binds specifically in a Y receptor assay (Example 10 of
WO 02/47712 and U.S. patent Publication No. 2002/0141985) or in a
competitive binding assay with labeled PYY or PYY 13-361 from
certain tissues having an abundance of Y receptors, including e.g.,
area postrema (Example 9 of WO 02/47712 and U.S. patent Publication
No. 2002/0141985), wherein the PYY agonist is not pancreatic
polypeptide. In some embodiments, PYY agonists would bind in such
assays with an affinity of greater than about 1 .mu.M, or with an
affinity of greater than about 1 nM to about 5 nM.
[0037] Such agonists can comprise a polypeptide having a functional
PYY domain, an active fragment of PYY, or a chemical or small
molecule. PYY agonists may be peptide or peptide-nonpeptide hybrid
molecules, and include "PYY agonist analogs," which refer to any
compound structurally similar to a PYY that have PYY activity
typically by virtue of binding to or otherwise directly or
indirectly interacting with a PYY receptor or other receptor or
receptors with which PYY itself may interact to elicit a biological
response. Such compounds include derivatives of PYY, fragments of
PYY, extended PYY molecules having more than 36 amino acids,
truncated PYY molecules having less than 36 amino acids, and
substituted PYY molecules having one or more different amino acids
as compared to the wild-type or consensus sequence, or any
combination of the above. Such compounds may also be modified by
processes such as pegylation, amidation, glycosylation, acylation,
sulfation, phosphorylation, acetylation and cyclization.
[0038] One such PYY agonist analog is PYY (3-36), identified as Ile
Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr
Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Ile Lys pro Glu Ala Pro Gly
Glu ASp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His
Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr Val Thr Arg Gln Arg Tyr
(SEQ ID NO:559); Eberlein, Eysselein et al., Peptides 10:797-803
(1989); and Grandy, Schimiczek et al., Regul Pept 51:151-9 (1994).
Additional PYY fragments and derivatives are described in U.S.
Patent Publication 20050002927 whose sequences follow: All of the
above referenced patent publications are incorporated by reference
herein.
[0039] PYY polypeptides also include the pharmaceutically
acceptable salts and prodrugs, and prodrugs of the salts,
polymorphs, hydrates, solvates, biologically-active fragments,
biologically active variants and stereoisomers of the
naturally-occurring human PYY as well as agonist, mimetic, and
antagonist variants of the naturally-occurring human PYY, and
polypeptide fusions thereof. Fusions comprising additional amino
acids at the amino terminus, carboxyl terminus, or both, are
encompassed by the term "PYY polypeptide." Exemplary fusions
include, but are not limited to, e.g., fusions with serum albumin
binding peptides; fusions with serum proteins such as serum
albumin; fusions with constant regions of immunoglobulin molecules
such as Fc; and fusions with fatty acids. The naturally-occurring
PYY nucleic acid and amino acid sequences are known, as are
variants such as single amino acid variants or splice variants.
[0040] The term "PYY polypeptide" encompasses PYY polypeptides
comprising one or more amino acid substitutions, additions or
deletions. Exemplary substitutions in a wide variety of amino acid
positions in naturally-occurring PYY have been described, including
but not limited to, substitutions that modulate one or more of the
biological activities of PYY, such as but not limited to, increase
agonist activity, increase solubility of the polypeptide, convert
the polypeptide into an antagonist, decrease peptidase or protease
susceptibility, etc. and are encompassed by the term "PYY
polypeptide."
[0041] In some embodiments, PYY polypeptides of the invention are
substantially identical to Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala
Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn
Leu Val Thr Arg Gln Arg Tyr (SEQ ID NO: 559) or any other sequence
of a PYY polypeptide (see, U.S. Patent Application Publication
2010-0048871). Nucleic acid molecules encoding PYY mutants and
mutant PYY polypeptides are well known.
[0042] Various references disclose modification of polypeptides by
polymer conjugation or glycosylation. The term analog includes
polypeptides conjugated to a polymer such as PEG and may be
comprised of one or more additional derivitizations of cysteine,
lysine, or other residues. In addition, analogs of the instant
invention may comprise a linker or polymer, wherein the amino acid
to which the linker or polymer is conjugated may be a non-natural
amino acid, or may be conjugated to a naturally encoded amino acid
utilizing techniques known in the art such as coupling to lysine or
cysteine.
[0043] Polymer modification of polypeptides has been reported. U.S.
Pat. No. 4,904,584 discloses PEGylated lysine depleted
polypeptides, wherein at least one lysine residue has been deleted
or replaced with any other amino acid residue. WO 99/67291
discloses a process for conjugating a protein with PEG, wherein at
least one amino acid residue on the protein is deleted and the
protein is contacted with PEG under conditions sufficient to
achieve conjugation to the protein. WO 99/03887 discloses PEGylated
variants of polypeptides belonging to the growth hormone
superfamily, wherein a cysteine residue has been substituted with a
non-essential amino acid residue located in a specified region of
the polypeptide. WO 00/26354 discloses a method of producing a
glycosylated polypeptide variant with reduced allergenicity, which
as compared to a corresponding parent polypeptide comprises at
least one additional glycosylation site. U.S. Pat. No. 5,218,092
discloses modification of granulocyte colony stimulating factor
(G-CSF) and other polypeptides so as to introduce at least one
additional carbohydrate chain as compared to the native
polypeptide. Examples of PEGylated peptides include GW395058, a
PEGylated peptide thrombopoietin receptor (TPOr) agonist (de Serres
M., et al., Stem Cells. 1999; 17(4):203-9), and a PEGylated
analogue of growth hormone releasing factor (PEG-GRP; D'Antonio M,
et al. Growth Horm IGF Res. 2004 June; 14(3):226-34).
[0044] The term analog also includes glycosylated analogs, such as
but not limited to, analogs glycosylated at any amino acid
position, N-linked or O-linked glycosylated forms of the
polypeptide. In addition, splice variants are also included. The
term analog also includes heterodimers, homodimers,
heteromultimers, or homomultimers of any one or more polypeptide,
protein, carbohydrate, polymer, small molecule, linker, ligand, or
other biologically active molecule of any type, linked by chemical
means or expressed as a fusion protein, as well as polypeptide
analogs containing, for example, specific deletions or other
modifications yet maintain biological activity.
[0045] Various references disclose additional variants of GLP-1 and
acylation of GLP-1, including, but not limited to, the GLP-1 parent
analogs and acylation sites described in J. of Med. Chem. (2000)
43:1664-1669, which is incorporated herein by reference.
[0046] Those of skill in the art will appreciate that amino acid
positions corresponding to positions in analogs can be readily
identified in any other molecule such as analog fusions, variants,
fragments, etc. For example, sequence alignment by visual means or
computer programs such as BLAST can be used to align and identify a
particular position in a protein that corresponds with a position
in the analog of polypeptide sequences identified in this
application or other GLP-1, VIP, PYY, IL-10, PACAP, Ghrelin,
ANP/BNP/CNP, Maxadilan/M65, Apolipoprotein mimetic polypeptides and
any other analog sequences are intended to also refer to
substitutions, deletions or additions in corresponding positions in
GLP-1, VIP, PYY, IL-10, PACAP, Ghrelin, ANP/BNP/CNP, Maxadilan/M65,
Apolipoprotein mimetic polypeptides fusions, variants, fragments,
etc. described herein or known in the art and are expressly
encompassed by the present invention.
[0047] The term analog encompasses polypeptides comprising one or
more amino acid substitutions, additions or deletions. Analogs of
the present invention may be comprised of modifications with one or
more natural amino acids in conjunction with one or more
non-natural amino acid modification. Exemplary substitutions in a
wide variety of amino acid positions in naturally-occurring analogs
have been described, including but not limited to substitutions
that modulate one or more of the biological activities of the
analogs, such as but not limited to, increase agonist activity,
increase solubility of the polypeptide, convert the polypeptide
into an antagonist, decrease peptidase or protease susceptibility,
etc. and are encompassed by the term analog.
[0048] Human GLP-1 antagonists include, but are not limited to,
those with a substitutions at: 19, 23, 26, 27, 28, 29, 30, and 33
of the consensus sequence identified in Table 4. In some
embodiments, the GLP-1 antagonist comprises a non-naturally encoded
amino acid linked to a water soluble polymer that is present in a
receptor binding region of the GLP-1 molecule. In some embodiments,
the water soluble polymer is coupled to the GLP-1 polypeptide at
one or more of the amino acid positions: 19, 23, 26, 27, 30, and 33
of the consensus sequence identified in Table 4.
[0049] In some embodiments, the analogs further comprise an
addition, substitution or deletion that modulates biological
activity of the analogs. For example, the additions, substitution
or deletions may modulate one or more properties or activities of
the analog. For example, the additions, substitutions or deletions
may modulate affinity for the analog receptor or binding partner,
modulate (including but not limited to, increases or decreases)
receptor dimerization, stabilize receptor dimers, modulate the
conformation or one or more biological activities of a binding
partner, modulate circulating half-life, modulate therapeutic
half-life, modulate stability of the polypeptide, modulate cleavage
by peptidases or proteases, modulate dose, modulate release or
bio-availability, facilitate purification, or improve or alter a
particular route of administration Similarly, analogs of the
present invention may comprise protease cleavage sequences,
reactive groups, antibody-binding domains (including but not
limited to, FLAG or poly-His) or other affinity based sequences
(including but not limited to, FLAG, poly-His, GST, etc.) or linked
molecules (including but not limited to, biotin) that improve
detection (including but not limited to, GFP), purification or
other traits of the polypeptide.
[0050] A "non-naturally encoded amino acid" refers to an amino acid
that is not one of the 20 common amino acids or pyrolysine or
seienocysteine. Other terms that may be used synonymously with the
term "non-naturally encoded amino acid" are "non-natural amino
acid," "unnatural amino acid," "non-naturally-occurring amino
acid," and variously hyphenated and non-hyphenated versions
thereof. The term "non-naturally encoded amino acid" also includes,
but is not limited to, amino acids that occur by modification (e.g.
post-translational modifications) of a naturally encoded amino acid
(including but not limited to, the 20 common amino acids or
pyrolysine and seienocysteine) but are not themselves naturally
incorporated into a growing polypeptide chain by the translation
complex. Examples of such non-naturally-occurring amino acids
include, but are not limited to, N-acetylglucosaminyl-L-serine ,
N-acetylglucosaminyl-L-threonine, and O-phosphotyrosine.
[0051] An "amino terminus modification group" refers to any
molecule that can be attached to the amino terminus of a
polypeptide. Similarly, a "carboxy terminus modification group"
refers to any molecule that can be attached to the carboxy terminus
of a polypeptide. Terminus modification groups include, but are not
limited to, various water soluble polymers, peptides or proteins
such as serum albumin, immunoglobulin constant region portions such
as Fc, or other moieties that increase serum half-life of
peptides.
[0052] The terms "functional group", "active moiety", "activating
group", "leaving group", "reactive site", "chemically reactive
group" and "chemically reactive moiety" are used in the art and
herein to refer to distinct, definable portions or units of a
molecule. The terms are somewhat synonymous in the chemical arts
and are used herein to indicate the portions of molecules that
perform some function or activity and are reactive with other
molecules.
[0053] The term "linkage" or "linker" is used herein to refer to
groups or bonds that normally are formed as the result of a
chemical reaction and typically are covalent linkages.
Hydrolytically stable linkages means that the linkages are
substantially stable in water and do not react with water at useful
pH values, including but not limited to, under physiological
conditions for an extended period of time, perhaps even
indefinitely. Hydrolytically unstable or degradable linkages mean
that the linkages are degradable in water or in aqueous solutions,
including for example, blood. Enzymatically unstable or degradable
linkages mean that the linkage can be degraded by one or more
enzymes. As understood in the art, PEG and related polymers may
include degradable linkages in the polymer backbone or in the
linker group between the polymer backbone and one or more of the
terminal functional groups of the polymer molecule. For example,
ester linkages formed by the reaction of PEG carboxylic acids or
activated PEG carboxylic acids with alcohol groups on a
biologically active agent generally hydrolyze under physiological
conditions to release the agent. Other hydrolytically degradable
linkages include, but are not limited to, carbonate linkages; imine
linkages resulted from reaction of an amine and an aldehyde;
phosphate ester linkages formed by reacting an alcohol with a
phosphate group; hydrazone linkages which are reaction product of a
hydrazide and an aldehyde; acetal linkages that are the reaction
product of an aldehyde and an alcohol; orthoester linkages that are
the reaction product of a formate and an alcohol; peptide linkages
formed by an amine group, including but not limited to, at an end
of a polymer such as PEG, and a carboxyl group of a peptide; and
oligonucleotide linkages formed by a phosphoramidite group,
including but not limited to, at the end of a polymer, and a 5'
hydroxyl group of an oligonucleotide.
[0054] The term "biologically active molecule", "biologically
active moiety" or "biologically active agent" when used herein
means any substance which can affect any physical or biochemical
properties of a biological system, pathway, molecule, or
interaction relating to an organism, including but not limited to,
viruses, bacteria, bacteriophage, transposon, prion, insects,
fungi, plants, animals, and humans In particular, as used herein,
biologically active molecules include, but are not limited to, any
substance intended for diagnosis, cure, mitigation, treatment, or
prevention of disease in humans or other animals, or to otherwise
enhance physical or mental well-being of humans or animals.
Examples of biologically active molecules include, but are not
limited to, peptides, proteins, enzymes, small molecule drugs, hard
drugs, soft drugs, carbohydrates, inorganic atoms or molecules,
dyes, lipids, nucleosides, radionuclides, oligonucleotides, toxins,
cells, viruses, liposomes, microparticles and micelles. Classes of
biologically active agents that are suitable for use with the
invention include, but are not limited to, drugs, prodrugs,
radionuclides, imaging agents, polymers, antibiotics, fungicides,
anti-viral agents, anti-inflammatory agents, anti-tumor agents,
cardiovascular agents, anti-anxiety agents, hormones, growth
factors, steroidal agents, microbially derived toxins, and the
like.
[0055] A "bifunctional polymer" refers to a polymer comprising two
discrete functional groups that are capable of reacting
specifically with other moieties (including but not limited to,
amino acid side groups) to form covalent or non-covalent linkages.
A bifunctional linker having one functional group reactive with a
group on a particular biologically active component, and another
group reactive with a group on a second biological component, may
be used to form a conjugate that includes the first biologically
active component, the bifunctional linker and the second
biologically active component. Many procedures and linker molecules
for attachment of various compounds to peptides are known. See,
e.g., European Patent Application No 188,256; U.S. Pat. Nos.
4,671,958, 4,659,839, 4,414,148, 4,699,784; 4,680,338; 4,569,789;
and 4,589,071 which are incorporated by reference herein. A
"multi-functional polymer" refers to a polymer comprising two or
more discrete functional groups that are capable of reacting
specifically with other moieties (including but not limited to,
amino acid side groups) to form covalent or non-covalent linkages.
A bi-functional polymer or multi-functional polymer may be any
desired molecular length or molecular weight, and may be selected
to provide a particular desired spacing or conformation between one
or more molecules linked to the analog and its binding partner or
the analog.
[0056] Representative non-limiting classes of polypeptides useful
in the present invention include those falling into the following
therapeutic categories: adrenocorticotropic hormone peptides,
adrenomedullin peptides, allatostatin peptides, amylin peptides,
amyloid beta-protein fragment peptides, angiotensin peptides,
antibiotic peptides, antigenic polypeptides, anti-microbial
peptides, apoptosis related peptides, atrial natriuretic peptides,
bag cell peptides, bombesin peptides, bone GLA peptides, bradykinin
peptides, brain natriuretic peptides, C-peptides, C-type
natriuretic peptides, calcitonin peptides, calcitonin gene related
peptides, CART peptides, casomorphin peptides, chemotactic
peptides, cholecystokinin peptides, colony-stimulating factor
peptides, corticortropin releasing factor peptides, cortistatin
peptides, cytokine peptides, dermorphin peptides, dynorphin
peptides, endorphin peptides, endothelin peptides, ETa receptor
antagonist peptides, ETh receptor antagonist peptides, enkephalin
peptides, fibronectin peptides, galanin peptides, gastrin peptides,
glucagon peptides, Gn-RH associated peptides, growth factor
peptides, growth hormone peptides, GTP-binding protein fragment
peptides, guanylin peptides, inhibin peptides, insulin peptides,
interleukin peptides, laminin peptides, leptin peptides, leucokinin
peptides, luteinizing hormone-releasing hormone peptides,
mastoparan peptides, mast cell degranulating peptides, melanocyte
stimulating hormone peptides, morphiceptin peptides, motilin
peptides, neuro-peptides, neuropeptide Y peptides, neurotropic
factor peptides, orexin peptides, opioid peptides, oxytocin
peptides, PACAP peptides, pancreastatin peptides, pancreatic
polypeptides, parathyroid hormone peptides, parathyroid
hormone-related peptides, peptide T peptides, prolactin-releasing
peptides, peptide YY peptides, renin substrate peptides, secretin
peptides, somatostatin peptides, substance P peptides, tachykinin
peptides, thyrotropin-releasing hormone peptides, toxin peptides,
vasoactive intestinal peptides, vasopressin peptides, and virus
related peptides. (see U.S. Pat. No. 6,858,580). Examples of
polypeptides include, but are not limited to, pituitary hormones
such as vasopressin, oxytocin, melanocyte stimulating hormones,
adrenocorticotropic hormones, growth hormones; hypothalamic
hormones such as growth hormone releasing factor, corticotropin
releasing factor, prolactin releasing peptides, gonadotropin
releasing hormone and its associated peptides, luteinizing hormone
release hormones, thyrotropin releasing hormone, orexins, and
somatostatin; thyroid hormones such as calcitonins, calcitonin
precursors, and calcitonin gene related peptides; parathyroid
hormones and their related proteins; pancreatic hormones such as
insulin and insulin-like peptides, glucagon, somatostatin,
pancreatic polypeptides, amylin, peptide YY, and neuropeptide Y;
digestive hormones such as gastrin, gastrin releasing peptides,
gastrin inhibitory peptides, cholecystokinin, secretin, motilin,
and vasoactive intestinal peptide; natriuretic peptides such as
atrial natriuretic peptides, brain natriuretic peptides, and C-type
natriuretic peptides; neurokinins such as neurokinin A, neurokinin
B, and substance P; renin related peptides such as renin substrates
and inhibitors and angiotensins; endothelins, including big
endothelin, endothelin A receptor antagonists, and sarafotoxin
peptides; and other peptides such as adrenomedullin peptides,
allatostatin peptides, amyloid beta protein fragments, antibiotic
and antimicrobial peptides, apoptosis related peptides, bag cell
peptides, bombesin, bone Gla protein peptides, CART peptides,
chemotactic peptides, cortistatin peptides, fibronectin fragments
and fibrin related peptides. FMRF and analog peptides, galanin and
related peptides, growth factors and related peptides, G
therapeutic peptide-binding protein fragments, guanylin and
uroguanylin, inhibin peptides, interleukin and interleukin receptor
proteins, laminin fragments, leptin fragment peptides, leucokinins,
mast cell degranulating peptides, pituitary adenylate cyclase
activating polypeptides, pancreastatin, peptide T, polypeptides,
virus related peptides, signal transduction reagents, toxins, and
miscellaneous peptides such as adjuvant peptide analogs, alpha
mating factor, antiarrhythmic peptide, antifreeze polypeptide,
anorexigenic peptide, bovine pineal antireproductive peptide,
bursin, C3 peptide P16, tumor necrosis factor, cadherin peptide,
chromogranin A fragment, contraceptive tetrapeptide, conantokin G,
conantokin T, crustacean cardioactive peptide, C-telopeptide,
cytochrome b588 peptide, decorsin, delicious peptide,
delta-sleep-inducing peptide, diazempam-binding inhibitor fragment,
nitric oxide synthase blocking peptide, OVA peptide, platelet
calpain inhibitor (P1), plasminogen activator inhibitor 1, rigin,
schizophrenia related peptide, serum thymic factor, sodium
potassium A therapeutic peptidease inhibitor-1, speract, sperm
activating peptide, systemin, thrombin receptor agonists, thymic
humoral gamma2 factor, thymopentin, thymosin alpha 1, thymus
factor, tuftsin, adipokinetic hormone, uremic pentapeptide,
glucose-dependent insulinotropic polypeptide (GIP), glucagon-like
peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-1), exendin-3,
exendin-4, and other therapeutic peptides or fragments thereof.
Additional examples of peptides include ghrelin, opioid peptides
(casomorphin peptides, demorphins, endorphins, enkephalins,
deltorphins, dynorphins, and analogs and derivatives of these),
thymic peptides (thymopoietin, thymulin, thymopentin, thymosin,
Thymic Humoral Factor (THF)), cell adhesion peptides, complement
inhibitors, thrombin inhibitors, trypsin inhibitors, alpha-1
antitrypsin, Sea Urchin Sperm Activating Peptide, Asterosap,
SHU-9119 MC3-R & MC4-R Antagonist, glaspimod (immunostimulant,
useful against bacterial infections, fungal infections, immune
deficiency immune disorder, leukopenia), HP-228 (melanocortin,
useful against chemotherapy induced emesis, toxicity, pain,
diabetes mellitus, inflammation, rheumatoid arthritis, obesity),
alpha 2-plasmin inhibitor (plasmin inhibitor), APC tumor suppressor
(tumor suppressor, useful against neoplasm), early pregnancy factor
(immunosuppressor), endozepine diazepam binding inhibitor (receptor
peptide), gamma interferon (useful against leukemia), glandular
kallikrein-1 (immunostimulant), placental ribonuclease inhibitor,
sarcolecin binding protein, surfactant protein D, Wilms' tumor
suppressor, GABAB lb receptor peptide, prion related peptide
(iPrP13), choline binding protein fragment (bacterial related
peptide), telomerase inhibitor, cardiostatin peptide, endostatin
derived peptide (angiogenesis inhibitor), prion inhibiting peptide,
N-methyl D-aspartate receptor antagonist, C-peptide analog (useful
against diabetic complications), RANTES, NTY receptors, NPY2-R
(neuropeptide Y type 2-receptor) ligands, NC4R peptides, or
fragments thereof. Other analogs and polypeptides upon which the
analogs of the instant invention are derived are found in U.S. Pat.
No. 6,849,714 which is incorporated by reference herein.
[0057] The hormones regulating insulin secretion belong to the
so-called enteroinsular axis, designating a group of hormones
released from the gastrointestinal mucosa in response to the
presence and absorption of nutrients in the gut, which promote an
early and potentiated release of insulin. The enhancing effect on
insulin secretion, the so-called incretin effect, is probably
essential for a normal glucose tolerance. Many of the
gastrointestinal hormones, including gastrin and secretin
(cholecystokinin is not insulinotropic in man), are insulinotropic,
but the only physiologically important ones, those that are
responsible for the incretin effect, are the glucose-dependent
insulinotropic polypeptide, GIP, and glucagon-like peptide-1
(GLP-1).
[0058] GIP is composed of 42 amino acids, processed from a 153
amino acid precursor (Takeda et al., PNAS USA (1987) 84:7005-7008).
GIP is secreted by K cells present in the duodenum and in the small
intestinal mucosa in response to carbohydrate and lipid containing
meals (Mortensen et al. Ann. NY Acad. Sci. (2000) 921:469-472).
Expression of the GIP receptor has been shown in pancreatic islets,
the adrenal cortex, gut, heart, adipose tissue, several regions of
the brain, and the pituitary gland (Usdin et al. (1993)
Endocrinology 133:2861-2870).
[0059] Because of its insulinotropic effect, GIP, isolated in 1973
(Pederson R A. Gastric Inhibitory Polypeptide. In Walsh J H,
Dockray G J (eds.) Gut peptides: Biochemistry and Physiology. Raven
Press, New York 1994, pp. 217-259) immediately attracted
considerable interest among diabetologists. However, numerous
investigations carried out during the following years clearly
indicated that a defective secretion of GIP was not involved in the
pathogenesis of insulin dependent diabetes mellitus (IDDM) or non
insulin-dependent diabetes mellitus (NIDDM) (Krarup T., Endocr Rev
1988; 9: 122-134). Furthermore, as an insulinotropic hormone, GIP
was found to be almost ineffective in NIDDM (Krarup T., Endocr Rev
1988; 9: 122-134). The other incretin hormone, GLP-1 is the most
potent insulinotropic substance known (O'rskov C., Diabetologia
1992; 35:701-711). Unlike GIP, it is surprisingly effective in
stimulating insulin secretion in NIDDM patients. In addition, and
in contrast to the other insulinotropic hormones (perhaps with the
exception of secretin), it also potently inhibits glucagon
secretion. Because of these actions, it has pronounced blood
glucose lowering effects particularly in patients with NIDDM.
[0060] GLP-1, a product of the proglucagon gene (Bell G I, et al.,
Nature 1983; 304: 368-371), is one of the members of the
secretin-VIP family of peptides, and is established as an important
gut hormone with regulatory function in glucose metabolism and
gastrointestinal secretion and metabolism (Hoist J J., 1994;
Gastroenterology. 1994 December; 107(6):1848-55). The glucagon gene
is processed differently in the pancreas and in the intestine. In
the pancreas (Hoist J J, et al., J Biol Chem, 1994; 269:
18827-18833), the processing leads to the formation and parallel
secretion of 1) glucagon itself, occupying positions 33-61 of
proglucagon (PG); 2) an N-terminal peptide of 30 amino acids (PG
(1-30)) often called glicentin-related pancreatic peptide, GRPP
(Moody A J, et al., Nature 1981; 289: 514-516; Thim L, et al.,
Biochim Biophys Acta 1982; 703:134-141); 3) a hexapeptide
corresponding to PG (64-69); 4) and, finally, the so-called major
proglucagon fragment (PG (72-158)), in which the two glucagon-like
sequences are buried (Hoist J J, et al., J Biol Chem, 1994; 269:
18827-18833). Glucagon seems to be the only biologically active
product. In contrast, in the intestinal mucosa, it is glucagon that
is buried in a larger molecule, while the two glucagon-like
peptides are formed separately (O'rskov C, et al., Endocrinology
1986; 119:1467-1475). The following products are formed and
secreted in parallel: 1) glicentin, corresponding to PG (1-69),
with the glucagon sequence occupying residues Nos. 33-61 (Thim L,
et al., Regul Pept 1981; 2:139-151); 2) GLP-1(7-36)amide (PG
(78-107))amide (O'rskov C, et al., J. Biol. Chem. 1989;
264:12826-12829), not as originally believed PG (72-107)amide or
108, which is inactive). Small amounts of C-terminally
glycine-extended but equally bioactive GLP-1(7-37), (PG (78-108))
are also formed (Orskov C, et al., Diabetes 1991; 43: 535-539); 3)
intervening peptide-2 (PG (111-122)amide) (Buhl T, et al., J. Biol.
Chem. 1988; 263:8621-8624); and 4) GLP-2 (PG (126-158)) (Buhl T, et
al., J. Biol. Chem. 1988; 263:8621-8624; O'rskov C, et al., FEBS
letters, 1989; 247:193-106). A fraction of glicentin is cleaved
further into GRPP (PG (1-30)) and oxyntomodulin (PG (33-69)) (Hoist
J J. Biochem J. 1980; 187:337-343; Bataille D, et al., FEBS Lett
1982; 146:79-86).
[0061] Being secreted in parallel with glicentin/enteroglucagon, it
follows that the many studies of enteroglucagon secretion (Hoist J
J., Gastroenterology 1983; 84:1602-1613; Hoist J J, et al.,
Glucagon and other proglucagon-derived peptides. In Walsh J H,
Dockray G J, eds. Gut peptides: Biochemistry and Physiology. Raven
Press, New York, pp. 305-340, 1993) to some extent also apply to
GLP-1 secretion, but GLP-1 is metabolized more quickly with a
plasma half-life in humans of 2 minutes (O'rskov C, et al.,
Diabetes 1993; 42:658-661). Carbohydrate or fat-rich meals
stimulate secretion (Elliott R M, et al., J Endocrinol 1993; 138:
159-166), presumably as a result of direct interaction of yet
unabsorbed nutrients with the microvilli of the open-type L-cells
of the gut mucosa.
[0062] The incretin function of GLP-1(29-31) has been clearly
illustrated in experiments with the GLP-1 receptor antagonist,
exendin 9-39, which dramatically reduces the incretin effect
elicited by oral glucose in rats (Kolligs F, et al., Diabetes 1995
44: 16-19; Wang Z, et al., J. Clin. Invest. 1995 95: 417-421). The
hormone interacts directly with the .beta.-cells via the GLP-1
receptor (Thorens B., Proc Natl Acad Sci 1992; 89:8641-4645, U.S.
Pat. Nos. 5,670,360 and 6,051,689, which are incorporated by
reference herein) which belongs to the glucagon/VIP/calcitonin
family of G-protein-coupled 7-transmembrane spanning receptors. The
importance of the GLP-1 receptor in regulating insulin secretion
was illustrated in recent experiments in which a targeted
disruption of the GLP-1 receptor gene was carried out in mice.
Animals homozygous for the disruption had greatly deteriorated
glucose tolerance and fasting hyperglycaemia, and even heterozygous
animals were glucose intolerant (Scrocchi L, et al., Diabetes 1996;
45: 21A). The signal transduction mechanism (Fehmann H C, et al.,
Endocrine Reviews, 1995; 16: 390-410) primarily involves activation
of adenylate cyclase, but elevations of intracellular Ca.sup.2+ are
also essential (Fehmann H C, et al., Endocrine Reviews, 1995; 16:
390-410; Gromada J, et al., Diabetes 1995; 44: 767-774). A model of
GLP-1 receptor-ligand interaction is shown in Lopez de Maturana, R.
et al. (2003) J. Biol. Chem. 278, 10195-10200. Lopez de Maturana et
al. indicate that the N-terminal domain of the receptor binds to
the conserved face of the central helix of exendin-4, GLP-1, and
exendin (9-39). The N-terminal regions of exendin-4 and GLP-1
interact with the extracellular loops and/or the transmembrane
regions of the GLP-1R. Also the N-terminal domain of the receptor
interacts with the Trp-cage portion of the exendin-4 and exendin
(9-39). Neidigh et al. Nature Structural Biology (2002)
9(6):425-430 describe the Trp-cage structure of Exendin-4 and
mutants thereof.
[0063] The action of the hormone is best described as a
potentiation of glucose stimulated insulin release (Fehmann H C, et
al., Endocrine Reviews, 1995; 16: 390-410), but the mechanism that
couples glucose and GLP-1 stimulation is not known. It may involve
a calcium-induced calcium release (Gromada J, et al., Diabetes
1995; 44: 767-774; Holz G G. et al., J Biol Chem, 1996; 270:
17749-17759). As already mentioned, the insulinotropic action of
GLP-1 is preserved in diabetic P-cells. The relation of the latter
to its ability to convey "glucose competence" to isolated
insulin-secreting cells (Gromada J, et al., Diabetes 1995, 44:
767-774; Holz G G, et al., Nature 1993, 361:362-365), which respond
poorly to glucose or GLP-1 alone, but fully to a combination of the
two, is also not known. Equally importantly, however, the hormone
also potently inhibits glucagon secretion (O'rskov C, et al.,
Endocrinology 1988; 123:2009-2013). The mechanism is not known, but
seems to be paracrine, via neighbouring insulin or somatostatin
cells (Fehmann H C, et al., Endocrine Reviews, 1995; 16: 390-410).
Also the glucagonostatic action is glucose-dependent, so that the
inhibitory effect decreases as blood glucose decreases. Because of
this dual effect, if the plasma GLP-1 concentrations increase
either by increased secretion or by exogenous infusion, the molar
ratio of insulin to glucagon in the blood that reaches the liver
via the portal circulation is greatly increased, whereby hepatic
glucose production decreases (Hvidberg A, et al., Metabolism 1994;
43:104-108). As a result blood glucose concentrations decrease.
Because of the glucose dependency of the insulinotropic and
glucagonostatic actions, the glucose lowering effect is
self-limiting, and the hormone, therefore, does not cause
hypoglycaemia regardless of dose (Qualmann C, et al., Acta
Diabetologica, 1995; 32: 13-16). The effects are preserved in
patients with diabetes mellitus (Nauck M A, et al., J Clin Invest
1993; 91:301-307), in whom infusions of slightly supraphysiological
doses of GLP-1 may completely normalise blood glucose values in
spite of poor metabolic control and secondary failure to
sulphonylurea (Nauck M A, et al., Diabetologia 1993; 36:741-744).
The importance of the glucagonostatic effect is illustrated by the
finding that GLP-1 also lowers blood glucose in type-I diabetic
patients without residual P-cell secretory capacity (Creutzfeldt W,
et al., Diabetes Care 1996; 19: 580-586).
[0064] GLP-1 is involved in increasing beta-cell mass as well as
regulating beta-cell differentiation, beta-cell proliferation and
beta-cell survival (Stoffers D A, Horm Metab Res. 2004
November-December; 36(11-12):811-21), and has a role in increasing
proinsulin gene transcription and biosynthesis.
[0065] In addition to its effects on the pancreatic islets, GLP-1
has powerful actions on the gastrointestinal tract. Infused in
physiological amounts, GLP-1 potently inhibits pentagastrin-induced
as well as meal-induced gastric acid secretion (Schjoldager B T G,
et al., Dig. Dis. Sci. 1989; 35:703-708; Wettergren A, et al., Dig
Dis Sci 1993; 38:665-673). It also inhibits gastric emptying rate
and pancreatic enzyme secretion (Wettergren A., et al., Dig Dis Sci
1993; 38:665-673). Similar inhibitory effects on gastric and
pancreatic secretion and motility may be elicited in humans upon
perfusion of the ileum with carbohydrate- or lipid-containing
solutions (Layer P, et al., Dig Dis Sci 1995; 40: 1074-1082; Layer
P, et al., Digestion 1993; 54: 385-386). Concomitantly, GLP-1
secretion is greatly stimulated, and it has been speculated that
GLP-1 may be at least partly responsible for this so-called
"ileal-brake" effect (Layer P, et al., Digestion 1993; 54:
385-386). In fact, recent studies suggest that, physiologically,
the ileal-brake effects of GLP-1 may be more important than its
effects on the pancreatic islets. Thus, in dose response studies
GLP-1 influences gastric emptying rate at infusion rates at least
as low as those required to influence islet secretion (Nauck M, et
al., Gut 1995; 37 (suppl. 2): A124).
[0066] GLP-1 seems to have an effect on food intake.
Intraventricular administration of GLP-1 profoundly inhibits food
intake in rats (Schick R R, vorm Walde T, Zimmermann J P,
Schusdziarra V, Classen M. Glucagon-like peptide 1--a novel brain
peptide involved in feeding regulation. in Ditschuneit H, Gries F
A, Hauner H, Schusdziarra V, Wechsler J G (eds.) Obesity in Europe.
John Libbey & Company Ltd., 1994; pp. 363-367; 42). This effect
seems to be highly specific. Thus, N-terminally extended GLP-1 (PG
72-107) amide is inactive and appropriate doses of the GLP-1
antagonist, exendin 9-39, abolish the effects of GLP-1. Acute,
peripheral administration of GLP-1 does not inhibit food intake
acutely in rats (Turton M D, et al., Nature 1996; 379: 69-72).
However, it remains possible that GLP-1 secreted from the
intestinal L-cells may also act as a satiety signal.
[0067] Not only the insulinotropic effects but also the effects of
GLP-1 on the gastrointestinal tract are preserved in diabetic
patients (Willms B, et al., Diabetologia 1994; 37, supp1.1: A118),
and may help curtailing meal-induced glucose excursions, but, more
importantly, may also influence food intake. Administered
intravenously, continuously for one week, GLP-1 at 4 ng/kg/min has
been demonstrated to dramatically improve glycaemic control in
NIDDM patients without significant side effects (Larsen J, et al.,
Diabetes 1996; 45, suppl. 2: 233A). The peptide is fully active
after subcutaneous administration (Ritzel R, et al., Diabetologia
1995; 38: 720-725), but is rapidly degraded mainly due to
degradation by dipeptidyl peptidase IV-like enzymes (Deacon C F, et
al., J Clin Endocrinol Metab 1995; 80: 952-957; Deacon C F, et al.,
Diabetes 44: 1126-1131).
[0068] The amino acid sequence of GLP-1 is disclosed in Schmidt et
al. (Diabetologia 28 704-707 (1985). Human GLP-1 is a 30-31 amino
acid residue peptide originating from preproglucagon which is
synthesized, i.a. in the L-cells in the distal ileum, in the
pancreas and in the brain. Processing of preproglucagon to
GLP-1(7-36)amide, GLP-1(7-37) and GLP-2 occurs mainly in the
L-cells. Although the interesting pharmacological properties of
GLP-1(7-37) and analogues thereof have attracted much attention in
recent years only little is known about the structure of these
molecules. The secondary structure of GLP-1 in micelles has been
described by Thorton et al. (Biochemistry 33: 3532-3539 (1994)),
but in normal solution, GLP-1 is considered a very flexible
molecule. Derivatisation of this relatively small and very flexible
molecule resulted in compounds whose plasma profile were highly
protracted and still had retained activity.
[0069] GLP-1 and analogues of GLP-1 and fragments thereof are
useful i.e. in the treatment of Type 1 and Type 2 diabetes and
obesity.
[0070] WO 87/06941 discloses GLP-1 fragments, including
GLP-1(7-37), and functional derivatives thereof and to their use as
an insulinotropic agent. GLP-1(7-37), certain derivatives thereof
and the use thereof to treat Diabetes mellitus in a mammal are
disclosed in U.S. Pat. No. 5,120,712, which is incorporated by
reference herein.
[0071] WO 90/11296 discloses GLP-1 fragments, including
GLP-1(7-36), and functional derivatives thereof which have an
insulinotropic activity which exceeds the insulinotropic activity
of GLP-1(1-36) or GLP-1(1-37) and to their use as insulinotropic
agents.
[0072] The amino acid sequence of GLP-1(7-36) and GLP-1(7-37) is:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-A-
la-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-X, wherein X is
NH.sub.2 for GLP-1(7-36) (SEQ ID NO: 1330) and X is Gly for
GLP-1(7-37) (SEQ ID NO: 1331).
[0073] WO 91/11457 discloses analogues of the active GLP-1 peptides
7-34, 7-35, 7-36, and 7-37 which can also be useful as GLP-1
moieties.
[0074] EP 0708179-A2 discloses GLP-1-like polypeptides and
derivatives that include an N-terminal imidazole group and
optionally an unbranched C.sub.6-C.sub.10 acyl group in attached to
the lysine residue in position 34.
[0075] EP 0699686-A2 discloses certain N-terminal truncated
fragments of GLP-1 that are reported to be biologically active.
[0076] In some embodiments the compositions, pharmaceutical
compositions comprise analogs, wherein the analog amino acid
sequence is based upon the GLP-1 fragments, polypeptides, and
functional derivatives disclosed above.
[0077] Another example of a peptide is T-20 (DP-178) which is a
peptide corresponding to amino acids 638 to 673 of the
HIV-1.sub.LAI transmembrane protein (TM) gp41, the
carboxyl-terminal helical segment of the extracellular portion of
gp41. The extracellular portion of gp41 has another .alpha.-helical
region which is the amino-terminal proposed zipper domain, DP-107,
DP-107 exhibits potent antiviral activity by inhibiting viral
fusion. It is a 38 amino acid peptide, corresponding to residues
558 to 595 of the HIV-1.sub.LAI transmembrane gp41 protein. Studies
with DP-107 have proven both are non-toxic in in vitro studies and
in animals. U.S. Pat. No. 5,656,480, which is incorporated by
reference herein, describes DP-107 and its antiviral activity. In
some embodiments the compositions, pharmaceutical compositions
comprise analogs, wherein the analog amino acid sequence is based
upon the DP-107 fragments, polypeptides, and functional derivatives
disclosed.
[0078] T-20 inhibits entry of HIV into cells by acting as a viral
fusion inhibitor. The fusion process of HIV is well characterized.
HIV binds to CD4 receptor via gp120, and upon binding to its
receptor, gp120 goes through a series of conformational changes
that allows it to bind to its coreceptors, CCR5 or CXCR4. After
binding to both receptor and coreceptor, gp120 exposes gp41 to
begin the fusion process. gp41 has two regions named heptad repeat
1 and 2 (HR1 and 2). The extracellular domain identified as HR1 is
an .beta..-helical region which is the amino-terminal of a proposed
zipper domain HR1 comes together with HR2 of gp41 to form a
hairpin. The structure that it is formed is a .alpha.-helix bundle
that places the HIV envelope in the proximity of the cellular
membrane causing fusion between the two membranes. T-20 prevents
the conformational changes necessary for viral fusion by binding
the first heptad-repeat (HR1) of the gp41 transmembrane
glycoprotein. Thus, the formation of the 6-helix bundle is blocked
by T-20's binding to the HR1 region of gp41. The DP107 and DP178
domains (i.e., the HR1 and HR2 domains) of the HIV gp41 protein
non-covalently complex with each other, and their interaction is
required for the normal infectivity of the virus. Compounds that
disrupt the interaction between DP107 and DP178, and/or between
DP107-like and DP178-like peptides are antifusogenic, including
antiviral.
[0079] DP-178 acts as a potent inhibitor of HIV-1 mediated
CD-4.sup.+ cell-cell fusion (i.e., syncytial formation) and
infection of CD-4.sup.+ cells by cell-free virus. Such
anti-retroviral activity includes, but is not limited to, the
inhibition of HIV transmission to uninfected CD-4.sup.+ cells.
DP-178 act at low concentrations, and it has been proven that it is
non-toxic in in vitro studies and in animals The amino acid
conservation within the DP-178--corresponding regions of HIV-1 and
HIV-2 has been described.
[0080] Potential uses for DP-178 peptides are described in U.S.
Pat. Nos. 5,464,933 and 6,133,418, as well as U.S. Pat. Nos.
6,750,008 and 6,824,783, all of which are incorporated by reference
herein, for use in inhibition of fusion events associated with HIV
transmission.
[0081] Portions and homologs of DP178 and DP-107 as well as
modulators of DP178/DP107, DP178-like/DP107-like or HR1/HR2
interactions have been investigated that show antiviral activity,
and/or show anti-membrane fusion capability, or an ability to
modulate intracellular processes involving coiled-coil peptide
structures in retroviruses other than HIV-1 and nonretroviral
viruses. Viruses in such studies include, simian immunodeficiency
virus (U.S. Pat. No. 6,017,536), respiratory synctial virus (U.S.
Pat. Nos. 6,228,983; 6,440,656; 6,479,055; 6,623,741), Epstein-Barr
virus (U.S. Pat. Nos. 6,093,794; 6,518,013), parainfluenza virus
(U.S. Pat. No. 6,333,395), influenza virus (U.S. Pat. Nos.
6,068,973; 6,060,065), and measles virus (U.S. Pat. No. 6,013,263).
All of which are incorporated by reference herein.
[0082] A commercially available form of DP-178 is Fuzeon.RTM.
(enfuvirtide, Roche Laboratories Inc. and Trimeris, Inc.).
Fuzeon.RTM. has an acetylated N terminus and a carboxamide as the
C-terminus, and is described by the following primary amino acid
sequence:
CH.sub.3CO-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF--NH.sub.2(SEQ ID
NO: 784). It is used in combination with other antivirals in HIV-1
patients that show HIV-1 replication despite ongoing antiretroviral
therapy.
[0083] U.S. Pat. Nos. 5,464,933 and 6,824,783, which are
incorporated by reference herein, describes DP-178, DP-178
fragments and homologs, including, but not limited to, molecules
with amino and carboxy terminal truncations, substitutions,
insertions, deletions, additions, or macromolecular carrier groups
as well as DP-178 molecules with chemical groups such as
hydrophobic groups present at their amino and/or carboxy termini
Additional variants, include but are not limited to, those
described in U.S. Pat. No. 6,830,893 and the derivatives of DP-178
disclosed in U.S. Pat. No. 6,861,059. A set of T-20 hybrid
polypeptides are described in U.S. Pat. Nos. 6,656,906, 6,562,787,
6,348,568 and 6,258,782, and a DP-178-toxin fusion is described in
U.S. Pat. No. 6,627,197. In some embodiments the compositions,
pharmaceutical compositions comprise analogs, wherein the analog
amino acid sequence is based upon the T-20 and DP-178 fragments,
polypeptides, and functional derivatives disclosed above.
[0084] HAART (Highly Active Anti-Retroviral Therapy) is the
standard of therapy for HIV which combines drugs from a few classes
of antiretroviral agents to reduce viral loads. U.S. Pat. No.
6,861,059, which is incorporated by reference herein, discloses
methods of treating HIV-1 infection or inhibiting HIV-1 replication
employing DP-178 or DP-107 or derivatives thereof, in combination
with at least one other antiviral therapeutic agent such as a
reverse transcriptase inhibitor (e.g. AZT, ddI, ddC, ddA, d4T, 3TC,
or other dideoxynucleotides or dideoxyfluoronucleosides) or an
inhibitor of HIV-1 protease (e.g. indinavir; ritonavir). Other
antivirals include cytokines (e.g., rIFN.alpha., rIFN.beta.,
rIFN.gamma.), inhibitors of viral mRNA capping (e.g. ribavirin),
inhibitors of HIV protease (e.g. ABT-538 and MK-639), amphotericin
B as a lipid-binding molecule with anti-HIV activity, and
castanospermine as an inhibitor of glycoprotein processing. In some
embodiments, the pharmaceutical compositions comprises an analog of
T20, wherein the analog amino acid sequence is based upon the T20
fragments, polypeptides, and functional derivatives disclosed
above. In some embodiments, the pharmaceutical composition
comprises an analog of T20, wherein the analog amino acid sequence
is based upon the T20 fragments, polypeptides, and functional
derivatives disclosed above and one other anti-viral agent. In some
embodiments the pharmaceutical composition of the claimed invention
comprises one another anti-viral agent chosen from the following:
reverse transcriptase inhibitors, integrase inhibitors, protease
inhibitors, cytokine antagonists, and chemokine receptor modulators
described U.S. Pat. Nos. 6,855,724; 6,844,340; 6,841,558;
6,833,457; 6,825,210; 6,811,780; 6,809,109; 6,806,265; 6,768,007;
6,750,230; 6,706,706; 6,696,494; 6,673,821; 6,673,791; 6,667,314;
6,642,237; 6,599,911; 6,596,729; 6,593,346; 6,589,962; 6,586,430;
6,541,515; 6,538,002; 6,531,484; 6,511,994; 6,506,777; 6,500,844;
6,498,161; 6,472,410; 6,432,981; 6,410,726; 6,399,619; 6,395,743;
6,358,979; 6,265,434; 6,248,755; 6,245,806; and 6,172,110, which
are incorporated by reference.
[0085] Potential delivery systems for DP-178 include, but are not
limited to those described in U.S. Pat. Nos. 6,844,324 and
6,706,892. In addition, a process for producing T-20 in inclusion
bodies was described in U.S. Pat. No. 6,858,410.
[0086] T20/DP178, T21/DP107, and fragments thereof have also been
found to interact with N-formyl peptide receptor (FPR members).
T-20 activates the N-formyl peptide receptor present in human
phagocytes (Su et al. (1999) Blood 93(11):3885-3892) and is a
chemoattractant and activator of monocytes and neutrophils (see
U.S. Pat. No. 6,830,893). The FPR class receptors are
G-protein-coupled, STM receptors that bind the chemoattractant fMLP
(N-formyl-methionyl-leucyl-phenylalanine) and are involved in
monocyte chemotaxis and the induction of a host immune response to
a pathogen. The prototype FPR class receptor, FPR, binds fMLP with
high affinity and is activated by low concentrations of fMLP. The
binding of FPR by fMLP induces a cascade of G protein-mediated
signaling events leading to phagocytic cell adhesion, chemotaxis,
release of oxygen intermediates, enhanced phagocytosis and
bacterial killing, as well as MAP kinase activation and gene
transcription. (Krump et al., J Biol Chem 272:937 (1997); Prossnitz
et al., Pharmacol Ther 74:73 (1997); Murphy, Annu. Rev. Immuno. 12:
593 (1994); and Murphy, The N-formyl peptide chemotactic receptors,
Chemoattractant ligands and their receptors. CRC Press, Boca Raton,
p. 269 (1996)). Another FPR class receptor is the highly homologous
variant of FPR, named FPRL1 (also referred to as FPRH2 and LXA4R).
FPRL1 was originally cloned as an orphan receptor (Murphy et al.,
J. Biol. Chem., 267:7637-7643 (1992); Ye et al., Biochem. Biophys.
Res. Commun., 184:582-589 (1992); Bao et al., Genomics, 13:437-440
(1992); Gao, J. L. and P. M. Murphy, J. Biol. Chem.,
268:25395-25401 (1993); and Nomura et al., Int. Immunol.,
5:1239-1249 (1993)) but was subsequently found to mediate Ca.sup.2+
mobilization in response to high concentrations of fMLP. (Ye et
al., Biochem. Biophys. Res. Commun., 184:582-589 (1992); and Gao,
J. L. and P. M. Murphy, J. Biol. Chem. 268:25395-25401 (1993)). In
some embodiments, the invention relates to a method of modulating
an FPR member or CCR5 by:
[0087] a) contacting the FPR member or CCR5 molecule with a T20
analog, wherein said analog comprises an .alpha.-amino acid and at
least one .beta.-amino acid;
[0088] b) measuring the association of the T20 analog to the FPR
member or CCR5 in the presence and absence of an unknown compound;
and
[0089] c) comparing the rate of association of the T20 analog to
the FPR member or CCR5 in the presence of an unknown compound to
the rate of association of the T20 analog to the FPR member or CCR5
in the absence of an unknown compound.
[0090] The chemokine receptor CCR5 is another G-protein-coupled,
STM receptor and is a major fusion-cofactor exploited by most
primary isolates of the human immunodeficiency virus type 1
(HIV-1). (Al Khatib et al., Science 1996, 272:1955; Doranz et al.,
Cell 1996, 85:1149; Deng et al., Nature 1996, 381:661; Dragic et
al., Nature 1996; 381:667; Horuk, Immunol Today, 20:89 (1999);
Dimitrov and Broder, "HIV and Membrane Receptors," HIV and membrane
fusion: Medical Intelligence Unit, Landes Bioscience, Austin, Tex.,
1997:99; and Berger, AIDS 11, Suppl A:S3 (1997)). Individuals that
fail to express CCR5 are largely resistant to HIV-1 infection. (Liu
et al., Cell 1996, 86:367-77; Huang, Y, Nat Med 1996, 2:1240; Dean,
et al., Science, 273:1856 (1996)). Due to its prominent role in
HIV-1 fusion and entry, investigators have focused considerable
research on developing molecules that interrupt the interaction
between the HIV-1 envelope and CCR5. Chemokine ligands and
antibodies specific for CCR5, for example, have been shown to
inhibit HIV-1 entry and replication. (Cocchi et al., Science,
270:1811 (1995); Wu et al., J Exp Med, 186: 373 (1997); Proudfoot
et al., J Biol Chem, 271:2599 (1996); Arenzana-Seisdedos et al.,
Nature, 383:400 (1996); Gong et al., J Biol Chem, 273:4289 (1998)).
U.S. Pat. No. 6,808,877 discusses DP-178 and its role in
phosphorylation and downregulation of CCR5 and/or the inhibition of
HIV infection by acting as a ligand to the N-formyl peptide
receptor.
[0091] Peptide YY (PYY) is a thirty six amino acid long peptide,
first isolated from porcine intestinal tissue and mainly localized
in intestinal endocrine cells. PYY is secreted postprandially by
endocrine cells of the distal gastrointestinal tract and acts at
the hypothalamus signaling satiety. See Batterham, R. L. et al.,
Nature 418:650-654 (2002), which is incorporated by reference
herein. It has many biological activities, including a range of
activities within the digestive system and potent inhibition of
intestinal electrolyte and fluid secretion. Like its relatives,
neuropeptide Y (NPY) and pancreatic polypeptide (PP), peptide YY
(PYY) is bent into hairpin configuration that is important in
bringing the free ends of the molecule together for binding to the
receptors.
[0092] Recent studies have shown that fasting and postprandial PYY
levels are low in obese subjects, which may account for their high
appetite and food consumption. When administered intravenously, it
suppresses appetite and food intake in both lean and obese subjects
(Batterham, R. L. et al., N Engl J Med 349:941-948 (2003)). Other
peptides from the pancreatic peptide (PP) family, like peptide YY
fragments (e.g. PYY{3-36}), and PYY agonists (including those not
in the PP family) also suppress appetite. Its oral activity,
however, is negligible due to its low absorption and rapid
degradation in the gastrointestinal tract. PYY {3-36} is identified
as Ile Lys pro Glu Ala Pro Gly Glu ASp Ala Ser Pro Glu Glu Leu Asn
Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu val Thr Arg Gln Arg
Tyr; Eberlein, Eysselein et al., Peptides 10:797-803 (1989); and
Grandy, Schimiczek et al., Regul Pept 51:151-9 (1994), which are
incorporated by reference herein.
[0093] PYY {3-36} has a sequence identical to PYY over amino acids
3 to 36. PYY{3-36} contains approximately 40% of total peptide
YY-like immunoreactivity in human and canine intestinal extracts
and about 36% of total plasma peptide YY immunoreactivity in a
fasting state to slightly over 50% following a meal. It is
apparently a dipeptidyl peptidase-IV (DPP4) cleavage product of
peptide YY. Peptide YY{3-36} is reportedly a selective ligand at
the Y2 and Y5 receptors, which appear pharmacologically unique in
preferring N-terminally truncated (i.e. C terminal fragments of)
neuropeptide Y analogs. A PYY agonist may bind to a PYY receptor
with higher or lower affinity, demonstrate a longer or shorter
half-life in vivo or in vitro, or be more or less effective than
native PYY. In some embodiments a functional fragment of PYY{3-36}
is a fragment of the above sequence that shares the
immunoreactivity in human and canine intestinal extracts.
[0094] Current antiobesity drugs have limited efficacy and numerous
side effects. Crowley, V. E., Yeo, G. S. & O'Rahilly, S., Nat.
Rev. Drug Discov 1, 276-86 (2002). With obesity reaching epidemic
proportions worldwide, there is a pressing need for the development
of adequate therapeutics in this area. In recent years, hormones
and neuropeptides involved in the regulation of appetite, body
energy expenditure, and fat mass accumulation such as PYY have
emerged as potential antiobesity drugs. See McMinn, J E, Baskin, D.
G. & Schwartz, M. W., Obes Rev 1:37-46 (2000), Drazen, D. L.
& Woods, S. C., Curr Opin Clin Nutr Metab Care 6:621-629
(2003), which are incorporated by reference herein.
[0095] According to Batterham et al., Nature 418:650-654 (2002),
which is hereby incorporated by reference, the peptide YY {3-36}
system may provide a therapeutic target for the treatment of
obesity. International Publication No. WO 02/47712 and U.S. Patent
Application Publication No. 2002/0141985 disclose methods for
treating obesity and diabetes with peptide YY and peptide YY
agonists, such as peptide YY13-361. U.S. Patent Application
Publication No. 20050002927 describes the use of at least one Y2
receptor-binding peptide, such as peptide YY, Neuropeptide Y (NPY)
or Pancreatic Peptide (PP) for treating a variety of diseases and
conditions in mammalian subjects such as obesity and epilepsy. In
some embodiments the compositions, pharmaceutical compositions
comprise analogs, wherein the analog amino acid sequence is based
upon the PPY or the peptide YY {3-36} fragments, polypeptides, and
functional derivatives disclosed above. In some embodiments, the
invention relates to a pharmaceutical composition that comprise a
PPY or peptide YY {3-36} analog, wherein the analog amino acid
sequence is based upon the fragments, polypeptides, and functional
derivatives disclosed above for treatment of obesity, diabetes,
seizures associated with temporal lobe epilepsy, ulcers, irritable
bowel disease and inflammatory bowel disease according to the
dosing regimens disclosed below.
[0096] In some embodiments, the compositions of the claimed
invention comprise analog of PYY(3-36), AC162352, Neuropeptide Y
(NPY) (U.S. Pat. No US 2005/0136036 A1).
[0097] In addition, treatment with DPP-IV inhibitors prevents
degradation of Peptide YY which has been linked to gastrointestinal
conditions such as ulcers, irritable bowel disease and inflammatory
bowel disease. Peptide YY and its analogs or agonists have been
used to manipulate endocrine regulation of cell proliferation,
nutrient transport, and intestinal water and electrolyte secretion.
(U.S. Pat. No. 5,604,203; WO9820885A1; EP692971A1; U.S. Pat. No.
5,912,227, which are incorporated by reference herein). A role for
peptide YY in the regulation of intestinal motility, secretion, and
blood flow has also been suggested, as well as its use in a
treatment of malabsorptive disorders. Analogs of PYY have been
reported that emulate and enhance the duration, effect, biological
activity and selectivity of the natural peptide in the treatment of
pancreatic tumors (See U.S. Ser. No. 5,574,010, incorporated herein
by reference).
[0098] Other suitable PYY agonists include those described in
International Publication No. WO 98/20885, which is hereby
incorporated by reference.
[0099] In one aspect, the invention provides a method of treating
obesity in an obese or overweight animal by administering a
therapeutically effective amount of PYY analog, a PYY agonist
analog, or a mixture thereof with at least one delivery agent
compound and to a subject in need thereof. While "obesity" is
generally defined as a body mass index over 30, for purposes of
this disclosure, any subject, including those with a body mass
index of less than 30, who needs or wishes to reduce body weight is
included in the scope of "obese." Subjects who are insulin
resistant, glucose intolerant, or have any form of diabetes
mellitus (e.g., type 1, 2 or gestational diabetes) can benefit from
this method.
[0100] In other aspects, the invention features methods of reducing
food intake, treating diabetes mellitus, and improving lipid
profile (including reducing LDL cholesterol and triglyceride levels
and/or changing HDL cholesterol levels) comprising administering to
a subject in need thereof a therapeutically effective amount of a
PYY analog, a PYY agonist analog, or a mixture thereof with at
least one delivery agent compound. In some embodiments, the methods
of the invention are used to treat conditions or disorders which
can be alleviated by reducing nutrient availability in a subject in
need thereof, comprising administering to said subject in need
thereof a therapeutically effective amount of a PYY analog, a PYY
agonist analog, or a mixture thereof with at least one delivery
agent compound. Such conditions and disorders include, but are not
limited to, hypertension, dyslipidemia, cardiovascular disease,
eating disorders, insulin-resistance, obesity, and diabetes
mellitus of any kind.
[0101] Suitable PYY agonist analogs may be derived or based upon
the amino acid sequence of PYY agonists that have a potency in one
of the assays described in WO 02/47712 and U.S. patent Publication
No. 2002/0141985 (which is herein incorporated by reference and
discloses the activity of food intake, gastric emptying, pancreatic
secretion, or weight reduction assays) which is greater than the
potency of NPY in that same assay. A PYY analog and/or a PYY
agonist analog with the delivery agent compound may be administered
separately or together with one or more other compounds and
compositions that exhibit a long term or short-term action to
reduce nutrient availability, including, but not limited to other
compounds and compositions that comprise an amylin or amylin
agonist, a cholecystokinin (CCK) or CCK agonist, a leptin (OB
protein) or leptin agonist, an exendin or exendin agonist, or a
GLP-1 or GLP-1 agonist as described in U.S. Patent Publication
20050009748. Suitable amylin agonists include, for example,
(25,28,29Pro-)-human amylin (also known as "pramlintide", and
described in U.S. Pat. Nos. 5,686,511 and 5,998,367), calcitonin
(e.g., salmon calcitonin), including those described in U.S. Pat.
No. 5,739,106, which is hereby incorporated by reference. The CCK
used is preferably CCK octopeptide (CCK-8). Leptin is discussed in,
for example, Pelleymounter, C. et al., Science 269: 540-543 (1995),
Halaas, G. et al., Science 269: 543-6 (1995) and Campfield, S. et
al., Science 269: 546-549 (1995). Suitable CCK agonist includes
those described in U.S. Pat. No. 5,739,106, which is hereby
incorporated by reference. Suitable exendins include exendin-3 and
exendin-4, and exendin agonist compounds include, for example,
those described in PCT Publications WO 99/07404, WO 99/25727, and
WO 99/25728, all of which are hereby incorporated by reference.
According to one embodiment, the composition of the present
invention includes at least one delivery agent compound, PYY, a PYY
agonist, or a mixture thereof, at least one amylin agonist, and a
CCK agonist. Suitable combinations of amylin agonist and CCK
agonist include, but are not limited to, those described in U.S.
Pat. No. 5,739,106, which is hereby incorporated by reference.
[0102] In some embodiments, the pharmaceutical compositions
comprises an analog of the polypeptides disclosed below, wherein
the analog amino acid sequence is based upon fragments,
polypeptides, and functional derivatives with 70%, 75%, 85%, 90%,
95%, 98%, or 99% sequence homology to the following polypeptides
disclosed below:
[0103] Adrenocorticotropic hormone (ACTH) peptides including, but
not limited to, ACTH, human; ACTH 1-10; ACTH 1-13, human; ACTH
1-16, human; ACTH 1-17; ACTH 1-24, human; ACTH 4-10; ACTH 4-11;
ACTH 6-24; ACTH 7-38, human; ACTH 18-39, human; ACTH, rat; ACTH
12-39, rat; beta-cell tropin (ACTH 22-39); biotinyl-ACTH 1-24,
human; biotinyl-ACTH 7-38, human; corticostatin, human;
corticostatin, rabbit; {Met(02).sup.4, DLys.sup.8, Phe.sup.9} ACTH
4-9, human; {Met(0).sup.4, DLys.sup.8, Phe.sup.9} ACTH 4-9, human;
N-acetyl, ACTH 1-17, human; and ebiratide.
[0104] Adrenomedullin peptides including, but not limited to,
adrenomedullin, adrenomedullin 1-52, human; adrenomedullin 1-12,
human; adrenomedullin 13-52, human; adrenomedullin 22-52, human;
pro-adrenomedullin 45-92, human; pro-adrenomedullin 153-185, human;
adrenomedullin 1-52, porcine; pro-adrenomedullin (N-20),
porcine;
[0105] adrenomedullin 1-50, rat; adrenomedullin 11-50, rat; and
proAM-N20 (proadrenomedullin N-terminal 20 peptide), rat.
[0106] Allatostatin peptides including, but not limited to,
allatostatin I; allatostatin II; allatostatin III; and allatostatin
IV.
[0107] Amylin peptides including, but not limited to, acetyl-amylin
8-37, human; acetylated amylin 8-37, rat; AC187 amylin antagonist;
AC253 amylin antagonist; AC625 amylin antagonist; amylin 8-37,
human; amylin (IAPP), cat; amylin (insulinoma or islet amyloid
polypeptide(IAPP)); amylin amide, human; amylin 1-13
(diabetes-associated peptide 1-13), human; amylin 20-29 (IAPP
20-29), human; AC625 amylin antagonist; amylin 8-37, human; amylin
(IAPP), cat; amylin, rat; amylin 8-37, rat; biotinyl-amylin, rat;
and biotinyl-amylin amide, human
[0108] Amyloid beta-protein fragment peptides including, but not
limited to, Alzheimer's disease beta-protein 12-28 (SP17); amyloid
beta-protein 25-35; amyloid beta/A4-protein precursor 328-332;
amyloid beta/A4 protein precursor (APP) 319-335; amyloid
beta-protein 1-43; amyloid beta-protein 1-42; amyloid beta-protein
1-40; amyloid beta-protein 10-20; amyloid beta-protein 22-35;
Alzheimer's disease beta-protein (SP28); beta-amyloid peptide 1-42,
rat; beta-amyloid peptide 1-40, rat; beta-amyloid 1-11;
beta-amyloid 31-35; beta-amyloid 32-35; beta-amyloid 35-25;
beta-amyloid/A4 protein precursor 96-110; beta-amyloid precursor
protein 657-676; beta-amyloid 1-38; (Gln.sup.11)-Alzheimer's
disease beta-protein; (Gln.sup.11)-beta-amyloid 1-40;
(Gln.sup.22)-beta-amyloid 6-40; non-A beta component of Alzheimer's
disease amyloid (NAC); P3, (A beta 17-40) Alzheimer's disease
amyloid .beta.-peptide; and SAP (serum amyloid P component)
194-204.
[0109] Angiotensin peptides including, but not limited to, A-779;
Ala-Pro-Gly-angiotensin II; (Ile.sup.3,Val.sup.5)-angiotensin II;
angiotensin III antipeptide; angiogenin fragment 108-122;
angiogenin fragment 108-123; angiotensin I converting enzyme
inhibitor; angiotensin I, human; angiotensin I converting enzyme
substrate; angiotensin I 1-7, human; angiopeptin; angiotensin II,
human; angiotensin II antipeptide; angiotensin II 1-4, human;
angiotensin II 3-8, human; angiotensin II 4-8, human; angiotensin
II 5-8, human; angiotensin III ({Des-Asp.sup.1}-angiotensin II),
human; angiotensin III inhibitor ({Ile.sup.7}-angiotensin III);
angiotensin-converting enzyme inhibitor (Neothunnus macropterus);
{Asn.sup.1, Val.sup.5}-angiotensin I, goosefish; {Asn.sup.1,
Val.sup.5, Asn.sup.9}-angiotensin I, salmon; {Asn.sup.1, Val.sup.5,
Gly.sup.9}-angiotensin I, eel; {Asn.sup.1, Val.sup.5}-angiotensin I
1-7, eel, goosefish, salmon; {Asn.sup.1,Val.sup.5}-angiotensin II;
biotinyl-angiotensin I, human; biotinyl-angiotensin II, human;
biotinyl-Ala-Ala-Ala-angiotensin II; {Des-Asp.sup.1}-angiotensin I,
human; {p-aminophenylalanine.sup.6}-angiotensin II; renin substrate
(angiotensinogen 1-13), human; preangiotensinogen 1-14 (renin
substrate tetradecapeptide), human; renin substrate
tetradecapeptide (angiotensinogen 1-14), porcine;
{Sar.sup.1}-angiotensin II, {Sar.sup.1}-angiotensin II 1-7 amide;
{Sar.sup.1, Ala.sup.8}-angiotensin II; {Sar.sup.1,
Ile.sup.8}-angiotensin II; {Sar.sup.1, Thr.sup.8}-angiotensin II;
{Sar.sup.1, Tyr(Me).sup.4}-angiotensin II (Sarmesin); {Sar.sup.1,
Val.sup.5, Ala.sup.8}-angiotensin II; {Sar.sup.1,
Ile.sup.7}-angiotensin III; synthetic tetradecapeptide renin
substrate (No. 2); {Val.sup.4}-angiotensin III;
{Val.sup.5}-angiotensin II; {Val.sup.5}-angiotensin I, human;
{Val.sup.5}-angiotensin I; {Val.sup.5, Asn.sup.9}-angiotensin I,
bullfrog; and {Val.sup.5, Ser.sup.9}-angiotensin I, fowl.
[0110] Antibiotic peptides including, but not limited to, Ac-SQNY;
bactenecin, bovine; CAP 37 (20-44);
carbormethoxycarbonyl-DPro-DPhe-OBz1; CD36 peptide P 139-155; CD36
peptide P 93-110; cecropin A-melittin hybrid peptide
{CA(1-7)M(2-9)NH.sub.2}; cecropin B, free acid; CYS(Bzl)84 CD
fragment 81-92; defensin (human) HNP-2; dermaseptin;
immunostimulating peptide, human; lactoferricin, bovine (BLFC); and
magainin spacer.
[0111] Antigenic polypeptides, which can elicit an enhanced immune
response, enhance an immune response and or cause an immunizingly
effective response to diseases and/or disease causing agents
including, but not limited to, adenoviruses; anthrax; Bordetella
pertussus; botulism; bovine rhinotracheitis; Branhamella
catarrhalis; canine hepatitis; canine distemper; Chlamydiae;
cholera; coccidiomycosis; cowpox; cytomegalovirus; Dengue fever;
dengue toxoplasmosis; diphtheria; encephalitis; enterotoxigenic E.
coli; Epstein Barr virus; equine encephalitis; equine infectious
anemia; equine influenza; equine pneumonia; equine rhinovirus;
Escherichia coli; feline leukemia; flavivirus; globulin;
Haemophilus influenza type b; Haemophilus influenzae; Haemophilus
pertussis; Helicobacter pylori; Hemophilus; hepatitis; hepatitis A;
hepatitis B; Hepatitis C; herpes viruses; HIV; HIV-1 viruses; HIV-2
viruses; HTLV; influenza; Japanese encephalitis; Klebsiellae
species; Legionella pneumophila; Leishmania; leprosy; lyme disease;
malaria immunogen; measles; meningitis; meningococcal;
Meningococcal polysaccharide group A; Meningococcal polysaccharide
group C; mumps; mumps virus; mycobacteria; Mycobacterium
tuberculosis; Neisseria; Neisseria gonorrhea; Neisseria
meningitidis; ovine blue tongue; ovine encephalitis; papilloma;
parainfluenza; paramyxoviruses; Pertussis; plague; pneumococcus;
Pneumocystis carinii; pneumonia; poliovirus; proteus species;
Pseudomonas aeruginosa; rabies; respiratory syncytial virus;
rotavirus; rubella; salmonellae; schistosomiasis; shigellae; simian
immunodeficiency virus; smallpox; Staphylococcus aureus;
Staphylococcus species; Streptococcus pneumoniae; Streptococcus
pyogenes; Streptococcus species; swine influenza; tetanus;
Treponema pallidum; typhoid; vaccinia; varicella-zoster virus; and
Vibrio cholerae.
[0112] Anti-microbial peptides including, but not limited to,
buforin I; buforin II; cecropin A; cecropin B; cecropin P1,
porcine; gaegurin 2 (Rana rugosa); gaegurin 5 (Rana rugosa);
indolicidin; protegrin-(PG)-I; magainin 1; and magainin 2; and T-22
{Tyr.sup.5,12, Lys.sup.7}-poly-phemusin II peptide.
[0113] Apoptosis related peptides including, but not limited to,
Alzheimer's disease beta-protein (SP28); calpain inhibitor peptide;
caspase-1 inhibitor V; caspase-3, substrate IV; caspase-1 inhibitor
I, cell-permeable; caspase-1 inhibitor VI; caspase-3 substrate III,
fluorogenic; caspase-1 substrate V, fluorogenic; caspase-3
inhibitor I, cell-permeable; caspase-6 ICE inhibitor III; {Des-Ac,
biotin}-ICE inhibitor III; IL-1B converting enzyme (ICE) inhibitor
II; IL-1 B converting enzyme (ICE) substrate IV; MDL 28170; and
MG-132.
[0114] Atrial natriuretic peptides including, but not limited to,
alpha-ANP (alpha-chANP), chicken; anantin; ANP 1-11, rat; ANP 8-30,
frog; ANP 11-30, frog; ANP-21 (fANP-21), frog; ANP-24 (fANP-24),
frog; ANP-30, frog; ANP fragment 5-28, human, canine; ANP-7-23,
human; ANP fragment 7-28, human, canine; alpha-atrial natriuretic
polypeptide 1-28, human, canine; A71915, rat; atrial natriuretic
factor 8-33, rat; atrial natriuretic polypeptide 3-28, human;
atrial natriuretic polypeptide 4-28, human, canine; atrial
natriuretic polypeptide 5-27; human; atrial natriuretic peptide
(ANP), eel; atriopeptin I, rat, rabbit, mouse; atriopeptin II, rat,
rabbit, mouse; atriopeptin III, rat, rabbit, mouse; atrial
natriuretic factor (rANF), rat, auriculin A (rat ANF 126-149);
auriculin B (rat ANF 126-150); beta-ANP (1-28, dimer,
antiparallel); beta-rANF 17-48; biotinyl-alpha-ANP 1-28, human,
canine; biotinyl-atrial natriuretic factor (biotinyl-rANF), rat;
cardiodilatin 1-16, human; C-ANF 4-23, rat; Des-{Cys.sup.105,
Cys.sup.121}-atrial natriuretic factor 104-126, rat;
{Met(O).sup.12} ANP 1-28, human; {Mpr.sup.7,DAla.sup.9}ANP 7-28,
amide, rat; prepro-ANF 104-116, human; prepro-ANF 26-55 (proANF
1-30), human; prepro-ANF 56-92 (proANF 31-67), human; prepro-ANF
104-123, human; {Tyr.sup.0}-atriopeptin I, rat, rabbit, mouse;
{Tyr.sup.0}-atriopeptin II, rat, rabbit, mouse; {Tyr.sup.0-prepro
ANF 104-123, human; urodilatin (CDD/ANP 95-126); ventricular
natriuretic peptide (VNP), eel; and ventricular natriuretic peptide
(VNP), rainbow trout.
[0115] Bag cell peptides including, but not limited to, alpha bag
cell peptide; alpha-bag cell peptide 1-9; alpha-bag cell peptide
1-8; alpha-bag cell peptide 1-7; beta-bag cell factor, and
gamma-bag cell factor.
[0116] Bombesin peptides including, but not limited to, alpha-s1
casein 101-123 (bovine milk); biotinyl-bombesin; bombesin 8-14;
bombesin; {Leu.sup.13-psi (CH.sub.2NH)Leu.sup.14}-bombesin;
{D-Phe.sup.6, Des-Met.sup.14}-bombesin 6-14 ethylamide;
{DPhe.sup.12} bombesin; {DPhe.sup.12,Leu.sup.14}-bombesin;
{Tyr.sup.4}-bombesin; and {Tyr.sup.4,DPhe.sup.12}-bombesin.
[0117] Bone GLA peptides (BGP) including, but not limited to, bone
GLA protein; bone GLA protein 45-49; {Glu.sup.17,
Gla.sup.21,24}-osteocalcin 1-49, human; myclopeptide-2 (MP-2);
osteocalcin 1-49 human; osteocalcin 37-49, human; and {Tyr.sup.38,
Phe.sup.42,46} bone GLA protein 38-49, human.
[0118] Bradykinin peptides including, but not limited to,
{Ala.sup.2,6, des-Pro.sup.3}-bradykinin; bradykinin; bradykinin
(Bowfin. Gar); bradykinin potentiating peptide; bradykinin 1-3;
bradykinin 1-5; bradykinin 1-6; bradykinin 1-7; bradykinin 2-7;
bradykinin 2-9; {DPhe.sup.7} bradykinin;
{Des-Arg.sup.9}-bradykinin; {Des-Arg.sup.10}-Lys-bradykinin
({Des-Arg.sup.10}-kallidin); {D-N-Me-Phe.sup.7}-bradykinin;
{Des-Arg.sup.9, Leu.sup.8}-bradykinin; Lys-bradykinin (kallidin);
Lys-(Des-Arg.sup.9, Leu.sup.8}-bradykinin ({Des-Arg.sup.10,
Leu.sup.9}-kallidin); {Lys.sup.0-Hyp.sup.3}-bradykinin; ovokinin;
{Lys.sup.0, Ala.sup.3}-bradykinin; Met-Lys-bradykinin; peptide K12
bradykinin potentiating peptide; {(pCl)Phe.sup.5,8}-bradykinin;
T-kinin (Ile-Ser-bradykinin); {Thi..sup.5,8,
D-Phe.sup.7}-bradykinin; {Tyr.sup.0}-bradykinin;
{Tyr.sup.5}-bradykinin; {Tyr.sup.8}-bradykinin; and kallikrein.
[0119] Brain natriuretic peptides (BNP) including, but not limited
to, BNP 32, canine; BNP-like Peptide, eel; BNP-32, human; BNP-45,
mouse; BNP-26, porcine; BNP-32, porcine; biotinyl-BNP-32, porcine;
BNP-32, rat; biotinyl-BNP-32, rat; BNP45 (BNP 51-95, 5K cardiac
natriuretic peptide), rat; and {Tyr.sup.0}-BNP 1-32, human.
[0120] C-peptides including, but not limited to, C-peptide; and
{Tyr.sup.0}-C-peptide, human.
[0121] C-type natriuretic peptides (CNP) including, but not limited
to, C-type natriuretic peptide, chicken; C-type natriuretic
peptide-22 (CNP-22), porcine, rat, human; C-type natriuretic
peptide-53 (CNP-53), human; C-type natriuretic peptide-53 (CNP-53),
porcine, rat; C-type natriuretic peptide-53 (porcine, rat) 1-29
(CNP-531-29); prepro-CNP 1-27, rat; prepro-CNP 30-50, porcine, rat;
vasonatrin peptide (VNP); and {Tyr.sup.0}-C-type natriuretic
peptide-22 ({Tyr.sup.0}-CNP-22).
[0122] Calcitonin peptides including, but not limited to,
biotinyl-calcitonin, human; biotinyl-calcitonin, rat;
biotinyl-calcitonin, salmon; calcitonin, chicken; calcitonin, eel;
calcitonin, human; calcitonin, porcine; calcitonin, rat;
calcitonin, salmon; calcitonin 1-7, human; calcitonin 8-32, salmon;
katacalcin (PDN-21) (C-procalcitonin); and N-proCT (amino-terminal
procalcitonin cleavage peptide), human.
[0123] Calcitonin gene related peptides (CGRP) including, but not
limited to, acetyl-alpha-CGRP 19-37, human; alpha-CGRP 19-37,
human; alpha-CGRP 23-37, human; biotinyl-CGRP, human; biotinyl-CGRP
II, human; biotinyl-CGRP, rat; beta-CGRP, rat; biotinyl-beta-CGRP,
rat; CGRP, rat; CGRP, human; calcitonin C-terminal adjacent
peptide; CGRP 1-19, human; CGRP 20-37, human; CGRP 8-37, human;
CGRP II, human; CGRP, rat; CGRP 8-37, rat; CGRP 29-37, rat; CGRP
30-37, rat; CGRP 31-37, rat; CGRP 32-37, rat; CGRP 33-37, rat; CGRP
31-37, rat; ({Cys(Acm).sup.2,7}-CGRP; elcatonin; {Tyr.sup.0}-CGRP,
human; {Tyr.sup.0}-CGRP II, human; {Tyr.sup.0}-CGRP 28-37, rat;
{Tyr.sup.0}-CGRP, rat; and {Tyr.sup.22}-CGRP 22-37, rat.
[0124] CART peptides including, but not limited to, CART, human;
CART 55-102, human; CART, rat; and CART 55-102, rat.
[0125] Casomorphin peptides including, but not limited to,
beta-casomorphin, human; beta-casomorphin 1-3; beta-casomorphin
1-3, amide; beta-casomorphin, bovine; beta-casomorphin 1-4, bovine;
beta-casomorphin 1-5, bovine; beta-casomorphin 1-5, amide, bovine;
beta-casomorphin 1-6, bovine; {DAla.sup.2}-beta-casomorphin 1-3,
amide, bovine; {DAla.sup.2,Hyp.sup.4,Tyr.sup.5}-beta-casomorphin
1-5 amide; {DAla.sup.2,DPro.sup.4,Tyr.sup.5}-beta-casomorphin 1-5,
amide; {DAla.sup.2,Tyr.sup.5}-beta-casomorphin 1-5, amide, bovine;
{DAla.sup.2,4,Tyr.sup.5}-beta-casomorphin 1-5, amide, bovine;
{DAla.sup.2, (pCl)Phe.sup.3}-beta-casomorphin, amide, bovine;
{DAla.sup.2}-beta-casomorphin 1-4, amide, bovine;
{DAla.sup.2}-beta-casomorphin 1-5, bovine;
{DAla.sup.2}-beta-casomorphin 1-5, amide, bovine;
{DAla.sup.2,Met.sup.5}-beta-casomorphin 1-5, bovine;
{DPro.sup.2}-beta-casomorphin 1-5, amide, bovine;
{DAla.sup.2}-beta-casomorphin 1-6, bovine;
{DPro.sup.2}-beta-casomorphin 1-4, amide;
{Des-Tyr.sup.1}-beta-casomorphin, bovine; {DAla.sup.2,4,
Tyr.sup.5}-beta-casomorphin 1-5, amide, bovine; {DAla.sup.2,
(pCl)Phe.sup.3}-beta-casomorphin, amide, bovine;
{DAla.sup.2}-beta-casomorphin 1-4, amide, bovine;
{DAla.sup.2}-beta-casomorphin 1-5, bovine;
{DAla.sup.2}-beta-casomorphin 1-5, amide, bovine;
{DAla.sup.2,Met.sup.5}-beta-casomorphin 1-5, bovine;
{DPro.sup.2}-beta-casomorphin 1-5, amide, bovine;
{DAla.sup.2}-beta-casomorphin 1-6, bovine;
{DPro.sup.2}-beta-casomorphin 14, amide;
{Des-Tyr.sup.1}-beta-casomorphin, bovine; and
{Val.sup.3}-beta-casomorphin 1-4, amide, bovine.
[0126] Chemotactic peptides including, but not limited to, defensin
1 (human) HNP-1 (human neutrophil peptide-1); and
N-formyl-Met-Leu-Phe.
[0127] Cholecystokinin (CCK) peptides including, but not limited
to, caerulein; cholecystokinin; cholecystokinin-pancreozymin;
CCK-33, human; cholecystokinin octapeptide 14 (non-sulfated) (CCK
26-29, unsulfated); cholecystokinin octapeptide (CCK 26-33);
cholecystokinin octapeptide (non-sulfated) (CCK 26-33, unsulfated);
cholecystokinin heptapeptide (CCK 27-33); cholecystokinin
tetrapeptide (CCK 30-33); CCK-33, porcine; CR 1409, cholecystokinin
antagonist; CCK flanking peptide (unsulfated); N-acetyl
cholecystokinin, CCK 26-30, sulfated; N-acetyl cholecystokinin, CCK
26-31, sulfated; N-acetyl cholecystokinin, CCK 26-31, non-sulfated;
prepro CCK fragment V-9-M; and proglumide.
[0128] Colony-stimulating factor peptides including, but not
limited to, colony-stimulating factor (CSF); GMCSF; MCSF; and
G-CSF.
[0129] Corticortropin releasing factor (CRF) peptides including,
but not limited to, astressin; alpha-helical CRF 12-41;
biotinyl-CRF, ovine; biotinyl-CRF, human, rat; CRF, bovine; CRF,
human, rat; CRF, ovine; CRF, porcine; {Cys.sup.21}-CRF, human, rat;
CRF antagonist (alpha-helical CRF 9-41); CRF 6-33, human, rat;
{DPro.sup.5}-CRF, human, rat; {D-Phe.sup.12, Nle.sup.21,38}-CRF
12-41, human, rat; eosinophilotactic peptide; {Met(0).sup.21}-CRF,
ovine; {Nle.sup.21,Tyr.sup.32}-CRF, ovine; prepro CRF 125-151,
human; sauvagine, frog; {Tyr.sup.0}-CRF, human, rat;
{Tyr.sup.0}-CRF, ovine; {Tyr.sup.0}-CRF 34-41, ovine;
{Tyr.sup.0}-urocortin; urocortin amide, human; urocortin, rat;
urotensin I (Catostomus commersoni); urotensin II; and urotensin II
(Rana ridibunda).
[0130] Cortistatin peptides including, but not limited to,
cortistatin 29; cortistatin 29 (1-13); {Tyr.sup.0}-cortistatin 29;
pro-cortistatin 28-47; and pro-cortistatin 51-81.
[0131] Cytokine peptides including, but not limited to, tumor
necrosis factor; and tumor necrosis factor-.beta. (TNF-.beta.).
[0132] Dermorphin peptides including, but not limited to,
dermorphin and dermorphin analog 1-4.
[0133] Dynorphin peptides including, but not limited to, big
dynorphin (prodynorphin 209-240), porcine; biotinyl-dynorphin A
(biotinyl-prodynorphin 209-225); {DAla.sup.2, DArg.sup.6}dynorphin
A 1-13, porcine; {D-Ala.sup.2}-dynorphin A, porcine;
{D-Ala.sup.2}-dynorphin A amide, porcine; {D-Ala.sup.2}-dynorphin A
1-13, amide, porcine; {D-Ala.sup.2}-dynorphin A 1-9, porcine;
{DArg.sup.6}-dynorphin A 1-13, porcine; {DArg.sup.8}-dynorphin A
1-13, porcine; {Des-Tyr.sup.1}-dynorphin A 1-8;
{D-Pro.sup.10}-dynorphin A 1-11, porcine; dynorphin A amide,
porcine; dynorphin A 1-6, porcine; dynorphin A 1-7, porcine;
dynorphin A 1-8, porcine; dynorphin A 1-9, porcine; dynorphin A
1-10, porcine; dynorphin A 1-10 amide, porcine; dynorphin A 1-11,
porcine; dynorphin A 1-12, porcine; dynorphin A 1-13, porcine;
dynorphin A 1-13 amide, porcine; DAKLI (dynorphin A-analogue kappa
ligand); DAKLI-biotin ({Arg.sup.11,13}-dynorphin A
(1-13)-Gly-NH(CH.sub.2).sub.5NH-biotin); dynorphin A 2-17, porcine;
dynorphin 2-17, amide, porcine; dynorphin A 2-12, porcine;
dynorphin A 3-17, amide, porcine; dynorphin A 3-8, porcine;
dynorphin A 3-13, porcine; dynorphin A 3-17, porcine; dynorphin A
7-17, porcine; dynorphin A 8-17, porcine; dynorphin A 6-17,
porcine; dynorphin A 13-17, porcine; dynorphin A (prodynorphin
209-225), porcine; dynorphin B 1-9; {MeTyr.sup.1, MeArg.sup.7,
D-Leu.sup.8}-dynorphin 1-8 ethyl amide; {(nMe)Tyr.sup.1} dynorphin
A 1-13, amide, porcine; {Phe.sup.7}-dynorphin A 1-7, porcine;
{Phe.sup.7}-dynorphin A 1-7, amide, porcine; and prodynorphin
228-256 (dynorphin B 29) (leumorphin), porcine.
[0134] Endorphin peptides including, but not limited to,
alpha-neo-endorphin, porcine; beta-neoendorphin; Ac-beta-endorphin,
camel, bovine, ovine; Ac-beta-endorphin 1-27, camel, bovine, ovine;
Ac-beta-endorphin, human; Ac-beta-endorphin 1-26, human;
Ac-beta-endorphin 1-27, human; Ac-gamma-endorphin
(Ac-beta-lipotropin 61-77); acetyl-alpha-endorphin; alpha-endorphin
(beta-lipotropin 61-76); alpha-neo-endorphin analog;
alpha-neo-endorphin 1-7; {Arg.sup.8}-alpha-neoendorphin 1-8;
beta-endorphin (beta-lipotropin 61-91), camel, bovine, ovine;
beta-endorphin 1-27, camel, bovine, ovine; beta-endorphin, equine;
beta-endorphin (beta-lipotropin 61-91), human; beta-endorphin
(1-5)+(16-31), human; beta-endorphin 1-26, human; beta-endorphin
1-27, human; beta-endorphin 6-31, human; beta-endorphin 18-31,
human; beta-endorphin, porcine; beta-endorphin, rat;
beta-lipotropin 1-10, porcine; beta-lipotropin 60-65;
beta-lipotropin 61-64; beta-lipotropin 61-69; beta-lipotropin
88-91; biotinyl-beta-endorphin (biotinyl-bets-lipotropin 61-91);
biocytin-beta-endorphin, human; gamma-endorphin (beta-lipotropin
61-77); {DAla.sup.2}-alpha-neo-endorphin 1-2, amide;
{DAla.sup.2}-beta-lipotropin 61-69; {DAla.sup.2}-gamma-endorphin;
{Des-Tyr.sup.1}-beta-endorphin, human;
{Des-Tyr.sup.1}-gamma-endorphin (beta-lipotropin 62-77);
{Leu.sup.5}-beta-endorphin, camel, bovine, ovine; {Met.sup.5,
Lys.sup.6}-alpha-neo-endorphin 1-6; {Met.sup.5,
Lys.sup.6,7}-alpha-neo-endorphin 1-7; and {Met.sup.5, Lys.sup.6,
Arg.sup.7}-alpha-neo-endorphin 1-7.
[0135] Endothelin peptides including, but not limited to,
endothelin-1 (ET-1); endothelin-1{Biotin-Lys.sup.9}; endothelin-1
(1-15), human; endothelin-1 (1-15), amide, human; Ac-endothelin-1
(16-21), human; Ac-{DTrp.sup.16}-endothelin-1 (16-21), human;
{Ala.sup.3,11}-endothelin-1; {Dpr1, Asp.sup.15}-endothelin-1;
{Ala.sup.2}-endothelin-3, human; {Ala.sup.18}-endothelin-1, human;
{Asn.sup.18}-endothelin-1, human; {Res-701-1}-endothelin B receptor
antagonist; Suc-{Glu.sup.9, Ala.sup.11,15}-endothelin-1 (8-21),
IRL-1620; endothelin-C-terminal hexapeptide; {D-Val.sup.22}-big
endothelin-1 (16-38), human; endothelin-2 (ET-2), human, canine;
endothelin-3 (ET-3), human, rat, porcine, rabbit;
biotinyl-endothelin-3 (biotinyl-ET-3); prepro-endothelin-1
(94-109), porcine; BQ-518; BQ-610; BQ-788; endothelium-dependent
relaxation antagonist; FR139317; IRL-1038; JKC-301; JKC-302;
PD-145065; PD-142893; sarafotoxin S6a (Atractaspis engaddensis);
sarafotoxin S6b (Atractaspis engaddensis); sarafotoxin S6c
(Atractaspis engaddensis); {Lys.sup.4}-sarafotoxin S6c; sarafotoxin
S6d; big endothelin-1, human; biotinyl-big endothelin-1, human; big
endothelin-1 (1-39), porcine; big endothelin-3 (22-41), amide,
human; big endothelin-1 (22-39), rat; big endothelin-1 (1-39),
bovine; big endothelin-1 (22-39), bovine; big endothelin-1 (19-38),
human; big endothelin-1 (22-38), human; big endothelin-2, human;
big endothelin-2 (22-37), human; big endothelin-3, human; big
endothelin-1, porcine; big endothelin-1 (22-39)
(prepro-endothelin-1 (74-91)); big endothelin-1, rat; big
endothelin-2 (1-38), human; big endothelin-2 (22-38), human; big
endothelin-3, rat; biotinyl-big endothelin-1, human; and
{Tyr.sup.123}-prepro-endothelin (110-130), amide, human
[0136] ETa receptor antagonist peptides including, but not limited
to, {BQ-123}; {BE18257B}; {BE-18257A}/{W-7338A}; {BQ-485};
FR139317; PD-151242; and TTA-386.
[0137] ETb receptor antagonist peptides including, but not limited
to, 03Q-30201; {RES-701-3}; and {IRL-1720}
[0138] Enkephalin peptides including, but not limited to,
adrenorphin, free acid; amidorphin (proenkephalin A
(104-129)-NII2), bovine; BAM-12P (bovine adrenal medulla
enkephalin; {D-Ala.sup.2, D-Leu.sup.5}-enkephalin; {D-Ala.sup.2,
D-Met.sup.5}-enkephalin; {DAla.sup.2}-Leu-enkephalin, amide;
{DAla.sup.2, Leu.sup.5, Arg.sup.6}-enkephalin;
{Des-Tyr.sup.1,DPen.sup.2,5}-enkephalin;
{Des-Tyr.sup.1,DPen.sup.2,Pen.sup.5}-enkephalin;
{Des-Tyr.sup.1}-Leu-enkephalin; {D-Pen.sup.2,5}-enkephalin;
{DPen.sup.2, Pen.sup.5}-enkephalin; enkephalinase substrate;
{D-Pen.sup.2, pCI-Phe.sup.4, D-Pen.sup.5}-enkephalin;
Leu-enkephalin; Leu-enkephalin, amide; biotinyl-Leu-enkephalin;
{D-Ala.sup.2}-Leu-enkephalin; {D-Ser.sup.2}-Leu-enkephalin-Thr
(delta-receptor peptide) (DSLET); {D-Thr.sup.2}-Leu-enkephalin-Thr
(DTLET); {Lys.sup.6}-Leu-enkephalin;
{Met.sup.5,Arg.sup.6}-enkephalin;
{Met.sup.5,Arg.sup.6-enkephalin-Arg;
{Met.sup.5,Arg.sup.6,Phe.sup.7}-enkephalin, amide; Met-enkephalin;
biotinyl-Met-enkephalin; {D-Ala.sup.2}-Met-enkephalin;
{D-Ala.sup.2}-Met-enkephalin, amide; Met-enkephalin-Arg-Phe;
Met-enkephalin, amide; {Ala.sup.2}-Met-enkephalin, amide;
{DMet.sup.2,Pro.sup.5}-enkephalin, amide;
{DTrp.sup.2}-Met-enkephalin, amide, metorphinamide (adrenorphin);
peptide B, bovine; 3200-Dalton adrenal peptide E, bovine; peptide
F, bovine; preproenkephalin B 186-204, human; spinorphin, bovine;
and thiorphan (D,L,3-mercapto-2-benzylpropanoyl-glycine).
[0139] Fibronectin peptides including, but not limited to platelet
factor-4 (58-70), human; echistatin (Echis carinatus); E, P, L
selectin conserved region; fibronectin analog; fibronectin-binding
protein; fibrinopeptide A, human; {Tyr.sup.0}-fibrinopeptide A,
human; fibrinopeptide B, human; {Glu.sup.3}-fibrinopeptide B,
human; {Tyr.sup.15}-fibrinopeptide B, human; fibrinogen beta-chain
fragment of 24-42; fibrinogen binding inhibitor peptide;
fibronectin related peptide (collagen binding fragment);
fibrinolysis inhibiting factor; FN--C/H-1 (fibronectin
heparin-binding fragment); FN--C/H--V (fibronectin heparin-binding
fragment); heparin-binding peptide; laminin penta peptide, amide;
Leu-Asp-Val-NH.sub.2 (LDV-NH.sub.2), human, bovine, rat, chicken;
necrofibrin, human; necrofibrin, rat; and platelet membrane
glycoprotein IIB peptide 296-306.
[0140] Galanin peptides including, but not limited to, galanin,
human; galanin 1-19, human; preprogalanin 1-30, human;
preprogalanin 65-88, human; preprogalanin 89-123, human; galanin,
porcine; galanin 1-16, porcine, rat; galanin, rat;
biotinyl-galanin, rat; preprogalanin 28-67, rat; galanin
1-13-bradykinin 2-9, amide; M40, galanin 1-13-Pro-Pro-(Ala-Leu)
2-Ala-amide; C7, galanin 1-13-spantide-amide; GMAP 1-41, amide;
GMAP 16-41, amide; GMAP 25-41, amide; galantide; and
entero-kassinin.
[0141] Gastrin peptides including, but not limited to, gastrin,
chicken; gastric inhibitory peptide (GIP), human; gastrin I, human;
biotinyl-gastrin I, human; big gastrin-1, human; gastrin releasing
peptide, human; gastrin releasing peptide 1-16, human; gastric
inhibitory polypeptide (GIP), porcine; gastrin releasing peptide,
porcine; biotinyl-gastrin releasing peptide, porcine; gastrin
releasing peptide 14-27, porcine, human; little gastrin, rat;
pentagastrin; gastric inhibitory peptide 1-30, porcine; gastric
inhibitory peptide 1-30, amide, porcine; {Tyr.sup.0-gastric
inhibitory peptide 23-42, human; and gastric inhibitory peptide,
rat.
[0142] Glucagon peptides including, but not limited to,
{Des-His.sup.1-Glu.sup.9}-glucagon, exendin-4, glucagon, human;
biotinyl-glucagon, human; glucagon 19-29, human; glucagon 22-29,
human; {Des-His.sup.1-Glu.sup.9}-glucagon, amide; glucagon-like
peptide 1, amide; glucagon-like peptide 1, human; glucagon-like
peptide 1 (7-36); glucagon-like peptide 2, rat;
biotinyl-glucagon-like peptide-1 (7-36) (biofinyl-preproglucagon
78-107, amide); glucagon-like peptide 2, human; intervening
peptide-2; oxyntomodulin/glucagon 37; and valosin (peptide VQY),
porcine.
[0143] Gn-RH associated peptides (GAP) including, but not limited
to, Gn-RH associated peptide 25-53, human; Gn-RH associated peptide
1-24, human; Gn-RH associated peptide 1-13, human; Gn-RH associated
peptide 1-13, rat; gonadotropin releasing peptide, follicular,
human; {Tyr.sup.0}-GAP ({Tyr.sup.0}-Gn-RH Precursor Peptide 14-69),
human; and proopiomelanocortin (POMC) precursor 27-52, porcine.
[0144] Growth factor peptides including, but not limited to, cell
growth factors; epidermal growth factors; tumor growth factor;
alpha-TGF; beta-TF; alpha-TGF 34-43, rat; EGF, human; acidic
fibroblast growth factor; basic fibroblast growth factor; basic
fibroblast growth factor 13-18; basic fibroblast growth factor
120-125; brain derived acidic fibroblast growth factor 1-11; brain
derived basic fibroblast growth factor 1-24; brain derived acidic
fibroblast growth factor 102-111; {Cys(Acm.sup.20,31)}-epidermal
growth factor 20-31; epidermal growth factor receptor peptide
985-996; insulin-like growth factor (IGF)-I, chicken; IGF-I, rat;
IGF-I, human; Des (1-3) IGF-I, human; R3 IGF-I, human; R3 IGF-I,
human; long R3 IGF-I, human; adjuvant peptide analog; anorexigenic
peptide; Des (1-6) IGF-II, human; R6 IGF-II, human; IGF-I analogue;
IGF 1 (24-41); IGF 1 (57-70); IGF I (30-41); IGF II; IGF II
(33-40); {Tyr.sup.0}-IGF II (33-40); liver cell growth factor;
midkine; midkine 60-121, human; N-acetyl, alpha-TGF 34-43, methyl
ester, rat; nerve growth factor (NGF), mouse; platelet-derived
growth factor; platelet-derived growth factor antagonist;
transforming growth factor-alpha, human; and transforming growth
factor-I, rat.
[0145] Growth hormone peptides including, but not limited to,
growth hormone (hGH), human; growth hormone 1-43, human; growth
hormone 6-13, human; growth hormone releasing factor, human; growth
hormone releasing factor, bovine; growth hormone releasing factor,
porcine; growth hormone releasing factor 1-29, amide, rat; growth
hormone pro-releasing factor, human; biotinyl-growth hormone
releasing factor, human; growth hormone releasing factor 1-29,
amide, human; {D-Ala.sup.2}-growth hormone releasing factor 1-29,
amide, human; {N-Ac-Tyr.sup.1, D-Arg.sup.2}-GRF 1-29, amide;
{His.sup.1, Nle.sup.27}-growth hormone releasing factor 1-32,
amide; growth hormone releasing factor 1-37, human; growth hormone
releasing factor 140, human; growth hormone releasing factor 1-40,
amide, human; growth hormone releasing factor 30-44, amide, human;
growth hormone releasing factor, mouse; growth hormone releasing
factor, ovine; growth hormone releasing factor, rat;
biotinyl-growth hormone releasing factor, rat; GHRP-6 ({His.sup.1,
Lys.sup.6}-GHRP); hexarelin (growth hormone releasing hexapeptide);
and {D-Lys.sup.3}-GHRP-6.
[0146] GTP-binding protein fragment peptides including, but not
limited to, {Arg.sup.8}-GTP-binding protein fragment, Gs alpha;
GTP-binding protein fragment, G beta; GTP-binding protein fragment,
GAlpha; GTP-binding protein fragment, Go Alpha; GTP-binding protein
fragment, Gs Alpha; and GTP-binding protein fragment, G Alpha
i2.
[0147] Guanylin peptides including, but not limited to, guanylin,
human; guanylin, rat; and uroguanylin.
[0148] Inhibin peptides including, but not limited to, inhibin,
bovine; inhibin, alpha-subunit 1-32, human; {Tyr.sup.0}-inhibin,
alpha-subunit 1-32, human; seminal plasma inhibin-like peptide,
human; {Tyr.sup.0}-seminal plasma inhibin-like peptide, human;
inhibin, alpha-subunit 1-32, porcine; and {Tyr.sup.0}-inhibin,
alpha-subunit 1-32, porcine.
[0149] Insulin peptides including, but not limited to, insulin,
human; insulin, porcine; IGF-I, human; insulin-like growth factor
II (69-84); pro-insulin-like growth factor 11 (68-102), human;
pro-insulin-like growth factor II (105-128), human;
{Asp.sup.B28}-insulin, human; {Lys.sup.B28}-insulin, human;
{Leu.sup.B28}-insulin, human; {Val.sup.B28}-insulin, human;
{Ala.sup.B28}-insulin, human; {Asp.sup.B28, Pro.sup.B29}-insulin,
human; {Lys.sup.B28, Pro.sup.B29}-insulin, human; {Leu.sup.B28
Pro.sup.B29}-insulin, human; {Val.sup.B28, Pro.sup.B29}-insulin,
human; {Ala.sup.B28, Pro.sup.B29}-insulin, human;
{Gly.sup.A21}-insulin, human; {Gly.sup.A21 Gln.sup.B30}-insulin,
human; {Ala.sup.A21}-insulin, human; {Ala.sup.A21 Gln.sup.B30}
insulin, human; {Gln.sup.B30}-insulin, human;
{Gln.sup.B30}-insulin, human; {Gly.sup.A21 Glu.sup.B30}-insulin,
human; {Gly.sup.A21 Gln.sup.B3 Glu.sup.B30}-insulin, human;
{Gln.sup.B3 Glu.sup.B30}-insulin, human; B22-B30 insulin, human;
B23-B30 insulin, human; B25-B30 insulin, human; B26-B30 insulin,
human; B27-B30 insulin, human; B29-B30 insulin, human; the A chain
of human insulin, and the B chain of human insulin.
[0150] Interleukin peptides including, but not limited to,
interleukin-1 beta 165-181, rat; and interleukin-8 (IL-8,
CINC/gro), rat.
[0151] Lamimin peptides including, but not limited to, laminin;
alpha1 (I)-CB3 435-438, rat; and laminin binding inhibitor.
[0152] Leptin peptides including, but not limited to, leptin
93-105, human; leptin 22-56, rat; Tyr-leptin 26-39, human; and
leptin 116-130, amide, mouse.
[0153] Leucokinin peptides including, but not limited to,
leucomyosuppressin (LMS); leucopyrokinin (LPK); leucokinin I;
leucokinin II; leucokinin III; leucokinin IV; leucokinin VI;
leucokinin VII; and leucokinin VIII.
[0154] Luteinizing hormone-releasing hormone peptides including,
but not limited to, antide; Gn-RH II, chicken; luteinizing
hormone-releasing hormone (LH-RH) (GnRH); biotinyl-LH-RH;
cetrorelix (D-20761); {D-Ala.sup.6}-LH-RH; {Gln.sup.8}-LH-RH
(Chicken LH-RH); {DLeu.sup.6, Val.sup.7} LH-RH 1-9, ethyl amide;
{D-Lys.sup.6}-LH-RH; {D-Phe.sup.2, Pro.sup.3, D-Phe.sup.6}-LH-RH;
{DPhe.sup.2, DAla.sup.6} LH-RH; {Des-Gly.sup.10}-LH-RH, ethyl
amide; {D-Ala.sup.6, Des-Gly.sup.10}-LH-RH, ethyl amide;
{DTrp.sup.6}-LH-RH, ethyl amide; {D-Trp.sup.6,
Des-Gly.sup.10}-LH-RH, ethyl amide (Deslorelin); {DSer(But).sub.6,
Des-Gly.sup.10}-LH-RH, ethyl amide; ethyl amide; leuprolide; LH-RH
4-10; LH-RH 7-10; LH-RH, free acid; LH-RH, lanprey; LH-RH, salmon;
{Lys.sup.8}-LH-RH; {Trp.sup.7,Leu.sup.8} LH-RH, free acid; and
{(t-Bu)DSer.sup.6, (Aza)Gly.sup.10}-LH-RH.
[0155] Mastoparan peptides including, but not limited to,
mastoparan; mas7; mas8; mas17; and mastoparan X.
[0156] Mast cell degranulating peptides including, but not limited
to, mast cell degranulating peptide HR-1; and mast cell
degranulating peptide HR-2.
[0157] Melanocyte stimulating hormone (MSH) peptides including, but
not limited to, {Ac-Cys.sup.4,DPhe.sup.7, Cys.sup.10} alpha-MSH
4-13, amide; alpha-melanocyte stimulating hormone; alpha-MSH, free
acid; beta-MSH, porcine; biotinyl-alpha-melanocyte stimulating
hormone; biotinyl-{Nle.sup.4, D-Phe.sup.7} alpha-melanocyte
stimulating hormone; {Des-Acetyl}-alpha-MSH;
{DPhe.sup.7}-alpha-MSH, amide; gamma-1-MSH, amide;
{Lys.sup.0}-gamma-1-MSH, amide; MSH release inhibiting factor,
amide; {Nle.sup.4}-alpha-MSH, amide; {Nle.sup.4,
D-Phe.sup.7}-alpha-MSH; N-Acetyl, {Nle.sup.4,DPhe.sup.7} alpha-MSH
4-10, amide; beta-MSH, human; and gamma-MSH.
[0158] Morphiceptin peptides including, but not limited to,
morphiceptin (beta-casomorphin 14 amide);
{D-Pro.sup.4}-morphiceptin; and
{N-MePhe.sup.3,D-Pro.sup.4}-morphiceptin.
[0159] Motilin peptides including, but not limited to, motilin,
canine; motilin, porcine; biotinyl-motilin, porcine; and
{Leu.sup.13}-motilin, porcine.
[0160] Neuro-peptides including, but not limited to, Ac-Asp-Glu;
Achatina cardio-excitatory peptide-1 (ACEP-1) (Achatina fulica);
adipokinetic hormone (AKH) (Locust); adipokinetic hormone
(Heliothis zea and Manduca sexta); alytesin; Tabanus atratus
adipokinetic hormone (Taa-AKH); adipokinetic hormone II (Locusta
migratoria); adipokinetic hormone II (Schistocera gregaria);
adipokinetic hormone III (AKH-3); adipokinetic hormone G (AKH-G)
(Gryllus bimaculatus); allatotropin (AT) (Manduca sexta);
allatotropin 6-13 (Manduca sexta); APGW amide (Lymnaea stagnalis);
buccalin; cerebellin; {Des-Ser.sup.1}-cerebellin; corazonin
(American Cockroach Periplaneta americana); crustacean cardioactive
peptide (CCAP); crustacean erythrophore; DF2 (Procambarus clarkii);
diazepam-binding inhibitor fragment, human; diazepam binding
inhibitor fragment (ODN); eledoisin related peptide; FMRF amide
(molluscan cardioexcitatory neuropeptide); Gly-Pro-Glu (GPE),
human; granuliberin R; head activator neuropeptide;
{His.sup.7}-corazonin; stick insect hypertrehalosaemic factor II;
Tabanus atratus hypotrehalosemic hormone (Taa-HoTH); isoguvacine
hydrochloride; bicuculline methiodide; piperidine-4-sulphonic acid;
joining peptide of proopiomelanocortin (POMC), bovine; joining
peptide, rat; KSAYMRF amide (P. redivivus); kassinin; kinetensin;
levitide; litorin; LUQ 81-91 (Aplysia californica); LUQ 83-91
(Aplysia californica); myoactive peptide I (Periplanetin CC-1)
(Neuro-hormone D); myoactive peptide II (Periplanetin CC-2);
myomodulin; neuron specific peptide; neuron specific enolase
404-443, rat; neuropeptide FF; neuropeptide K, porcine; NEI
(prepro-MCH 131-143) neuropeptide, rat; NGE (prepro-MCH110-128)
neuropeptide, rat; NFI (Procambarus clarkii); PBAN-1 (Bombyx mori);
Hez-PBAN (Heliothis zea); SCPB (cardioactive peptide from aplysia);
secretoneurin, rat; uperolein; urechistachykinin I;
urechistachykinin II; xenopsin-related peptide I; xenopsin-related
peptide II; pedal peptide (Pep), aplysia; peptide F1, lobster,
phyllomedusin; polistes mastoparan; proctolin; ranatensin; Ro I
(Lubber Grasshopper, Romalea microptera); Ro II (Lubber
Grasshopper, Romalea microptera); SALMF amide 1 (S1); SALMF amide 2
(S2); and SCPA.
[0161] Neuropeptide Y (NPY) peptides including, but not limited to,
{Leu.sup.31, Pro.sup.34} neuropeptide Y, human; neuropeptide F
(Moniezia expansa); B1BP3226 NPY antagonist; Bis (31/31')
{{Cys.sup.31, Trp.sup.32, Nva.sup.34} NPY 31-36}; neuropeptide Y,
human, rat; neuropeptide Y 1-24 amide, human; biotinyl-neuropeptide
Y; {D-Tyr27,36, D-Thr.sup.32}-NPY 27-36; Des 10-17 (cyclo 7-21)
{Cys.sup.7,21, Pro.sup.34}-NPY; C.sub.2-NPY; {Leu.sup.31,
Pro.sup.34} neuropeptide Y, human neuropeptide Y, free acid, human;
neuropeptide Y, free acid, porcine; prepro NPY 68-97, human;
N-acetyl-{Leu.sup.28, Leu.sup.31} NPY 24-36; neuropeptide Y,
porcine; {D-Trp.sup.32}-neuropeptide Y, porcine; {D-Trp.sup.32} NPY
1-36, human; {Leu.sup.17,DTrp.sup.32} neuropeptide Y, human;
{Leu.sup.31, Pro.sup.34}-NPY, porcine; NPY 2-36, porcine; NPY 3-36,
human; NPY 3-36, porcine; NPY 13-36, human; NPY 13-36, porcine; NPY
16-36, porcine; NPY 18-36, porcine; NPY 20-36; NFY 22-36; NPY
26-36; {Pro.sup.34}-NPY 1-36, human; {Pro.sup.34}-neuropeptide Y,
porcine; PYX-1; PYX-2; T4-{NPY(33-36)}4; and
Tyr(OMe).sup.21}-neuropeptide Y, human.
[0162] Neurotropic factor peptides including, but not limited to,
glial derived neurotropic factor (GDNF); brain derived neurotropic
factor (BDNF); and ciliary neurotropic factor (CNTF).
[0163] Orexin peptides including, but not limited to, orexin A;
orexin B, human; orexin B, rat, mouse.
[0164] Opioid peptides including, but not limited to, alpha-casein
fragment 90-95; BAM-18P; casomokinin L; casoxin D; crystalline;
DALDA; dermenkephalin (deltorphin) (Phylomedusa sauvagei);
{D-Ala.sup.2}-deltorphin I; {D-Ala.sup.2}-deltorphin II;
endomorphin-1; endomorphin-2; kyotorphin; {DArg.sup.2}-kyotorphin;
morphine tolerance peptide; morphine modulating peptide, C-terminal
fragment; morphine modulating neuropeptide (A-18-F--NH2);
nociceptin {orphanin FQ} (ORL1 agonist); TIPP; Tyr-MIF-1;
Tyr-W-MIF-1; valorphin; LW-hemorphin-6, human; Leu-valorphin-Arg;
and Z-Pro-D-Leu.
[0165] Oxytocin peptides including, but not limited to,
{Asu.sup.6}-oxytocin; oxytocin; biotinyl-oxytocin; {Thr.sup.4,
Gly.sup.7}-oxytocin; and tocinoic acid ({Ile.sup.3}-pressinoic
acid).
[0166] PACAP (pituitary adenylating cyclase activating peptide)
peptides including, but not limited to, PACAP 1-27, human, ovine,
rat; PACAP (1-27)-Gly-Lys-Arg-NH.sub.2, human;
{Des-Gln.sup.16}-PACAP 6-27, human, ovine, rat; PACAP38, frog;
PACAP27-NH.sub.2, human, ovine, rat; biotinyl-PACAP27-NH2, human,
ovine, rat; PACAP 6-27, human, ovine, rat; PACAP38, human, ovine,
rat; biotinyl-PACAP38, human, ovine, rat; PACAP 6-38, human, ovine,
rat; PACAP27-NH.sub.2, human, ovine, rat;
biotinyl-PACAP27-NH.sub.2, human, ovine, rat; PACAP 6-27, human,
ovine, rat; PACAP38, human, ovine, rat; biotinyl-PACAP38, human,
ovine, rat; PACAP 6-38, human, ovine, rat; PACAP38 16-38, human,
ovine, rat; PACAP38 31-38, human, ovine, rat; PACAP38 31-38, human,
ovine, rat; PACAP-related peptide (PRP), human; and PACAP-related
peptide (PRP), rat.
[0167] Pancreastatin peptides including, but not limited to,
chromostatin, bovine; pancreastatin (hPST-52) (chromogranin A
250-301, amide); pancreastatin 24-52 (hPST-29), human; chromogranin
A 286-301, amide, human; pancreastatin, porcine;
biotinyl-pancreastatin, porcine; {Nle.sup.8}-pancreastatin,
porcine; {Tyr.sup.0,Nle.sup.8}-pancreastatin, porcine;
{Tyr.sup.0}-pancreastatin, porcine; parastatin 1-19 (chromogranin A
347-365), porcine; pancreastatin (chromogranin A 264-314-amide,
rat; biotinyl-pancreastatin (biotinyl-chromogranin A 264-314-amide;
{Tyr.sup.0}-pancreastatin, rat; pancreastatin 26-51, rat; and
pancreastatin 33-49, porcine.
[0168] Pancreatic polypeptides including, but not limited to,
pancreatic polypeptide, avian; pancreatic polypeptide, human;
C-fragment pancreatic polypeptide acid, human; C-fragment
pancreatic polypeptide amide, human; pancreatic polypeptide (Rana
temporaria); pancreatic polypeptide, rat; and pancreatic
polypeptide, salmon.
[0169] Parathyroid hormone peptides including, but not limited to,
{Asp.sup.76-parathyroid hormone 39-84, human;
{Asp.sup.76}-parathyroid hormone 53-84, human;
{Asp.sup.76}-parathyroid hormone 1-84, hormone;
{Asn.sup.76}-parathyroid hormone 64-84, human; {Asn.sup.8,
Leu.sup.18}-parathyroid hormone 1-34, human;
{Cys.sup.5,28}-parathyroid hormone 1-34, human; hypercalcemia
malignancy factor 1-40; {Leu.sup.18}-parathyroid hormone 1-34,
human; {Lys(biotinyl).sup.13, Nle.sup.8,18, Tyr.sup.34}-parathyroid
hormone 1-34 amide; {Nle.sup.8,18, Tyr.sup.34}-parathyroid hormone
1-34 amide; {Nle.sup.8,18, Tyr.sup.34}-parathyroid hormone 3-34
amide, bovine; {Nle.sup.8,18, Tyr.sup.34}-parathyroid hormone 1-34,
human; {Nle.sup.8,18, Tyr.sup.34}-parathyroid hormone 1-34 amide
human; {Nle.sup.8,18, Tyr.sup.34}-parathyroid hormone 3-34 amide,
human; {Nle.sup.8,18, Tyr.sup.34}-parathyroid hormone 7-34 amide,
bovine; {Nle.sup.8,21, Tyr.sup.34}-parathyroid hormone 1-34 amide,
rat; parathyroid hormone 44-68, human; parathyroid hormone 1-34,
bovine; parathyroid hormone 3-34, bovine; parathyroid hormone 1-31
amide, human; parathyroid hormone 1-34, human; parathyroid hormone
13-34, human; parathyroid hormone 1-34, rat; parathyroid hormone
1-38, human; parathyroid hormone 1-44, human; parathyroid hormone
28-48, human; parathyroid hormone 39-68, human; parathyroid hormone
39-84, human; parathyroid hormone 53-84, human; parathyroid hormone
69-84, human; parathyroid hormone 70-84, human;
{Pro.sup.34}-peptide YY (PYY), human; {Tyr.sup.0}-hypercalcemia
malignancy factor 1-40; {Tyr.sup.0}-parathyroid hormone 1-44,
human; {Tyr.sup.0}-parathyroid hormone 1-34, human;
{Tyr.sup.1}-parathyroid hormone 1-34, human;
{Tyr.sup.27}-parathyroid hormone 27-48, human;
{Tyr.sup.34}-parathyroid hormone 7-34 amide, bovine;
{Tyr.sup.43}-parathyroid hormone 43-68, human; {Tyr.sup.52,
Asn.sup.76}-parathyroid hormone 52-84, human; and
{Tyr.sup.63}-parathyroid hormone 63-84, human.
[0170] Parathyroid hormone (PTH)-related peptides including, but
not limited to, PTHrP ({Tyr.sup.36}-PTHrP 1-36 amide), chicken;
hHCF-(1-34)--NH2 (humoral hypercalcemic factor), human; PTH-related
protein 1-34, human; biotinyl-PTH-related protein 1-34, human;
{Tyr.sup.0}-PTH-related protein 1-34, human;
{Tyr.sup.34}-PTH-related protein 1-34 amide, human; PTH-related
protein 1-37, human; PTH-related protein 7-34 amide, human;
PTH-related protein 38-64 amide, human; PTH-related protein 67-86
amide, human; PTH-related protein 107-111, human, rat, mouse;
PTH-related protein 107-111 free acid; PTH-related protein 107-138,
human; and PTH-related protein 109-111, human.
[0171] Peptide T peptides including, but not limited to, peptide T;
{D-Ala.sup.1}-peptide T; and {D-Ala.sup.1}-peptide T amide.
[0172] Prolactin-releasing peptides including, but not limited to,
prolactin-releasing peptide 31, human; prolactin-releasing peptide
20, human; prolactin-releasing peptide 31, rat; prolactin-releasing
peptide 20, rat; prolactin-releasing peptide 31, bovine; and
prolactin-releasing peptide 20, bovine.
[0173] Peptide YY (PYY) peptides including, but not limited to,
PYY, human; PYY 3-36, human; biotinyl-PYY, human; PYY, porcine,
rat; and {Leu.sup.31, Pro.sup.34}-PYY, human
[0174] Renin substrate peptides including, but not limited to,
acetyl, angiotensinogen 1-14, human; angiotensinogen 1-14, porcine;
renin substrate tetradecapeptide, rat; {Cys.sup.8}-renin substrate
tetradecapeptide, rat; {Leu.sup.8}-renin substrate
tetradecapeptide, rat; and {Val.sup.8}-renin substrate
tetradecapeptide, rat.
[0175] Secretin peptides including, but not limited to, secretin,
canine; secretin, chicken; secretin, human; biotinyl-secretin,
human; secretin, porcine; and secretin, rat.
[0176] Somatostatin (GIF) peptides including, but not limited to,
BIM-23027; biotinyl-somatostatin; biotinylated cortistatin 17,
human; cortistatin 14, rat; cortistatin 17, human;
{Tyr.sup.0}-cortistatin 17, human; cortistatin 29, rat;
{D-Trp.sup.8}-somatostatin; {DTrp.sup.8,DCys.sup.14}-somatostatin;
{DTrp.sup.8,Tyr.sup.11}-somatostatin; {D-Trp.sup.11}-somatostatin;
NTB (Naltriben); {Nle.sup.8}-somatostatin 1-28; octreotide (SMS
201-995); prosomatostatin 1-32, porcine; {Tyr.sup.0}-somatostatin;
{Tyr.sup.0}-somatostatin;{Tyr.sup.1}-somatostatin 28 (1-14);
{Tyr.sup.11}-somatostatin; {Tyr.sup.0}, D-Trp.sup.8}-somatostatin;
somatostatin; somatostatin antagonist; somatostatin-25;
somatostatin-28; somatostatin 28 (1-12); biotinyl-somatostatin-28;
{Tyr.sup.0}-somatostatin-28; {Leu8, D-Trp.sup.22,
Tyr.sup.25}-somatostatin 28; biotinyl-{Leu.sup.8, D-Trp.sup.22,
Tyr.sup.25}-somatostatin-28; somatostatin-28 (1-14); and
somatostatin analog, RC-160.
[0177] Substance P peptides including, but not limited to, G
protein antagonist-2; Ac-{Arg.sup.6, Sar.sup.9,
Met(02).sup.11}-substance P 6-11; {Arg.sup.3}-substance P;
Ac-Trp-3,5-bis(trifluoromethyl)benzyl ester; Ac-{Arg.sup.6,
Sar.sup.9, Met(O2).sup.11}-substance P 6-11;
{D-Ala.sup.4}-substance P 4-11; {Tyr.sup.6, D-Phe.sup.7,
D-His.sup.9}-substance P 6-11 (sendide); biotinyl-substance P;
biotinyl-NTE{Arg.sup.3}-substance P; (Tyr.sup.8}-substance P;
{Sar.sup.9, Met(O2).sup.11}-substance P; {D-Pro.sup.2,
DTrp.sup.7,9}-substance P; {D-Pro.sup.4, O-Trp.sup.7,9}-substance P
4-11; substance P 4-11; {DTrp.sup.2,7,9}-substance P;
{(Dehydro)Pro.sup.2,4, Pro.sup.9}-substance P;
{Dehydro-Pro.sup.4}-substance P 4-11;
{Glp.sup.5,(Me)Phe.sup.8,Sar.sup.9}-substance P 5-11;
{Glp.sup.5,Sar.sup.9}-substance P 5-11; {Glp.sup.5}-substance P
5-11; hepta-substance P (substance P 5-11); hexa-substance
P(substance P 6-11); {MePhe.sup.8,Sar.sup.9}-substance P;
{Nle.sup.11}-substance P; Octa-substance P(substance P 4-11);
{pGlu.sup.1}-hexa-substance P ({pGlu.sup.6}-substance P 6-11);
{pGlu.sup.6, D-Pro.sup.9}-substance P 6-11; {(pNO.sub.2)Phe.sup.7
Nle.sup.11}-substance P; penta-substance P (substance P 7-11);
{Pro.sup.9}-substance P; GR73632, substance P 7-11;
{Sar.sup.4}-substance P 4-11; {Sar.sup.9}-substance P; septide
({pGlu.sup.6, Pro.sup.9}-substance P 6-11); spantide I; spantide
II; substance P; substance P, cod; substance P, trout; substance P
antagonist; substance P-Gly-Lys-Arg; substance P 1-4; substance P
1-6; substance P 1-7; substance P 1-9; deca-substance P (substance
P 2-11); nona-substance P (substance P 3-11); substance P
tetrapeptide (substance P 8-11); substance P tripeptide (substance
P 9-11); substance P, free acid; substance P methyl ester, and
{Tyr.sup.8,Nle.sup.11} substance P.
[0178] Tachykinin peptides including, but not limited to,
{Ala.sup.5, beta-Ala.sup.8} neurokinin A 4-10; eledoisin;
locustatachykinin I (Lom-TK-I) (Locusta migratoria);
locustatachykinin II (Lom-TK-II) (Locusta migratoria); neurokinin A
4-10; neurokinin A (neuromedin L, substance K); neurokinin A, cod
and trout; biotinyl-neurokinin A (biotinyl-neuromedin L,
biotinyl-substance K); {Tyr.sup.0}-neurokinin A;
{Tyr.sup.6}-substance K; FR64349; {Lys.sup.3,
Gly.sup.8-(R)-gamma-lactam-Leu.sup.9}-neurokinin A 3-10; GR83074;
GR87389; GR94800; {Beta-Ala.sup.8}-neurokinin A 4-10;
{Nle.sup.10}-neurokinin A 4-10; {Trp.sup.7,
beta-Ala.sup.8}-neurokinin A 4-10; neurokinin B (neuromedin K);
biotinyl-neurokinin B (biotinyl-neuromedin K);
{MePhe.sup.7}-neurokinin B; {Pro.sup.7}-neurokinin B;
{Tyr.sup.0}-neurokinin B; neuromedin B, porcine;
biotinyl-neuromedin B, porcine; neuromedin B-30, porcine;
neuromedin B-32, porcine; neuromedin B receptor antagonist;
neuromedin C, porcine; neuromedin N, porcine; neuromedin (U-8),
porcine; neuromedin (U-25), porcine; neuromedin U, rat;
neuropeptide-gamma (gamma-preprotachykinin 72-92); PG-KII;
phyllolitorin; {Leu.sup.8}-phyllolitorin (Phyllomedusa sauvagei);
physalaemin; physalaemin 1-11; scyliorhinin II, amide, dogfish;
senktide, selective neurokinin B receptor peptide;
{Ser.sup.2}-neuromedin C; beta-preprotachykinin 69-91, human;
beta-preprotachykinin 111-129, human; tachyplesin I; xenopsin; and
xenopsin 25 (xenin 25), human
[0179] Thyrotropin-releasing hormone (TRH) peptides including, but
not limited to, biotinyl-thyrotropin-releasing hormone;
{Glu.sup.1}-TRH; His-Pro-diketopiperazine; {3-Me-His.sup.2}-TRH;
pGlu-Gln-Pro-amide; pGlu-His; {Phe.sup.2}-TRH; prepro TRH 53-74;
prepro TRH 83-106; prepro-TRH 160-169 (Ps4, TRH-potentiating
peptide); prepro-TRH 178-199, thyrotropin-releasing hormone (TRH);
TRH, free acid; TRH--SH Pro; and TRH precursor peptide.
[0180] Toxin peptides including, but not limited to, omega-agatoxin
TK; agelenin, (spider, Agelena opulenta); apamin (honeybee, Apis
mellifera); calcicudine (CaC) (green mamba, Dedroaspis
angusticeps); calciseptine (black mamba, Dendroaspis polylepis
polylepis); charybdotoxin (ChTX) (scorpion, Leiurus quinquestriatus
var. hebraeus); chlorotoxin; conotoxin GI (marine snail, Conus
geographus); conotoxin GS (marine snail, Conus geographus);
conotoxin MI (Marine Conus magus); alpha-conotoxin EI, Conus
ermineus; alpha-conotoxin SIA; alpha-conotoxin ImI; alpha-conotoxin
SI (cone snail, Conus striatus); micro-conotoxin GIIIB (marine
snail, Conus geographus); omega-conotoxin GVIA (marine snail, Conus
geographus); omega-conotoxin MVIIA (Conus magus); omega-conotoxin
MVIIC (Conus magus); omega-conotoxin SVIB, (cone snail, Conus
striatus); endotoxin inhibitor; geographutoxin I (GTX-I)
(.mu.-Conotoxin GIIIA); iberiotoxin (IbTX) (scorpion, Buthus
tamulus); kaliotoxin 1-37; kaliotoxin (scorpion, Androctonus
mauretanicus mauretanicus); mast cell-degranulating peptide
(MCD-peptide, peptide 401); margatoxin (MgTX) (scorpion,
Centruriodes margaritatus); neurotoxin NSTX-3 (Papua New Guinean
spider, Nephilia maculata); PLTX-II (spider, Plectreurys tristes);
scyllatoxin (leiurotoxin I); and stichodactyla toxin (ShK).
[0181] Vasoactive intestinal peptides (VIP/PHI) including, but not
limited to, VIP, human, porcine, rat, ovine;
VIP-Gly-Lys-Arg-NH.sub.2; biotinyl-PHI (biotinyl-PHI-27), porcine;
{Glp.sup.16} VIP 16-28, porcine; PHI (PHI-27), porcine; PHI
(PHI-27), rat; PHM-27 (PHI), human; prepro VIP 81-122, human;
prepro VIP/PHM 111-122; prepro VIP/PHM 156-170; biotinyl-PHM-27
(biotinyl-PHI), human; vasoactive intestinal contractor
(endothelin-beta); vasoactive intestinal octacosa-peptide, chicken;
vasoactive intestinal peptide, guinea pig; biotinyl-VIP, human,
porcine, rat; vasoactive intestinal peptide 1-12, human, porcine,
rat; vasoactive intestinal peptide 10-28, human, porcine, rat;
vasoactive intestinal peptide 11-28, human, porcine, rat, ovine;
vasoactive intestinal peptide (cod, Gadus morhua); vasoactive
intestinal peptide 6-28; vasoactive intestinal peptide antagonist;
vasoactive intestinal peptide antagonist ({Ac-Tyr.sup.1,
D-Phe.sup.2}-GHRF 1-29 amide); vasoactive intestinal peptide
receptor antagonist (4-Cl-D-Phe.sup.6, Leu.sup.17}-VIP); and
vasoactive intestinal peptide receptor binding inhibitor, L-8-K.
Additional constructs include but are not limited to,
Ala{.sup.11,22,28} VIP, Ala{.sup.2,8,9,11,19,22,24,25,27,28}VIP,
{K.sup.15, R.sup.16, L.sup.27}-VIP(1-7)/GRF(8-27), Ro25-1553,
Ro25-1392, BAY55-9837, R3P65, Maxadilan, PG97-269, PG99-465,
Max.d.4., and M65 (Dickson & Finlayson, Pharmacology &
Therapeutics, Volume 121, Issue 3, March 2009, Pages 294-316).
[0182] Vasopressin (ADH) peptides including, but not limited to,
vasopressin; {Asu.sup.1,6,Arg.sup.8}-vasopressin; vasotocin;
{Asu.sup.1,6,Arg.sup.8}-vasotocin; {Lys.sup.8}-vasopressin;
pressinoic acid; {Arg.sup.8}-desamino vasopressin desglycinamide;
{Arg.sup.8}-vasopressin (AVP); {Arg.sup.8}-vasopressin
desglycinamide; biotinyl-{Arg.sup.8}-vasopressin (biotinyl-AVP);
{D-Arg.sup.8}-vasopressin; desamino-{Arg.sup.8}-vasopressin;
desamino-{D-Arg.sup.8}-vasopressin (DDAVP);
{deamino-{D-3-(3'-pyridyl-Ala)}-{Arg.sup.8}-vasopressin;
{1-(beta-Mercapto-beta, beta-cyclopentamethylene propionic acid),
2-(O-methyl)tyrosinel-{Arg.sup.8}-vasopressin; vasopressin
metabolite neuropeptide {pGlu.sup.4, Cys.sup.6}; vasopressin
metabolite neuropeptide {pGlu.sup.4, Cys.sup.6};
{Lys.sup.8}-deamino vasopressin desglycinamide;
{Lys.sup.8}-vasopressin;
{Mpr.sup.1,Val.sup.4,DArg.sup.8}-vasopressin; {Phe.sup.2,
Ile.sup.3, Orn.sup.8}-vasopressin ({Phe.sup.2,
Orn.sup.8}-vasotocin); {Arg.sup.8}-vasotocin; and
{d(CH.sub.2).sub.5, Tyr(Me).sub.2, Orn.sup.8}-vasotocin.
[0183] Virus related peptides including, but not limited to, viral
membrane fusion proteins, fluorogenic human CMV protease substrate;
HCV core protein 59-68; HCV NS4A protein 1840 (JT strain); HCV NS4A
protein 21-34 (JT strain); hepatitis B virus receptor binding
fragment; hepatitis B virus pre-S region 120-145;
{Ala.sup.127}-hepatitis B virus pre-S region 120-131; herpes virus
inhibitor 2; HIV envelope protein fragment 254-274; HIV gag
fragment 129-135; HIV substrate; P 18 peptide; peptide T; {3,5
diiodo-Tyr.sup.7} peptide T; RISK HIV-1 inhibitory peptide; T20;
T21; V3 decapeptide P 18-110; and virus replication inhibiting
peptide.
[0184] The human hormone glucagon is a 29-amino acid peptide
hormone produced in the A-cells of the pancreas. The hormone
belongs to a multi-gene family of structurally related peptides
that include secretin, gastric inhibitory peptide, vasoactive
intestinal peptide and glicentin. These peptides variously regulate
carbohydrate metabolism, gastrointestinal mobility and secretory
processing. The principal recognized actions of pancreatic
glucagon, however, are to promote hepatic glycogenolysis and
glyconeogenesis, resulting in an elevation of blood sugar levels.
In this regard, the actions of glucagon are counter regulatory to
those of insulin and may contribute to the hyperglycemia that
accompanies Diabetes mellitus {(Lund, P. K., et al., Proc. Natl.
Acad. Sci. U.S.A., 79:345-349 (1982)}.
[0185] Glucagon has been found to be capable of binding to specific
receptors which lie on the surface of insulin producing cells.
Glucagon, when bound to these receptors, stimulates the rapid
synthesis of cAMP by these cells. cAMP, in turn, has been found to
stimulate insulin expression {Korman, L. Y., et al., Diabetes,
34:717-722 (1985)}. Insulin acts to inhibit glucagon synthesis
{Ganong, W. F., Review of Medical Physiology, Lange Publications,
Los Altos, Calif., p. 273 (1979)}. Thus, the expression of glucagon
is carefully regulated by insulin, and ultimately by the serum
glucose level.
[0186] The glucagon gene is initially translated from a 360 base
pair precursor to form the polypeptide, preproglucagon {Lund, et
al., Proc. Natl. Acad. Sci. U.S.A. 79:345-349 (1982)}. This
polypeptide is subsequently processed to form proglucagon. Patzelt,
C., et al., Nature, 282:260-266 (1979) demonstrated that
proglucagon was subsequently cleaved into glucagon and a second
polypeptide. Subsequent work by Lund, P. K., et al. supra, Lopez L.
C., et al., Proc. Natl. Acad. Sci. U.S.A., 80:5485-5489 (1983), and
Bell, G. I., et al., Nature 302:716-718 (1983), demonstrated that
the proglucagon molecule was cleaved immediately after
lysine-arginine dipeptide residues. Studies of proglucagon produced
by channel catfish (Ictalurus punctata) indicated that glucagon
from this animal was also proteolytically cleaved after adjacent
lysine-arginine dipeptide residues {Andrews P. C., et al., J. Biol.
Chem., 260:3910-3914 (1985), Lopez, L. C., et al., Proc. Natl.
Acad. Sci. U.S.A., 80:5485-5489 (1983)}. Bell, G. I., et al.,
supra, discovered that mammalian proglucagon was cleaved at
lysine-arginine or arginine-arginine dipeptides, and demonstrated
that the proglucagon molecule contained three discrete and highly
homologous peptide molecules which were designated glucagon,
glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2
(GLP-2). Lopez, et al., concluded that glucagon-like peptide 1 was
37 amino acid residues long and that glucagon-like peptide 2 was 34
amino acid residues long. Analogous studies on the structure of rat
preproglucagon revealed a similar pattern of proteolytic cleavage
between adjacent lysine-arginine or arginine-arginine dipeptide
residues, resulting in the formation of glucagon, GLP-1 and GLP-2
{Heinrich, G., et al., Endocrinol., 115:2176-2181 (1984)}.
[0187] Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide
expressed in a tissue-specific manner from the pleiotropic glucagon
gene. GLP-2 shows remarkable homology in terms of amino acid
sequence to glucagon and Glucagon-like peptide-1 (GLP-1). Further,
different mammalian forms of GLP-2 are highly conserved. The
sequence of human GLP-2, is as follows:
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-A-
-la-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp.
Further, a large number of agonist GLP-2 peptides that are
described in PCT Application PCT/CA97/00252, filed Apr. 11, 1997.
Analogs are described in U.S. Pat. No. 6,051,557, and examples of
GLP-2 variants are found in U.S. Pat. Nos. 5,990,077 and
6,184,201.
[0188] Recently it was demonstrated that GLP-2 is an
intestinotrophic peptide hormone (Drucker et al., (1996) PNAS,
93:7911-7916). When given exogenously, GLP-2 can produce a marked
increase in the proliferation of small intestinal epithelium of the
test mice, apparently with no undesirable side effects.
Subsequently it was shown that peptide analogs of native GLP-2 with
certain modifications to the peptide sequence possess enhanced
intestinotrophic activity (U.S. patent application Ser. No.
08/669,791). Moreover, GLP-2 has also been shown to increase
D-Glucose maximal transport rate across the intestinal basolateral
membrane (Cheeseman and Tseng (1996) American Journal of Physiology
271:G477-G482).
[0189] A number of peptide hormones (IGF-2, IGF-1, GH),
structurally unrelated to GLP-2, have been demonstrated to have
varying degrees of intestinotrophic activity. (U.S. Pat. No.
5,482,926, WO 91/12018, U.S. Pat. No. 5,288,703). However, none of
the above peptide hormones possess the efficacy or specificity of
GLP-2 in promoting proliferation of the intestine epithelium. GLP-2
acts synergistically with the peptide hormones IGF-1 and/or GH to
promote the proliferation of cells in the large intestine.
Furthermore, the intestinotrophic effects on the small and large
intestines of this combination therapy are greater than that seen
with any one of alone. Coadministration of GLP-2 with IGF-2 to
promote growth of small and/or large intestine tissue is discussed
in U.S. Pat. No. 5,952,301.
[0190] Nucleic acid encoding the GLP-2 receptor has been isolated
and methods to identify GLP-2 receptor agonists are described (U.S.
patent application Ser. No. 08/767,224 and U.S. Ser. No.
08/845,546). GLP-2's role in diseases involving the esophagus and
the stomach, in assisting patients at risk of developing a
malfunctioning of the upper gastrointestinal tract, and in
increasing tissue growth in the upper gastrointestinal tract have
been discussed (see U.S. Pat. No. 6,051,557). GLP-2 receptor
agonists act to enhance functioning of the large intestine. (U.S.
Pat. No. 6,297,214). GLP-2 and peptidic agonists of GLP-2 can cause
proliferation of the tissue of large intestine. GLP-2 may also be
useful to treat or prevent inflammatory conditions of the large
intestine, including inflammatory bowel diseases (U.S. Pat. No.
6,586,399).
[0191] A very wide variety of non-naturally encoded amino acids are
suitable for use in the present invention. Any number of
non-naturally encoded amino acids can be introduced into an analog.
In general, the introduced non-naturally encoded amino acids are
substantially chemically inert toward the 20 common,
genetically-encoded amino acids (i.e., alanine, arginine,
asparagine, aspartic acid, cysteine, glutamine, glutamic acid,
glycine, histidine, isoleucine, leucine, lysine, methionine,
phenylalanine, proline, serine, threonine, tryptophan, tyrosine,
and valine). In some embodiments, the non-naturally encoded amino
acids include side chain functional groups that react efficiently
and selectively with functional groups not found in the 20 common
amino acids (including but not limited to, azido, ketone, aldehyde
and aminooxy groups) to form stable conjugates. For example, an
analog that includes a non-naturally encoded amino acid containing
an azido functional group can be reacted with a polymer (including
but not limited to, poly(ethylene glycol) or, alternatively, a
second polypeptide containing an alkyne moiety to form a stable
conjugate resulting for the selective reaction of the azide and the
alkyne functional groups to form a Huisgen {3+2} cycloaddition
product.
[0192] In some embodiments, the composition or pharmaceutical
compositions of the claimed invention comprises an analog of a
polypeptide, wherein the analog amino acid sequence is based upon
the fragments, polypeptides, and functional derivatives disclosed
herein and wherein the analog comprises at least one or a plurality
of non-natural amino acids and at least one or a plurality of
.beta.-amino acid residues. A non-natural amino acid typically
possesses an R group that is any substituent other than one
component of the twenty natural amino acids, and may be suitable
for use in the present invention. Because the non-naturally encoded
amino acids of the invention typically differ from the natural
amino acids only in the structure of the side chain, the
non-naturally encoded amino acids form amide bonds with other amino
acids, including but not limited to, natural or non-naturally
encoded, in the same manner in which they are formed in naturally
occurring polypeptides. However, the non-natural amino acids have
side chain groups that distinguish them from the natural amino
acids. For example, R optionally comprises an alkyl-, aryl-, acyl-,
keto-, azido-, hydroxyl-, hydrazine, cyano-, halo-, hydrazide,
alkenyl, alkynyl, ether, thiol, seleno-, sulfonyl-, borate,
boronate, phospho, phosphono, phosphine, heterocyclic, enone,
imine, aldehyde, ester, thioacid, hydroxylamine, amino group, or
the like or any combination thereof. Other non-naturally occurring
amino acids of interest that may be suitable for use in the present
invention include, but are not limited to, amino acids comprising a
photoactivatable cross-linker, spin-labeled amino acids,
fluorescent amino acids, metal binding amino acids,
metal-containing amino acids, radioactive amino acids, amino acids
with novel functional groups, amino acids that covalently or
noncovalently interact with other molecules, photocaged and/or
photoisomerizable amino acids, amino acids comprising biotin or a
biotin analogue, glycosylated amino acids such as a sugar
substituted serine, other carbohydrate modified amino acids,
keto-containing amino acids, amino acids comprising polyethylene
glycol or polyether, heavy atom substituted amino acids, chemically
cleavable and/or photocleavable amino acids, amino acids with an
elongated side chains as compared to natural amino acids, including
but not limited to, polyethers or long chain hydrocarbons,
including but not limited to, greater than about 5 or greater than
about 10 carbons, carbon-linked sugar-containing amino acids,
redox-active amino acids, amino thioacid containing amino acids,
and amino acids comprising one or more toxic moiety.
[0193] Exemplary non-natural amino acids that may be suitable for
use in the present invention and that are useful for reactions with
water soluble polymers include, but are not limited to, those with
carbonyl, aminooxy, hydrazine, hydrazide, semicarbazide, azide and
alkyne reactive groups. In some embodiments, non-naturally encoded
amino acids comprise a saccharide moiety. Examples of such amino
acids include N-acetyl-L-glucosaminyl-L-serine,
N-acetyl-L-galactosaminyl-L-serine,
N-acetyl-L-glucosaminyl-L-threonine,
N-acetyl-L-glucosaminyl-L-asparagine and O-mannosaminyl-L-serine.
Examples of such amino acids also include examples where the
naturally-occurring N- or O-linkage between the amino acid and the
saccharide is replaced by a covalent linkage not commonly found in
nature--including but not limited to, an alkene, an oxime, a
thioether, an amide and the like. Examples of such amino acids also
include saccharides that are not commonly found in
naturally-occurring proteins such as 2-deoxy-glucose,
2-deoxygalactose and the like.
[0194] Many of the non-naturally encoded amino acids provided
herein are commercially available, e.g., from Sigma-Aldrich (St.
Louis, Mo., USA), Novabiochem (a division of EMD Biosciences,
Darmstadt, Germany), or Peptech (Burlington, Mass., USA). Those
that are not commercially available are optionally synthesized as
provided herein or using standard methods known to those of skill
in the art. In some embodiments, the invention relates to a method
of manufacturing a polypeptide analog wherein the polypeptide
analog is manufactured using a synthesis technique disclosed in the
following references, which are incorporated herein by reference:
For organic synthesis techniques, see, e.g., Organic Chemistry by
Fessendon and Fessendon, (1982, Second Edition, Willard Grant
Press, Boston Mass.); Advanced Organic Chemistry by March (Third
Edition, 1985, Wiley and Sons, New York); and Advanced Organic
Chemistry by Carey and Sundberg (Third Edition, Parts A and B,
1990, Plenum Press, New York). See, also, U.S. Patent Application
Publications 2003/0082575 and 2003/0108885, which is incorporated
by reference herein. In addition to unnatural (or non-natural)
amino acids that contain novel side chains, unnatural amino acids
that may be suitable for use in the present invention also
optionally comprise modified backbone structures, including but not
limited to, as illustrated by the structures of Formula II and III
of U.S. Patent Application Publication 2010-0048871, wherein Z
typically comprises OH, NH.sub.2, SH, NH--R, or S--R; X and Y,
which can be the same or different, typically comprise S or O, and
R and R, which are optionally the same or different, are typically
selected from the same list of constituents for the R group
described above for the unnatural amino acids as well as hydrogen.
For example, unnatural amino acids of the invention optionally
comprise substitutions in the amino or carboxyl group as
illustrated by Formulas II and III. Unnatural amino acids of this
type include, but are not limited to, .alpha.-hydroxy acids,
.alpha.-thioacids, .alpha.-aminothiocarboxylates, including but not
limited to, with side chains corresponding to the common twenty
natural amino acids or unnatural side chains. In addition,
substitutions at the .alpha.-carbon optionally include, but are not
limited to, L, D, or .alpha.-.alpha.-disubstituted amino acids such
as D-glutamate, D-alanine, D-methyl-O-tyrosine, aminobutyric acid,
and the like. Other structural alternatives include cyclic amino
acids, such as proline analogues as well as 3, 4, 6, 7, 8, and 9
membered ring proline analogues, .beta. amino acids such as
substituted .beta.-alanine.
[0195] In some embodiments, the composition or pharmaceutical
compositions of the claimed invention comprises an analog of a
polypeptide, wherein the analog amino acid sequence is based upon
the fragments, polypeptides, and functional derivatives disclosed
herein and wherein the analog comprises at least one or a plurality
of unnatural amino acid or non-natural amino acid and at least one
or a plurality of .beta.-amino acid residues, wherein the unnatural
amino acids based on natural amino acids, such as tyrosine,
glutamine, phenylalanine, and the like, and are suitable for use in
the present invention. Tyrosine analogs include, but are not
limited to, para-substituted tyrosines, ortho-substituted
tyrosines, and meta substituted tyrosines, where the substituted
tyrosine comprises, including but not limited to, a keto group
(including but not limited to, an acetyl group), a benzoyl group,
an amino group, a hydrazine, an hydroxyamine, a thiol group, a
carboxy group, an isopropyl group, a methyl group, a
C.sub.6-C.sub.20 straight chain or branched hydrocarbon, a
saturated or unsaturated hydrocarbon, an O-methyl group, a
polyether group, a nitro group, an alkynyl group or the like. In
addition, multiply substituted aryl rings are also contemplated.
Glutamine analogs that may be suitable for use in the present
invention include, but are not limited to, .alpha..-hydroxy
derivatives, cyclic derivatives, and amide substituted glutamine
derivatives. Example phenylalanine analogs that may be suitable for
use in the present invention include, but are not limited to,
para-substituted phenylalanines, ortho-substituted phenylalanines,
and meta-substituted phenylalanines, where the substituent
comprises, including but not limited to, a hydroxy group, a methoxy
group, a methyl group, an allyl group, an aldehyde, an azido, an
iodo, a bromo, a keto group (including but not limited to, an
acetyl group), a benzoyl, an alkynyl group, or the like. Specific
examples of unnatural amino acids that may be suitable for use in
the present invention include, but are not limited to, a
p-acetyl-L-phenylalanine, an O-methyl-L-tyrosine, an
L-3-(2-naphthyl)alanine, a 3-methyl-phenylalanine, an
0-4-allyl-L-tyrosine, a 4-propyl-L-tyrosine, a
tri-O-acetyl-GlcNAc.beta.-serine, an L-Dopa, a fluorinated
phenylalanine, an isopropyl-L-phenylalanine, a
p-azido-L-phenylalanine, a p-acyl-L-phenylalanine, a
p-benzoyl-L-phenylalanine, an L-phosphoserine, a phosphonoserine, a
phosphonotyrosine, a p-iodo-phenylalanine, a p-bromophenylalanine,
a p-amino-L-phenylalanine, an isopropyl-L-phenylalanine, and a
p-propargyloxy-phenylalanine, and the like. Examples of structures
of a variety of unnatural amino acids that may be suitable for use
in the present invention are provided in, for example, WO
2002/085923 entitled "In vivo incorporation of unnatural amino
acids." See also Kiick et al., (2002). Incorporation of azides into
recombinant proteins for chemoselective modification by the
Staudinger ligation, PNAS 99:19-24, for additional methionine
analogs.
[0196] The chemical moieties via unnatural amino acids that can be
incorporated into analogs offer a variety of advantages and
manipulations of the protein. For example, the unique reactivity of
a keto functional group allows selective modification of proteins
with any of a number of hydrazine- or hydroxylamine-containing
reagents in vitro and in vivo. A heavy atom unnatural amino acid,
for example, can be useful for phasing X-ray structure data. The
site-specific introduction of heavy atoms using unnatural amino
acids also provides selectivity and flexibility in choosing
positions for heavy atoms. In some embodiments, the composition or
pharmaceutical compositions of the claimed invention comprises an
analog of a polypeptide, wherein the analog amino acid sequence is
based upon the fragments, polypeptides, and functional derivatives
disclosed herein and wherein the analog comprises at least one or a
plurality of unnatural amino acid or non-natural amino acid and at
least one or a plurality of .beta.-amino acid residues, wherein the
unnatural amino is a photoreactive unnatural amino acid chosen from
(including but not limited to, amino acids with benzophenone and
arylazides (including but not limited to, phenylazide) side
chains), for example, allow for efficient in vivo and in vitro
photocrosslinking of protein. Examples of photoreactive unnatural
amino acids include, but are not limited to, p-azido-phenylalanine
and p-benzoyl-phenylalanine. The protein with the photoreactive
unnatural amino acids can then be crosslinked at will by excitation
of the photoreactive group-providing temporal control. In one
example, the methyl group of an unnatural amino can be substituted
with an isotopically labeled, including but not limited to, methyl
group, as a probe of local structure and dynamics, including but
not limited to, with the use of nuclear magnetic resonance and
vibrational spectroscopy. Alkynyl or azido functional groups, for
example, allow the selective modification of proteins with
molecules through a {3+2} cycloaddition reaction.
[0197] A non-natural amino acid incorporated into a polypeptide at
the amino terminus can be composed of an R group that is any
substituent other than one used in the twenty natural amino acids
and a second reactive group different from the NH.sub.2 group
normally present in .alpha.-amino acids. A similar non-natural
amino acid can be incorporated at the carboxyl terminus with a
second reactive group different from the COOH group normally
present in .alpha.-amino acids.
[0198] Many of the unnatural amino acids suitable for use in the
present invention are commercially available, e.g., from Sigma
(USA) or Aldrich (Milwaukee, Wis., USA). Those that are not
commercially available are optionally synthesized as provided
herein or as provided in various publications or using standard
methods known to those of skill in the art. For organic synthesis
techniques, see, e.g., Organic Chemistry by Fessendon and
Fessendon, (1982, Second Edition, Willard Grant Press, Boston,
Mass.); Advanced Organic Chemistry by March (Third Edition, 1985,
Wiley and Sons, New York); and Advanced Organic Chemistry by Carey
and Sundberg (Third Edition, Parts A and B, 1990, Plenum Press, New
York). Additional publications describing the synthesis of
unnatural amino acids include, e.g., WO 2002/085923 entitled "In
vivo incorporation of Unnatural Amino Acids;" Matsoukas et al.,
(1995) J. Med. Chem., 38, 4660-4669; King, F. E. & Kidd, D. A.
A. (1949) A New Synthesis of Glutamine and of .gamma.-Dipeptides of
Glutamic Acid from Phthylated Intermediates. J. Chem. Soc.,
3315-3319; Friedman, O. M. & Chattenji, R. (1959) Synthesis of
Derivatives of Glutamine as Model Substrates for Anti-Tumor Agents.
J. Am. Chem. Soc. 81, 3750-3752; Craig, J. C. et al. (1988)
Absolute Configuration of the Enantiomers of 7-Chloro-4
{{4-(diethylamino)-}-methylbutyl}amino}quinoline (Chloroquine). J.
Org. Chem. 53, 1167-1170; Azoulay, M., Vilmont, M. & Frappier,
F. (1991) Glutamine analogues as Potential Antimalarials, Eur. J.
Med. Chem. 26, 201-5; Koskinen, A. M. P. & Rapoport, H. (1989)
Synthesis of 4-Substituted Prolines as Conformationally Constrained
Amino Acid Analogues. J. Org. Chem. 54, 1859-1866; Christie, B. D.
& Rapoport, H. (1985) Synthesis of Optically Pure Pipecolates
from L-Asparagine. Application to the Total Synthesis of
(+)-Apovincamine through Amino Acid Decarbonylation and Iminium Ion
Cyclization. J. Org. Chem. 50:1239-1246; Barton et al., (1987)
Synthesis of Novel alpha-Amino-Acids and Derivatives Using Radical
Chemistry: Synthesis of L- and D-alpha-Amino-Adipic Acids,
L-alpha-aminopimelic Acid and Appropriate Unsaturated Derivatives.
Tetrahedron 43:4297-4308; and, Subasinghe et al., (1992) Quisqualic
acid analogues: synthesis of beta-heterocyclic 2-aminopropanoic
acid derivatives and their activity at a novel
quisqualate-sensitized site. J. Med. Chem. 35:4602-7. See also,
patent applications entitled "Protein Arrays," filed Dec. 22, 2003,
Ser. No. 10/744,899 and Ser. No. 60/435,821 filed on Dec. 22,
2002.
[0199] In some embodiments, the composition comprises a
transcription factor analog wherein the total number of
.beta.-amino acids in the analog is from about 10 percent to about
60 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises an enkephlin analog
wherein the total number of .beta.-amino acids in the analog is
from about 10 percent to about 60 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises an LHRH analog wherein the total number of .beta.-amino
acids in the analog is from about 10 percent to about 60 percent of
the total number of amino acids of the analog. In some embodiments,
the composition comprises a neuropeptide analog wherein the total
number of .beta.-amino acids in the analog is from about 10 percent
to about 60 percent of the total number of amino acids of the
analog. In some embodiments, the composition comprises an
glycointegrin analog wherein the total number of .beta.-amino acids
in the analog is from about 10 percent to about 60 percent of the
total number of amino acids of the analog. In some embodiments, the
composition comprises an integrin analog wherein the total number
of .beta.-amino acids in the analog is from about 10 percent to
about 60 percent of the total number of amino acids of the analog.
In some embodiments, the composition comprises a glucagon or
glucagon-like peptide analog wherein the total number of
.beta.-amino acids in the analog is from about 10 percent to about
60 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises an antithrombotic
peptides analog wherein the total number of .beta.-amino acids in
the analog is from about 10 percent to about 60 percent of the
total number of amino acids of the analog. In some embodiments, the
composition comprises a vassopressin analog wherein the total
number of .beta.-amino acids in the analog is from about 10 percent
to about 60 percent of the total number of amino acids of the
analog. In some embodiments, the composition comprises a cytokine
or interleukin analog wherein the total number of .beta.-amino
acids in the analog is from about 10 percent to about 60 percent of
the total number of amino acids of the analog. In some embodiments,
the composition comprises an interferon analog wherein the total
number of .beta.-amino acids in the analog is from about 10 percent
to about 60 percent of the total number of amino acids of the
analog. In some embodiments, the composition comprises an
endothelin analog wherein the total number of .beta.-amino acids in
the analog is from about 10 percent to about 60 percent of the
total number of amino acids of the analog. In some embodiments, the
composition comprises an natriuretic hormone analog wherein the
total number of .beta.-amino acids in the analog is from about 10
percent to about 60 percent of the total number of amino acids of
the analog. In some embodiments, the composition comprises an
extracellular kinase ligand analog wherein the total number of
.beta.-amino acids in the analog is from about 10 percent to about
60 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises an angiotensin enzyme
inhibitor analog wherein the total number of .beta.-amino acids in
the analog is from about 10 percent to about 60 percent of the
total number of amino acids of the analog. In some embodiments, the
composition comprises an antiviral peptide analog wherein the total
number of .beta.-amino acids in the analog is from about 10 percent
to about 60 percent of the total number of amino acids of the
analog. In some embodiments, the composition comprises a thrombin
analog wherein the total number of .beta.-amino acids in the analog
is from about 10 percent to about 60 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a substance P analog wherein the total number of
.beta.-amino acids in the analog is from about 10 percent to about
60 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a substance G analog
wherein the total number of .beta.-amino acids in the analog is
from about 10 percent to about 60 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a somatotropin analog wherein the total number of
.beta.-amino acids in the analog is from about 10 percent to about
60 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a somatostatin analog
wherein the total number of .beta.-amino acids in the analog is
from about 10 percent to about 60 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a GnRH analog wherein the total number of .beta.-amino
acids in the analog is from about 10 percent to about 60 percent of
the total number of amino acids of the analog. In some embodiments,
the composition comprises a bradykinin analog wherein the total
number of .beta.-amino acids in the analog is from about 10 percent
to about 60 percent of the total number of amino acids of the
analog. In some embodiments, the composition comprises an insulin
analog wherein the total number of .beta.-amino acids in the analog
is from about 10 percent to about 60 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a growth factor analog wherein the total number of
.beta.-amino acids in the analog is from about 10 percent to about
60 percent of the total number of amino acids of the analog. Any of
the compositions above may be used in the methods disclosed in this
instant specification.
[0200] In some embodiments, the composition comprises a VIP analog
wherein the total number of .beta.-amino acids in the analog is
from about 10 percent to about 60 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a VIP analog wherein the total number of .beta.-amino
acids in the analog is from about 12 percent to about 50 percent of
the total number of amino acids of the analog. In some embodiments,
the composition comprises a VIP analog wherein the total number of
.beta.-amino acids in the analog is from about 14 percent to about
50 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a VIP analog wherein
the total number of .beta.-amino acids in the analog is from about
16 percent to about 50 percent of the total number of amino acids
of the analog. In some embodiments, the composition comprises a VIP
analog wherein the total number of .beta.-amino acids in the analog
is from about 18 percent to about 50 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a VIP analog wherein the total number of .beta.-amino
acids in the analog is from about 20 percent to about 50 percent of
the total number of amino acids of the analog. In some embodiments,
the composition comprises a VIP analog wherein the total number of
.beta.-amino acids in the analog is from about 30 percent to about
50 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a VIP analog wherein
the total number of .beta.-amino acids in the analog is from about
40 percent to about 50 percent of the total number of amino acids
of the analog. In some embodiments, the composition comprises a VIP
analog wherein the total number of .beta.-amino acids in the analog
is from about 45 percent to about 50 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a VIP analog wherein the total number of .beta.-amino
acids in the analog is from about 40 percent to about 45 percent of
the total number of amino acids of the analog. In some embodiments,
the composition comprises a VIP analog wherein the total number of
.beta.-amino acids in the analog is from about 30 percent to about
40 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a VIP analog wherein
the total number of .beta.-amino acids in the analog is from about
35 percent to about 40 percent of the total number of amino acids
of the analog. In some embodiments, the composition comprises a VIP
analog wherein the total number of .beta.-amino acids in the analog
is from about 20 percent to about 30 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a VIP analog wherein the total number of .beta.-amino
acids in the analog is from about 10 percent to about 20 percent of
the total number of amino acids of the analog. In some embodiments,
the composition comprises a VIP analog wherein the total number of
.beta.-amino acids in the analog is from about 15 percent to about
20 percent of the total number of amino acids of the analog. In
some embodiments, the composition comprises a VIP analog wherein
the total number of .beta.-amino acids in the analog is from about
20 percent to about 25 percent of the total number of amino acids
of the analog. In some embodiments, the composition comprises a VIP
analog wherein the total number of .beta.-amino acids in the analog
is from about 25 percent to about 30 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises a VIP analog wherein the total number of .beta.-amino
acids in the analog is from about 30 percent to about 35 percent of
the total number of amino acids of the analog.
[0201] In some embodiments, the composition comprises a VIP analog,
wherein the ratio of total .beta.-amino acids in the analog is from
1 to 3 .beta.-amino acids for every 7 amino acids of the analog. In
some embodiments, the composition comprises a VIP analog, wherein
the ratio of total .beta.-amino acids in the analog is from 2 to 4
.beta.-amino acids for every 7 amino acids of the analog. In some
embodiments, the composition comprises a VIP analog, wherein the
ratio of total .beta.-amino acids to amino acids in the analog is
from 3 to 5 .beta.-amino acids for every 7 amino acids of the
analog. In some embodiments, the composition comprises a VIP
analog, wherein the ratio of total .beta.-amino acids to amino
acids in the analog is from 4 to 6 .beta.-amino acids for every 7
amino acids of the analog. In some embodiments, the composition
comprises a VIP analog, wherein the ratio of total .beta.-amino
acids to amino acids in the analog is from 5 to 7 .beta.-amino
acids for every 7 amino acids of the analog. In some embodiments,
the composition comprises a VIP analog, wherein the ratio of total
.beta.-amino acids to amino acids in the analog is 1 .beta.-amino
acid for every 7 amino acids of the analog. In some embodiments,
the composition comprises a VIP analog, wherein the ratio of total
.beta.-amino acids to amino acids in the analog is 2 .beta.-amino
acids for every 7 amino acids of the analog. In some embodiments,
the composition comprises a VIP analog, wherein the ratio of total
.beta.-amino acids to amino acids in the analog is 3 .beta.-amino
acids for every 7 amino acids of the analog. In some embodiments,
the composition comprises a VIP analog, wherein the ratio of total
.beta.-amino acids to amino acids in the analog is 4 .beta.-amino
acids for every 7 amino acids of the analog. In some embodiments,
the composition comprises a VIP analog, wherein the ratio of total
.beta.-amino acids to amino acids in the analog is 5 .beta.-amino
acids for every 7 amino acids of the analog. In some embodiments,
the composition comprises a VIP analog, wherein the ratio of total
.beta.-amino acids to amino acids in the analog is 6 .beta.-amino
acids for every 7 amino acids of the analog.
[0202] In another embodiment of the invention, the composition
comprises a VIP analog, wherein the analog comprises a repetitive
pattern of .beta.-amino acids from the amino-terminus to the
carboxy-terminus selected from the following:
.alpha..alpha..alpha..alpha..alpha..alpha..beta.,
.alpha..alpha..alpha..alpha..alpha..beta..alpha.,
.alpha..alpha..alpha..alpha..beta..alpha..alpha.,
.alpha..alpha..alpha..beta..alpha..alpha..alpha.,
.alpha..alpha..beta..alpha..alpha..alpha..alpha.,
.alpha..beta..alpha..alpha..alpha..alpha..alpha.,
.beta..alpha..alpha..alpha..alpha..alpha..alpha.,
.alpha..alpha..alpha..alpha..alpha..beta..beta.,
.alpha..alpha..alpha..alpha..beta..beta..alpha.,
.alpha..alpha..alpha..beta..beta..alpha..alpha.,
.alpha..alpha..beta..beta..alpha..alpha..alpha.,
.alpha..beta..beta..alpha..alpha..alpha..alpha.,
.beta..beta..alpha..alpha..alpha..alpha..alpha.,
.beta..alpha..alpha..alpha..alpha..alpha..beta.,
.beta..alpha..alpha..alpha..alpha..beta..alpha.,
.beta..alpha..alpha..alpha..beta..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha., .beta.
.beta..alpha..alpha..alpha..alpha.,
.alpha..beta..alpha..alpha..alpha..alpha..beta.,
.alpha..beta..alpha..alpha..alpha..beta..alpha.,
.alpha..beta..alpha..alpha..beta..alpha..alpha.,
.alpha..beta..alpha..beta..alpha..alpha..alpha.,
.alpha..alpha..beta..alpha..alpha..alpha..beta.,
.alpha..alpha..beta..alpha..alpha..beta..alpha.,
.alpha..alpha..beta..alpha..beta..alpha..alpha.,
.alpha..alpha..alpha..beta..alpha..alpha..beta.,
.alpha..alpha..alpha..beta..alpha..beta..alpha., and
.alpha..alpha..alpha..alpha..beta..alpha..beta..
[0203] Some embodiments of the claimed invention include
pharmaceutical compositions. In some embodiments, the
pharmaceutical composition comprises any of the aforementioned
compositions in combination with a pharmaceutically acceptable
carrier. In another embodiment of the invention, the pharmaceutical
composition comprises a secretin analog and one other active agent,
wherein the secretin analog comprises at least one .alpha.-amino
acid and at least one .beta.-amino acid.
[0204] In another embodiment of the invention, the pharmaceutical
composition comprises a VIP analog and one other active agent,
wherein the VIP analog comprises at least one .alpha.-amino acid
and at least one .beta.-amino acid.
[0205] The invention further relates to uses of a composition
comprising a secretin analog in the preparation of a medicament for
treating or preventing pulmonary hypertension, primary arterial
hypertension, pulmonary hypertension associated to post-ventricular
septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary
arterial hypertension, CREST syndrome--Calcinosis; Raynaud's
disease; loss of muscle control of the Esophagus; Sclerodactyly;
Telangiectasia, Acute respiratory distress, congestive heart
failure, chronic obstructed pulmonary disorder, asthma, chronic
obstructive pulmonary disease, sarcoidosis, small lung cell cancer,
autoimmune disease, inflammatory disease, sepsis, Hirschsprung's
Disease, sexual dysfunction, erectile dysfunction, Parkinson's
disease, Alzheimer's disease, circadian rhythm dysfunction, pain,
colorectal cancer, hepatocellular cancer, elevated blood pressure
levels, elevated blood glucose levels, hyperglycemia, diabetes,
insulin resistance, metabolic acidosis, obesity, Type I diabetes,
Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's
syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual
dysfunction. The invention further relates to use of a composition
comprising a VIP analog in the preparation of a medicament for
treating or preventing pulmonary hypertension, primary arterial
hypertension, pulmonary hypertension associated to post-ventricular
septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary
arterial hypertension, CREST syndrome--Calcinosis; Raynaud's
disease; loss of muscle control of the Esophagus; Sclerodactyly;
Telangiectasia, Acute respiratory distress, congestive heart
failure, chronic obstructed pulmonary disorder, asthma, chronic
obstructive pulmonary disease, sarcoidosis, small lung cell cancer,
autoimmune disease, inflammatory disease, sepsis, Hirschsprung's
Disease, sexual dysfunction, erectile dysfunction, Parkinson's
disease, Alzheimer's disease, circadian rhythm dysfunction, pain,
colorectal cancer, hepatocellular cancer, elevated blood pressure
levels, elevated blood glucose levels, hyperglycemia, diabetes,
insulin resistance, metabolic acidosis, obesity, Type I diabetes,
Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's
syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual
dysfunction.
[0206] In some embodiments, the invention relates to methods of
manufacturing any one of the aforementioned compositions,
pharmaceutical compositions, or a pharmaceutical salt derived
therefrom comprising catalyzing a reaction between at least one
.alpha.-amino acid with at least one .beta.-amino acid.
[0207] The invention also relates to methods of treating or
preventing pulmonary hypertension, primary arterial hypertension,
pulmonary hypertension associated to post-ventricular septal
defect, idiopathic pulmonary fibrosis, idiopathic pulmonary
arterial hypertension, CREST syndrome--Calcinosis; Raynaud's
disease; loss of muscle control of the Esophagus; Sclerodactyly;
Telangiectasia, Acute respiratory distress, congestive heart
failure, chronic obstructed pulmonary disorder, asthma, chronic
obstructive pulmonary disease, sarcoidosis, small lung cell cancer,
autoimmune disease, inflammatory disease, sepsis, Hirschsprung's
Disease, sexual dysfunction, erectile dysfunction, Parkinson's
disease, Alzheimer's disease, circadian rhythm dysfunction, pain,
colorectal cancer, hepatocellular cancer, elevated blood pressure
levels, elevated blood glucose levels, hyperglycemia, diabetes,
insulin resistance, metabolic acidosis, obesity, Type I diabetes,
Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's
syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual
dysfunction comprising administrating any one of the compositions
or pharmaceutical compositions comprising a secretin family analog,
or a pharmaceutical salt derived therefrom, to a subject in need
thereof.
[0208] The present invention also relates to methods of inhibiting
secretion of TNF-.alpha. in a subject comprising administering a
composition comprising a vasoactive intestinal peptide (VIP) analog
to a subject, wherein said analog comprises an .alpha.-amino acid
and at least one .beta.-amino acid. In some embodiments, the method
comprises administering the composition comprising any of the
percentages of .beta.-amino acids.
[0209] The present invention is also directed towards kits
comprising any of the aforementioned compositions or pharmaceutical
compositions comprising a secretin analog, wherein the secretin
analog comprises an .alpha.-amino acid and at least one
.beta.-amino The present invention is directed toward kits
comprising any of the aforementioned compositions or pharmaceutical
compositions comprising a VIP analog, wherein the VIP analog
comprises an .alpha.-amino acid and at least on .beta.-amino acid.
In some embodiments, the kit further comprises a vehicle for
administration of the composition.
[0210] The present invention also relates to methods of identifying
a modulator of human receptor activity comprising:
[0211] a) contacting a human receptor with a secretin analog,
wherein the analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid;
[0212] b) measuring the association of the secretin analog to the
human receptor in the presence and absence of an unknown compound;
and
[0213] c) comparing the rate of association of the secretin analog
to the human receptor in the presence of an unknown compound to the
rate of association of the secretin analog to the human receptor in
the absence of an unknown compound.
[0214] The present invention also relates to methods of identifying
a modulator of animal receptor activity comprising:
[0215] a) contacting an animal receptor with a secretin analog,
wherein the analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid;
[0216] b) measuring the association of the secretin analog to the
animal receptor in the presence and absence of an unknown compound;
and
[0217] c) comparing the rate of association of the secretin analog
to the animal receptor in the presence of an unknown compound to
the rate of association of the secretin analog to the animal
receptor in the absence of an unknown compound.
[0218] The present invention also relates to methods of identifying
a modulator of human secretin receptor activity comprising:
[0219] a) contacting a human secretin receptor with a secretin
analog, wherein the analog comprises an .alpha.-amino acid and at
least one .beta.-amino acid;
[0220] b) measuring the association of the secretin analog to the
human secretin receptor in the presence and absence of an unknown
compound; and
[0221] c) comparing the rate of association of the secretin analog
to the human secretin receptor in the presence of an unknown
compound to the rate of association of the secretin analog to the
human secretin receptor in the absence of an unknown compound.
[0222] The present invention also relates to methods of identifying
a modulator of human VIP receptor activity comprising:
[0223] a) contacting a human VIP receptor with the VIP analog,
wherein the analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid;
[0224] b) measuring the association of the VIP analog to the human
VIP receptor in the presence and absence of an unknown compound;
and
[0225] c) comparing the rate of association of the VIP analog to
the human VIP receptor in the presence of an unknown compound to
the rate of association of the VIP analog to the human VIP receptor
in the absence of an unknown compound.
BRIEF DESCRIPTION OF DRAWINGS
[0226] FIG. 1 shows MALDI-TOF data of a purified VIP analogue which
illustrates the expected mass (within a reasonable tolerance) of
both singly charged and doubly charged species of the analogue
after chemical synthesis, cleavage from resin, and subsequent
purification of the analogue through a C18 HPLC column.
[0227] FIG. 2 presents circular dichroism data of a VIP analogue
diluted in a 10 mM sodium phosphate buffer at pH of 7.5. The signal
exhibited for the structure of the VIP analogue is similar to
previously characterized .alpha.-amino acid/.beta. amino acid
peptides of similar backbone length and concentration, which
indicates a substantial helical content (Home et. al., J. Am. Chem.
Soc., 2007, 129 (14), pp 4178-4180; Home et. al. PNAS, Sep. 1,
2009, vol. 106, no. 35, 14751-14756).
[0228] FIG. 3 illustrates in vitro functional EC.sub.50 data of a
VIP analogue tested in the presence of VIPR1 (VPAC.sub.1) or VIPR2
(VPAC.sub.2) receptors as compared to the binding of wild-type VIP
protein to the same receptors. The data show that the analogue
achieves full activation of VIPR1 (.about.100%, relative to maximum
activation), but has an EC.sub.50 at a concentration higher than
the EC.sub.50 of wild-type VIP protein.
[0229] FIG. 4 illustrates data from an in vitro antagonist
inhibition assay in which competition for VIPR1 (VPAC.sub.1) or
VIPR2 (VPAC.sub.2) was measured by the amount of VIP analogue
capable of inhibiting the association of wild-type VIP to its
receptors.
[0230] FIG. 5 illustrates helical wheel diagrams of repeating
patterns of .alpha.- or .beta.-amino acids residues in alignment
along one longitudinal axis of a folded molecular structure from
N-terminus to C-terminus when the unnatural polypeptides adopt a
helical conformation, where the position of .beta.-amino acids are
represented by solid dots.
[0231] FIG. 6 illustrates a helical wheel diagram of the predicted
.alpha.-helical portion of VIP polypeptide, positions 10-28.
[0232] FIG. 7 illustrates multiple VIP analog sequences and their
corresponding helical wheel diagrams, where the position of
.beta.-amino acids are represented by solid dots.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0233] Various terms relating to the methods and other aspects of
the present invention are used throughout the specification and
claims. Such terms are to be given their ordinary meaning in the
art unless otherwise indicated. Other specifically defined terms
are to be construed in a manner consistent with the definition
provided herein.
[0234] As used in this specification and the appended claims, the
singular forms "a," "an," and "the" include plural referents unless
the content clearly dictates otherwise.
[0235] The term "about" as used herein when referring to a
measurable value such as an amount, a temporal duration, and the
like, is meant to encompass variations of .+-.20%, .+-.10%, .+-.5%,
.+-.1%, or .+-.0.1% from the specified value, as such variations
are appropriate to perform the disclosed methods.
[0236] The term "active state" refers to the conformation or set of
conformations of a polypeptide that allows functional domain or
domains of the polypeptide to associate or disassociate with
another compound, macromolecule, or ligand. In some embodiments,
the association or disassociation of the polypeptide with another
compound, macromolecule, or ligand may propagate or inhibit a
biologic signal.
[0237] The terms "amino acid" refer to a molecule containing both
an amino group and a carboxyl group bound to a carbon which is
designated the .alpha.-carbon. Suitable amino acids include,
without limitation, both the D- and L-isomers of the
naturally-occurring amino acids, as well as non-naturally occurring
amino acids prepared by organic synthesis or other metabolic
routes. in some embodiments, a single "amino acid" might have
multiple sidechain moieties, as available per an extended aliphatic
or aromatic backbone scaffold. Unless the context specifically
indicates otherwise, the term amino acid, as used herein, is
intended to include amino acid analogs.
[0238] The term "analog" refers to any polypeptide comprising at
least one .alpha.-amino acid and at least one .beta.-amino acid
residue, wherein the polypeptide is structurally similar to a
naturally occurring full-length protein and shares the biochemical
or biological activity of the naturally occurring full-length
protein upon which the analog is based. In some embodiments, an
analog is any polypeptide comprising at least one .beta.-amino acid
residue, wherein the polypeptide is structurally similar to a
naturally occurring full-length protein and shares the biochemical
or biological activity of the naturally occurring full-length
protein upon which the analog is based and wherein the addition of
one or more .beta.-amino acid residues constrains an alpha helical
structure in the polypeptide. In some embodiments, an analog is any
polypeptide comprising at least one .beta.-amino acid residue,
wherein the polypeptide is structurally similar to a naturally
occurring full-length protein and shares the biochemical or
biological activity of the naturally occurring full-length protein
upon which the analog is based. In some embodiments, the
non-natural amino acid residue is a monomer of an aliphatic
polypeptide. In some embodiments the aliphatic analogs are chosen
from oligoureas, azapeptides, pyrrolinones,
.alpha.-aminoxy-peptides, and sugar-based peptides. In some
embodiments, the composition comprises a non-natural .beta.-amino
acid. In some embodiments, the analog is a fragment of the
full-length protein upon which the analog is based. In some
embodiments, fragments are from about 5 to about 75 amino acids in
length as compared to the naturally occurring, fully translated and
fully processed protein sequences. In some embodiments, the analogs
comprise a fragment of a naturally translated full-length protein
that induces the biochemical or biological activity of a biological
pathway of a subject at a level equivalent to or increased as
compared to the activity induced by a naturally occurring
full-length protein upon which the analog is derived. In some
embodiments, the analog is a truncated polypeptide as compared to
the full-length, naturally translated or naturally occurring
polypeptide upon which the truncated polypeptide is derived. In
some embodiments, the analog is a synthetic polypeptide, wherein at
least one of the amino acid residues of the polypeptide comprises
at least one non-natural side chain. In some embodiments, the
analogs of the invention comprise at least one non-natural amino
acid chosen from one of the following structures aminoisobutyric
acid, 3-Aminobutyric acid, and 2-hydroxy-4-(4-nitrophenyl)butyric
acid. In some embodiments, the analog has a polypeptide backbone of
identical length and similar homology to the polypeptides disclosed
in Tables 1, 2, 3, and/or 4. In some embodiments, the analog is
about 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% homologous to at
least one of the polypeptides disclosed in Tables 1, 2, 3, and/or
4. In some embodiments, the analog is an agonist or antagonist of
one or more of the following receptors: VPAC1, VPAC2, or PAC1. In
some embodiments, the analog is a fragment of one of the
polypeptides disclosed in Tables 1, 2, 3, and 4 and shares the same
or improved biological or biochemical activity as compared to the
biological or biochemical activity of the polypeptides disclosed in
Tables 1, 2, 3, and/or 4 upon which the analog amino acid sequence
is derived. In some embodiments, the analog is an agonist or
antagonist of the receptor of the the full-length, naturally
translated or naturally occurring polypeptide upon which the amino
acid sequence of the agonist or antagonist is derived. In some
embodiments, the analog is an agonist or antagonist of the receptor
of the polypeptides disclosed in Tables 1, 2, 3, and/or 4. In such
embodiments, the amino acid sequence of the agonists or antagonists
are derived from the amino acid sequence of the the polypeptides
disclosed in Tables 1, 2, 3, and/or 4. In some embodiments the
analog of the present invention is modified by a bioactive lipid
moiety on at least one amino acid residue of the analog. In such
embodiments, the lipid moieties may be chosen from the following
lipid molecules: LPA, progesterone, prostanoids, S1P, LPA,
cannabinoids, 2-arachidonylglycerol. In some embodiments, the side
chain or terminal end of the amino acid residues of the
polypeptides disclosed in Tables 1, 2, 3, and/or 4 may be modified
with the bioreactive lipid moieties. In some embodiments, the
analogs of the present invention are derived from one of the
following sequences:
TABLE-US-00001 (SEQ ID NO: 6)
HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH.sub.2; (SEQ ID NO: 5)
HSDGIFTDSYSRYRKQMAVKKYLAAVL-NH.sub.2; (SEQ ID NO: 9)
HSDGTFTSELSRLRDSARLQRLLQGLV-NH.sub.2; (SEQ ID NO: 1335)
HSDGTFTSDYSKYLDSRRAQDFVQWLMNT-NH.sub.2; (SEQ ID NO: 7)
HADGVFTSDFSKLLGQLSAKKYLESLM-NH.sub.2
[0239] The term ".alpha.-amino acid" refers to any and all natural
and unnatural .alpha.-amino acids and their respective residues
(i.e., the form of the amino acid when incorporated into a
polypeptide molecule), without limitation. In some embodiments,
".alpha.-amino acid" explicitly encompasses the conventional and
well-known naturally occurring amino acids, as well as all
synthetic variations, derivatives, and analogs thereof. In some
embodiments, ".alpha.-amino acid" means alanine, arginine,
asparagine, aspartic acid, cysteine, glutamine, glutamic acid,
glycine, histidine, isoleucine, leucine, lysine, methionine,
phenylalanine, proline, serine, threonine, tryptophan, tyrosine,
and/or valine. In some embodiments, .alpha.-amino acids also
include analogs such as N-methylated .alpha.-amino acids,
hydroxylated .alpha.-amino acids, and aminoxy acids. In some
embodiments, .alpha.-amino refers to include N-alkyl .alpha.-amino
acids (such as N-methyl glycine), hydroxylysine, 3-hydroxyproline,
4-hydroxyproline, nor-valine, nor-leucine, and ornithine.
[0240] The terms ".beta.-amino acid" and ".beta.-amino acid
residue" refer to any and all .beta.-amino acids and their
respective residues (i.e., the form of the amino acid when
incorporated into a polypeptide molecule), without limitation. In
some embodiments, the terms ".beta.-amino acid" refers to those
.beta.-amino acids described in U.S. Pat. No. 6,060,585, issued May
9, 2000, incorporated herein by reference, and those described in
allowed U.S. Pat. No. 6,683,154, issued Jan. 27, 2004; U.S. Pat.
No. 6,710,186, issued Mar. 23, 2004; and U.S. Pat. No. 6,727,368,
issued Apr. 27, 2004, all of which are incorporated herein by
reference. Further still, cyclic imino carboxylic acids and
gem-di-substituted cyclic imino carboxylic acids (both of which are
a type of cyclically-constrained .beta.-amino acid) may also be
used in the invention. In some embodiments, the term ".beta.-amino
acid" refers to residues disclosed in U.S. Pat. No. 6,958,384,
issued Oct. 25, 2005, incorporated herein by reference. Further
still, these .beta.-residues may also take the form of the
gem-di-substituted cyclic amino acids disclosed in U.S. Pat. No.
6,710,186, incorporated herein by reference. In some embodiments,
the terms ".beta.-amino acid" refers to .beta.-homo amino acids. In
some embodiments the .beta.-amino acids refers to the selection of
an amino acid chosen from the following:
##STR00001##
R.sup.1 is selected from the group consisting hydrogen and an amino
protecting group; R.sup.2 is selected from the group consisting of
hydrogen and a carboxy protecting group; and when R.sup.3 is bonded
to a carbon atom, R.sup.3 is selected from the group consisting of
hydrogen, hydroxy, linear or branched C.sub.1-C.sub.6-alkyl,
alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic
heteroaryl having up to 5 heteroatoms selected from N, O, and S;
mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic
heteroaryl-C.sub.1-C.sub.6-alkyl, --(CH.sub.2).sub.n+1, --OR.sup.4,
--(CH.sub.2).sub.n+1--SR.sup.4,
--(CH.sub.2).sub.n+1--S(.dbd.O)--CH.sub.2--R.sup.4,
--(CH.sub.2).sub.n+1--S(.dbd.O).sub.2--CH.sub.2--R.sup.4,
--(CH.sub.2).sub.n+1--NR.sup.4R.sup.4,
--(CH.sub.2).sub.n+1--NHC(.dbd.O)R.sup.4,
--(CH.sub.2).sub.n+1--NHS(.dbd.O).sub.2--CH.sub.2--R.sup.4,
--(CH.sub.2).sub.n+1--O--(CH.sub.2).sub.m--R.sup.5,
--(CH.sub.2).sub.n+1--S--(CH.sub.2).sub.mR.sup.5,
--(CH.sub.2).sub.n+1--S(.dbd.O)--(CH.sub.2).sub.m--R.sup.5,
--(CH.sub.2).sub.n+1--S(.dbd.O).sub.2--(CH.sub.2).sub.m--R.sup.5,
--(CH.sub.2).sub.n+1--NH-(CH.sub.2).sub.m--R.sup.5,
--(CH.sub.2).sub.n+1--N--{(CH.sub.2).sub.m--R.sup.5}.sub.2,
--(CH.sub.2).sub.n+1--NHC(.dbd.O)--(CH.sub.2).sub.n+1--R.sup.5, and
--(CH.sub.2).sub.n+1--NHS(.dbd.O).sub.2--(CH.sub.2).sub.m--R.sup.5;
wherein each R.sup.4 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl, alkenyl, or alkynyl;
mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to S
heteroatoms selected from N, O, and S; mono- or bicyclic
aryl-C.sub.1-C.sub.6alkyl, mono- or bicyclic
heteroaryl-C.sub.1-C.sub.6alkyl; and wherein R.sup.5 is selected
from the group consisting of hydroxy, C.sub.1-C.sub.6alkyloxy,
aryloxy, heteroaryloxy, thio, C.sub.1-C.sub.6alkylthio,
C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl,
arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio,
heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or
di-C.sub.1-C.sub.6alkylamino, mono- or diarylamino, mono- or
diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino,
N-aryl-N-heteroarylamino, aryl-C.sub.1-C.sub.6alkylamino,
carboxylic acid, carboxamide, mono- or
di-C.sub.1-C.sub.6alkylcarboxamide, mono- or diarylcarboxamide,
mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide,
N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide,
sulfonic acid, sulfonamide, mono- or
di-C.sub.1-C.sub.6alkylsulfonamide, mono- or diarylsulfonamide,
mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide,
N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide,
urea; mono- di- or tri-substituted urea, wherein the substituent(s)
is selected from the group consisting of C.sub.1-C.sub.6alkyl,
aryl, heteroaryl; O-alkylurethane, O-arylurethane, and
O-heteroarylurethane; and m is an integer of from 2-6 and n is an
integer of from 0-6; and when R.sup.3 is bonded to a nitrogen atom,
R.sup.3 is independently selected from the group consisting of
those listed above for when R.sup.3 is attached to a carbon atom,
and further selected from the group consisting of
--S(.dbd.O).sub.2--CH.sub.2--R.sup.4,
--C(.dbd.O)--R.sup.4--S(.dbd.O).sub.2--(CH.sub.2).sub.mR.sup.5, and
--C(.dbd.O)--(CH.sub.2).sub.n+1--R.sup.5; wherein R.sup.4 and
R.sup.5 are as defined hereinabove, and m is an integer of from 2-6
and n is an integer of from 0-6; provided that when the
.beta.-amino acid is of formula R.sup.3 is not hydrogen; racemic
mixtures thereof, isolated or enriched enantiomers thereof;
isolated or enriched diastereomers thereof; and salts thereof. In
some embodiments the .beta.-amino acids refers to the selection of
an amino acid chosen from the following:
##STR00002##
In some embodiments the .beta.-amino acids refers to the following
formula:
##STR00003##
In some embodiments the .beta.-amino acids refers to the following
formula:
##STR00004##
wherein the NH.sub.2 and/or COOH groups are replaced with
functional peptide bonds.
[0241] In some embodiments the term ".beta.-amino acid" refers
to:
##STR00005## [0242] wherein X and Y combined, together with the
carbon atoms to which they are bonded, define a substituted or
unsubstituted C.sub.4-C.sub.8 cycloalkyl, cycloalkenyl or
heterocyclic ring having one or more nitrogen atoms as the sole
heteroatom; [0243] the substituents on carbon atoms of the rings
being independently selected from the group consisting of linear or
branched C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl; mono- or
bicyclic aryl, mono- or bicyclic heteroaryl having up to 5
heteroatoms selected from N, O, and S; mono- or bicyclic
aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic
heteroaryl-C.sub.1-C.sub.6-alkyl, --(CH.sub.2).sub.n+1--OR.sup.4,
--(CH.sub.2).sub.n+1--SR.sup.4,
--(CH.sub.2).sub.n+1--S(.dbd.O)--CH.sub.2--R.sup.4,
--(CH.sub.2).sub.n+1--S(.dbd.O).sub.2--CH.sub.2--R.sup.4,
--(CH.sub.2).sub.n+1--NR.sup.4R.sup.4,
--(CH.sub.2).sub.n+1--NHC(.dbd.O)R.sup.4,
--(CH.sub.2).sub.n+1--NHS(.dbd.O).sub.2--CH.sub.2--R.sup.4,
--(CH.sub.2).sub.n+1--O--(CH.sub.2).sub.m--R.sup.5,
--(CH.sub.2).sub.n+1--S--(CH.sub.2).sub.m--R.sup.5,
--(CH.sub.2).sub.n+1--S(.dbd.O)--(CH.sub.2).sub.m--R.sup.5,
--(CH.sub.2).sub.n+1--S(.dbd.O).sub.2--(CH.sub.2).sub.m--R.sup.5,
--(CH.sub.2).sub.n+1--NH--(CH.sub.2).sub.m--R.sup.5,
--(CH.sub.2).sub.n+1--N--{(CH.sub.2).sub.m--R.sup.5}.sub.2,
--(CH.sub.2).sub.n+1--NHC(.dbd.O)--(CH.sub.2).sub.n+1--R.sup.5, and
(CH.sub.2).sub.n+1--NHS(.dbd.O).sub.2--(CH.sub.2).sub.m--R.sup.5;
[0244] wherein R.sup.4 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl;
mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5
heteroatoms selected from N, O, and S; mono- or bicyclic
aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic
heteroaryl-C.sub.1-C.sub.6-alkyl; and [0245] wherein R.sup.5 is
selected from the group consisting of hydroxy,
C.sub.1-C.sub.6-alkyloxy, aryloxy, heteroaryloxy, thio,
C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, arylthio, arylsulfinyl,
arylsulfonyl, heteroarylthio, heteroarylsulfinyl,
heteroarylsulfonyl, amino, mono- or di-C.sub.1-C.sub.6-alkylamino,
mono- or diarylamino, mono- or diheteroarylamino,
N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino,
N-aryl-N-heteroarylamino, aryl-C.sub.1-C.sub.6-alkylamino,
carboxylic acid, carboxamide, mono- or
di-C.sub.1-C.sub.6-alkylcarboxamide, mono- or diarylcarboxamide,
mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide,
N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide,
sulfonic acid, sulfonamide, mono- or
di-C.sub.1-C.sub.6-alkylsulfonamide, mono- or diarylsulfonamide,
mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide,
N-alkyl-N-heteroaryl-sulfonamide, N-aryl-N-heteroarylsulfonamide,
urea; mono- di- or tri-substituted urea, wherein the substituent(s)
is selected from the group consisting of C.sub.1-C.sub.6-alkyl,
aryl, heteroaryl; O-alkylurethane, O-arylurethane, and
O-heteroarylurethane; and [0246] m is an integer of from 2-6 and n
is an integer of from 0-6; [0247] the substituents on heteroatoms
of the ring being independently selected from the group consisting
of
--S(.dbd.O).sup.2--CH.sub.2--R.sup.4--C(.dbd.O)--R.sup.4--S(.dbd.O).sub.2-
--(CH.sub.2).sub.m--R.sup.5, and
--C(.dbd.O)--(CH.sub.2).sub.n+1--R.sup.5; wherein R.sup.4 and
R.sup.5 are as defined hereinabove, and m is an integer of from 2-6
and n is an integer of from 0-6; [0248] provided that when X &
Y together with the carbons to which they are bonded define a five-
or six-membered cycloalkyl or a five-membered heterocyclic ring
having one nitrogen as the sole heteroatom, and the nitrogen is
bonded to a carbon atom adjacent to the carboxy carbon of Formula
I, the cycloalkyl or heterocyclic ring is substituted; [0249]
R.sup.1 is selected from the group consisting hydrogen and an amino
protecting group; [0250] R.sup.2 is selected. from the group
consisting of hydrogen and a carboxy protecting group; [0251]
racemic mixtures thereof, isolated or enriched enantiomers thereof;
isolated or enriched diastereomers thereof; [0252] and salts
thereof.
[0253] In some embodiments the term ".beta.-amino acid" refers to
selection of an amino acid chosen from the following: .beta..sup.3
or .beta..sup.2. In some embodiments the term ".beta.-amino acid"
refers to selection of an amino acid chosen from the following:
##STR00006##
wherein R, R', R'', and R''' are any substituent.
[0254] In some embodiments the term ".beta.-amino acid" refers to
selection of an amino acid chosen from the following:
##STR00007##
wherein R, R', R'', and R''' is an amine, hydroxy, hydroxyl,
carbonyl, H, .dbd.O, --OH, --COOH, --N, --CH.sub.3, --CH.sub.2--X,
halo, aryl, arylalkoxy, arylalkyl, alkynyl, alkenyl, alkylene,
alkyl, alkylhalo, arylamido, alkylheterocycle, alkylamino,
alkylguanidino, alkanol, alkylcarboxy, cycloalkyl, heteroaryl,
heteroarylalkyl, heteroarylalkoxy, or heterocyclyl; wherein X is
any substituent.
[0255] In some embodiments the term ".beta.-amino acid" refers to
selection of an amino acid chosen from the following:
##STR00008##
wherein R, R', R'', and R''' are any substituent, provided that:
(i) R is not O, N, or halo when the R is in a .beta..sup.3-residue,
(ii) R and R' are not O, N, or halo when the R and R' are in a
.beta..sup.3,3-residue; (iii) R is not O, N, or halo when the R is
in a .beta..sup., 3-residue; (iv) R and R' are not O, N, or halo
when the R and R' are in a .beta..sup.2,3,3-residue; (v) R'' is not
O, N, or halo when the R'' is in a .beta..sup.2,2,3-residue; (vi) R
and R' are not O, N, or halo when the R and R' are in a
.beta..sup.2,2,3,3-residue.
[0256] In some embodiments the term ".beta.-amino acid" refers to
selection of an amino acid chosen from the following:
##STR00009##
wherein R, R', R'', and R''' is an amine, hydroxy, hydroxyl,
carbonyl, H, .dbd.O, --OH, --COOH, --N, --CH.sub.3, --CH.sub.2--X,
halo, aryl, arylalkoxy, arylalkyl, alkynyl, alkenyl, alkylene,
alkyl, alkylhalo, arylamido, alkylheterocycle, alkylamino,
alkylguanidino, alkanol, alkylcarboxy, cycloalkyl, heteroaryl,
heteroarylalkyl, heteroarylalkoxy, or heterocyclyl; wherein X is
any substituent; , provided that: (i) R is not O, N, or halo when
the R is in a .beta..sup.3-residue, (ii) R and R' are not O, N, or
halo when the R and R' are in a .beta..sup.3,3-residue; (iii) R is
not O, N, or halo when the R is in a .beta..sup.2,3-residue; (iv) R
and R' are not O, N, or halo when the R and R' are in a
.beta..sup.2,3,3-residue; (v) R'' is not O, N, or halo when the R''
is in a .beta..sup.2,2,3-residue; (vi) R and R' are not O, N, or
halo when the R and R' are in a .beta..sup.2,2,3,3-residue.
[0257] A "cyclic" beta-amino acid is acid is an amino acid of the
following formula I:
##STR00010##
wherein X and Y combined, together with the carbon atoms to which
they are bonded, define a substituted or unsubstituted
C.sub.4-C.sub.8 cycloalkyl or cycloalkenyl group; wherein
substituents on carbon atoms of the rings being independently
selected from the group consisting of linear or branched
C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl,
mono- or bicyclic heteroaryl having up to 5 heteroatoms selected
from N, O, and S; mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl,
mono- or bicyclic heteroaryl-C.sub.1-C.sub.6-alkyl,
--(CH2).sub.n+1-OR.sub.4, --(CH2).sub.n+1-SR.sub.4,
--(CH.sub.2).sub.n+1--S(.dbd.O)--CH.sub.2--R.sub.4,
--(CH.sub.2).sub.n+1--S(.dbd.O).sub.2--CH.sub.2--R.sub.4,
--(CH.sub.2).sub.n+1--NR.sub.4R.sub.4,
--(CH.sub.2).sub.n+1--NHC(.dbd.O)R.sub.4,
--(CH.sub.2).sub.n+1--NHS(.dbd.O).sub.2--CH.sub.2--R.sub.4,
--(CH.sub.2).sub.n+1--O--(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--S--(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--S(.dbd.O)--(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--S(.dbd.O).sub.2--(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--NH--(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--N--{(CH.sub.2).sub.m--R.sub.5}.sub.2,
--(CH.sub.2).sub.n+1--NHC(.dbd.O)--(CH.sub.2).sub.n+1--R.sub.5, and
--(CH.sub.2).sub.n+1--NHS(.dbd.O).sub.2--(CH.sub.2).sub.m--R.sub.5;
wherein R.sub.4 is independently selected from the group consisting
of hydrogen, C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl; mono- or
bicyclic aryl, mono- or bicyclic heteroaryl having up to 5
heteroatoms selected from N, O, and S; mono- or bicyclic
aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic
heteroaryl-C.sub.1-C.sub.6-alkyl; and wherein R.sub.5 is selected
from the group consisting of hydroxy, C.sub.1-C.sub.6-alkyloxy,
aryloxy, heteroaryloxy, thio, C.sub.1-C.sub.6-alkylthio,
C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl,
arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio,
heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or
di-C.sub.1-C.sub.6-alkylamino, mono- or diarylamino, mono- or
diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino,
N-aryl-N-heteroarylamino, aryl-C.sub.1-C.sub.6-alkylamino,
carboxylic acid, carboxamide, mono- or
di-C.sub.1-C.sub.6-alkylcarboxamide, mono- or diarylcarboxamide,
mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide,
N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide,
sulfonic acid, sulfonamide, mono- or
di-C.sub.1-C.sub.6-alkylsulfonamide, mono- or diarylsulfonamide,
mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide,
N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide,
urea; mono- di- or tri-substituted urea, wherein the substituent(s)
is selected from the group consisting of C.sub.1-C.sub.6-alkyl,
aryl, heteroaryl; O-alkylurethane, O-arylurethane, and
O-heteroarylurethane; and m is an integer of from 2-6 and n is an
integer of from 0-6; the substituents on heteroatoms of the ring
being independently selected from the group consisting of
--S(.dbd.O).sub.2--CH.sub.2--R.sub.4--C(.dbd.O)--R.sub.4--S(.dbd.O).sub.2-
--(CH.sub.2).sub.m--R.sub.5, and
--C(.dbd.O)--(CH.sub.2).sub.n+1--R.sub.5; wherein R.sub.4 and
R.sub.5 are as defined hereinabove, and m is an integer of from 2-6
and n is an integer between 0 and 6; provided that when X and Y
together with the carbons to which they are bonded define a five-
or six-membered cycloalkyl or a five-membered heterocyclic ring
having one nitrogen as the sole heteroatom, and the nitrogen is
bonded to a carbon atom adjacent to the carboxy carbon of Formula
I, the cycloalkyl or heterocyclic ring is substituted; R.sub.1 is
selected from the group consisting hydrogen and an amino protecting
group; R.sub.2 is selected from the group consisting of hydrogen
and a carboxy protecting group; racemic mixtures thereof, isolated
or enriched enantiomers thereof; isolated or enriched diastereomers
thereof; and salts thereof.
[0258] A "heterocyclic" beta-amino acid is an amino acid of formula
I, wherein X and Y combined, together with the carbon atoms to
which they are bonded, define a substituted or unsubstituted
C.sub.4-C.sub.8 cyclically or cycloalkenyl group having one or more
nitrogen, oxygen or sulfur atoms as a heteroatom(s) within the
cycloalkyl or cycloalkenyl group; wherein substituents on carbon
atoms of the cycloalkyl or cycloalkenyl rings being independently
selected from the group consisting of linear or branched
C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl,
mono- or bicyclic heteroaryl having up to 5 heteroatoms selected
from N, O, and S; mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl,
mono- or bicyclic heteroaryl-C.sub.1-C.sub.6-alkyl,
--(CH.sub.2).sub.n+1--OR.sub.4, --(CH2).sub.n+1-SR.sub.4,
--(CH.sub.2).sub.n+1--S(.dbd.O)--CH.sub.2--R.sub.4,
--(CH.sub.2).sub.n+1--S(.dbd.O).sub.2CH.sub.2--R.sub.4,
--(CH.sub.2).sub.n+1--NR.sub.4R.sub.4,
--(CH.sub.2).sub.n+1--NHC(.dbd.O)R.sub.4,
--(CH.sub.2).sub.n+1--NHS(.dbd.O).sub.2--CH.sub.2--R.sub.4,
--(CH.sub.2).sub.n+1--O--(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--S--(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--S(.dbd.O)(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--S(.dbd.O).sub.2--(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--NH--(CH.sub.2).sub.m--R.sub.5,
--(CH.sub.2).sub.n+1--N--{(CH.sub.2).sub.m--R.sub.5}.sub.2,
--(CH.sub.2).sub.n+1--NHC(.dbd.O)--(CH.sub.2).sub.n+1--R.sub.5, and
--(CH.sub.2).sub.n+1--NHS(.dbd.O).sub.2--(CH.sub.2).sub.m--R.sub.5;
wherein R.sub.4 is independently selected from the group consisting
of hydrogen, C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl; mono- or
bicyclic aryl, mono- or bicyclic heteroaryl having up to 5
heteroatoms selected from N, O, and S; mono- or bicyclic
aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic
heteroaryl-C.sub.1-C.sub.6-alkyl; and wherein R.sub.5 is selected
from the group consisting of hydroxy, C.sub.1-C.sub.6-alkyloxy,
aryloxy, heteroaryloxy, thio, C.sub.1-C.sub.6-alkylthio,
C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl,
arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio,
heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or
di-C.sub.1-C.sub.6-alkylamino, mono- or diarylamino, mono- or
diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino,
N-aryl-N-heteroarylamino, aryl-C.sub.1-C.sub.6-alkylamino,
carboxylic acid, carboxamide, mono- or
di-C.sub.1-C.sub.6-alkylcarboxamide, mono- or diarylcarboxamide,
mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide,
N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide,
sulfonic acid, sulfonamide, mono- or
di-C.sub.1-C.sub.6-alkylsulfonamide, mono- or diarylsulfonamide,
mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide,
N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide,
urea; mono- di- or tri-substituted urea, wherein the substituent(s)
is selected from the group consisting of C.sub.1-C.sub.6-alkyl,
aryl, heteroaryl; O-alkylurethane, O-arylurethane, and
O-heteroarylurethane; and m is an integer of from 2-6 and n is an
integer of from 0-6; the substituents on heteroatoms of the ring
being independently selected from the group consisting of
--S(.dbd.O).sub.2--CH.sub.2--R.sub.4--C(.dbd.O)--R.sub.4--S(.dbd.O).sub.2-
--(CH.sub.2).sub.m--R.sub.5, and
--C(.dbd.O)--(CH.sub.2).sub.n+1--R.sub.5; wherein R.sub.4 and
R.sub.5 are as defined hereinabove, and m is an integer of from 2-6
and n is an integer between 0 and 6; provided that when X and Y
together with the carbons to which they are bonded define a five-
or six-membered cycloalkyl or a five-membered heterocyclic ring
having one nitrogen as the sole heteroatom, and the nitrogen is
bonded to a carbon atom adjacent to the carboxy carbon of Formula
I, the cycloalkyl or heterocyclic ring is substituted; R.sub.1 is
selected from the group consisting hydrogen and an amino protecting
group; R2 is selected from the group consisting of hydrogen and a
carboxy protecting group; racemic mixtures thereof, isolated or
enriched enantiomers thereof; isolated or enriched diastereomers
thereof; and salts thereof.
[0259] In some embodiments, at least one of the .beta.-amino acid
residues in the analog is replaced with at least one .beta.-amino
acid residue that is cyclically constrained via a ring encompassing
its .beta..sup.2 and .beta..sup.3 carbon atoms. In another
embodiment of the invention, most or all of the inserted
.beta.-amino acid residues are cyclically constrained. In another
version of the invention, at least one of the .beta.-amino acid
residues is unsubstituted at its .beta..sup.2 and .beta..sup.3
carbon atoms. Alternatively, all of the .beta.-amino acid residues
may be substituted at their .beta..sup.2 and .beta..sup.3 carbon
atoms (with linear, branched or cyclic substituents). In some
embodiments, the cyclic substituents of the claimed invention
comprise side chains that are covalently bonded to the side chains
of other contiguous amino acids. In some embodiments, the cyclic
substituents of the claimed invention comprise side chains that are
covalently bonded to the side chains of other non-contiguous amino
acids. In some embodiments the cyclic substituents of the claimed
invention do not include side chains that are covalently bonded to
the side chains of other contiguous or non-contiguous amino acids.
In some embodiments the terms beta-3 or beta-2 amino acid refers to
.beta.3-homo .beta.2-homo amino acids.
[0260] A "conservative amino acid substitution" is one in which the
amino acid residue is replaced with an amino acid residue having a
similar side chain Families of amino acid residues having similar
side chains have been defined in the art. These families include
amino acids with basic side chains (e.g., K, R, H), acidic side
chains (e.g., D, E), uncharged polar side chains (e.g., G, N, Q, S,
T, Y, C, H), nonpolar side chains (e.g., G, A, V, L, I, P, F, M,
W), beta-branched side chains (e.g., T, V, I) and aromatic side
chains (e.g., Y, F, W, H). Thus, a predicted nonessential amino
acid residue in a VIP analog, for example, replaced with another
amino acid residue from the same side chain family. Other examples
of acceptable substitutions are substitutions based on isosteric
considerations (e.g. norleucine for methionine) or other properties
(e.g. 2-thienylalanine for phenylalanine).
[0261] As used herein, the term "derived from" in the context of
the relationship between a chemical structure or amino acid
sequence and a related chemical structure or related amino acid
sequence describes a chemical structure or amino acid sequence that
may be homologous to or structurally similar to the related
chemical structure or related amino acid sequence.
[0262] As used herein, the term "inflammatory disease" refers to
any disease, condition, or ailment that results from an immune
response or a pathogen infection, which in some instances may be
characterized by one or more of pain, swelling, and redness of a
tissue types. In some embodiments, inflammatory disease refers to
rheumatoid arthritis, Crohn's disease, sepsis, ulcerative colitis,
irritable bowel disease, chronic irritable bowel syndrome, and
allergies such as allergic rhinitis.
[0263] A "non-essential" amino acid residue is a residue that can
be altered from the wild-type sequence of a polypeptide (e.g., a
short domain of VIP) without abolishing or substantially altering
its essential biological or biochemical activity (e.g., receptor
binding or activation). An "essential" amino acid residue is a
residue that, when altered from the wild-type sequence of the
polypeptide, results in abolishing or substantially abolishing the
polypeptide's essential biological or biochemical activity.
[0264] A "non-natural side chain" is a modified or synthetic chain
of atoms joined by covalent bond to the .alpha.-carbon atom,
.beta.-carbon atom, or .gamma.-carbon atom which does not make up
the backbone of the polypeptide chain of amino acids. The natural
side chain, or R group, of of alanine is a methyl group. In some
embodiments, the non-natural side chain of the composition is a
methyl group in which on e or more of the hydrogen atoms is
replaced by a deuterium atom.
[0265] The term "polypeptide" encompasses two or more naturally or
non-naturally-occurring amino acids joined by a covalent bond
(e.g., an amide bond). Polypeptides as described herein include
full-length proteins (e.g., fully processed pro-proteins or
full-length synthetic polypeptides) as well as shorter amino acid
sequences (e.g., fragments of naturally-occurring proteins or
synthetic polypeptide fragments).
[0266] The term "salt" refers to acidic salts formed with inorganic
and/or organic acids, as well as basic salts formed with inorganic
and/or organic bases. Examples of these acids and bases are well
known to those of ordinary skill in the art. Such acid addition
salts will normally be pharmaceutically acceptable although salts
of non-pharmaceutically acceptable acids may be of utility in the
preparation and purification of the compound in question. Salts
include those formed from hydrochloric, hydrobromic, sulphuric,
phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic,
fumaric, maleic, methanesulphonic and benzenesulphonic acids.
[0267] In some embodiments, salts of the compositions comprising
either a secretin or VIP analog may be formed by reacting the free
base, or a salt, enantiomer or racemate thereof, with one or more
equivalents of the appropriate acid. In some embodiments,
pharmaceutical acceptable salts of the present invention refer to
analogs having at least one basic group or at least one basic
radical. In some embodiments, pharmaceutical acceptable salts of
the present invention comprise a free amino group, a free guanidino
group, a pyrazinyl radical, or a pyridyl radical that forms acid
addition salts. In some embodiments, the pharmaceutical acceptable
salts of the present invention refer to analogs that are acid
addition salts of the subject compounds with (for example)
inorganic acids, such as hydrochloric acid, sulfuric acid or a
phosphoric acid, or with suitable organic carboxylic or sulfonic
acids, for example aliphatic mono- or di-carboxylic acids, such as
trifluoroacetic acid, acetic acid, propionic acid, glycolic acid,
succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic
acid, tartaric acid, citric acid or oxalic acid, or amino acids
such as arginine or lysine, aromatic carboxylic acids, such as
benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxybenzoic acid,
salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic
carboxylic acids, such as mandelic acid or cinnamic acid,
heteroaromatic carboxylic acids, such as nicotinic acid or
isonicotinic acid, aliphatic sulfonic acids, such as methane-,
ethane- or 2-hydroxyethane-sulfonic acid, or aromatic sulfonic
acids, for example benzene-, p-toluene- or naphthalene-2-sulfonic
acid. When several basic groups are present mono- or poly-acid
addition salts may be formed. The reaction may be carried out in a
solvent or medium in which the salt is insoluble or in a solvent in
which the salt is soluble, for example, water, dioxane, ethanol,
tetrahydrofuran or diethyl ether, or a mixture of solvents, which
may be removed in vacuo or by freeze drying. The reaction may also
be a metathetical process or it may be carried out on an ion
exchange resin. In some embodiments, the salts may be those that
are physiologically tolerated by a patient. Salts according to the
present invention may be found in their anhydrous form or as in
hydrated crystalline form (i.e., complexed or crystallized with one
or more molecules of water).
[0268] The term "subject" is used throughout the specification to
describe an animal to whom treatment with the compositions
according to the present invention is provided or administered. For
treatment of those conditions which are specific for a specific
subject, such as a human being, the term "patient" may be
interchangeably used. In some instances in the description of the
present invention, the term "patient" will refer to human patients.
In some embodiments, the subject may be a mammal to whom the
present invention is provided or administered. In some embodiments,
the subject may be a non-human animal to whom the present invention
is provided or administered.
[0269] The term "soluble" or "water soluble" refers to solubility
that is higher than 1/100,000 (mg/ml). The solubility of a
substance, or solute, is the maximum mass of that substance that
can be dissolved completely in a specified mass of the solvent,
such as water. "Practically insoluble" or "insoluble," on the other
hand, refers to an aqueous solubility that is 1/10,000 (mg/ml) or
less. Water soluble or soluble substances include, for example,
polyethylene glycol. In some embodiments, the polypeptide of the
claimed invention may be bound by polyethylene glycol to better
solubilize the composition comprising the peptide.
[0270] The terms "treating" and "to treat", mean to alleviate
symptoms, eliminate the causation either on a temporary or
permanent basis, or to prevent or slow the appearance of symptoms.
The term "treatment" includes alleviation, elimination of causation
(temporary or permanent) of, or prevention of symptoms and
disorders associated with any condition. The treatment may be a
pre-treatment as well as a treatment at the onset of symptoms.
[0271] "Effective amount" refers to an amount of a compound,
material, or composition, as described herein effective to achieve
a particular biological result such as, but not limited to,
biological results disclosed, described, or exemplified herein.
Such results may include, but are not limited to, the effective
reduction of symptoms associated with any of the disease states
mentioned herein, as determined by any means suitable in the art.
The effective amount of the composition may be dependent on any
number of variables, including without limitation, the species,
breed, size, height, weight, age, overall health of the subject,
the type of formulation, the mode or manner or administration, the
type and/or severity of the particular condition being treated, or
the need to modulate the activity of the molecular pathway induced
by association of the analog to its receptor. The appropriate
effective amount can be routinely determined by those of skill in
the art using routine optimization techniques and the skilled and
informed judgment of the practitioner and other factors evident to
those skilled in the art. A therapeutically effective dose of the
analogs described herein may provide partial or complete biological
activity as compared to the biological activity induced by the
wild-type or naturally occurring polypeptides upon which the
analogs are derived. A therapeutically effective dose of the
analogs described herein may provide a sustained biochemical or
biological affect and/or an increased resistance to degradation
when placed in solution as compared with the normal affect observed
when the naturally occurring and fully processed translated protein
is administered to the same subject.
[0272] The term "fragment" refers to any analog of a naturally
occurring polypeptide disclosed herein that comprises at least 4
amino acids identical to the naturally occurring polypeptide upon
which the analog is based. The term "functional fragment" refers to
any fragment of any analog of a naturally occurring polypeptide
disclosed herein that comprises at least 4 amino acids identical to
the naturally occurring polypeptide upon which the analog is based
and shares the function of the naturally occurring polypeptide upon
which the analog is based. In some embodiments, the compositions or
pharmaceutical composition comprises an analog comprising at least
one .beta.-amino acid. wherein the analog is a fragment of VIP, a
secretin family member, an interleukin, or any of the polypeptides
disclosed in the instant application. In some embodiments, the
compositions or pharmaceutical composition comprises an analog
comprising at least one .beta.-amino acid, wherein the analog is a
fragment of VIP, a secretin family member, an interleukin, or any
of the polypeptides disclosed in the instant application and
wherein the fragment shares at least 4 contiguous amino acid
residues with the naturally occurring polypeptide upon which the
analog is based and wherein the fragment retains the biological
activity of the naturally occurring polypeptide upon which the
analog is based. In some embodiments, the VIP analog is a fragment
that comprises between about 1 to about 27 amino acids of the
naturally occurring VIP sequence. In some embodiments, the VIP
analog is a fragment that comprises between about 1 to about 26
amino acids of the naturally occurring VIP sequence. In some
embodiments, the VIP analog is a fragment that comprises between
about 1 to about 25 amino acids of the naturally occurring VIP
sequence. In some embodiments, the VIP analog is a fragment that
comprises between about 1 to about 24 amino acids of the naturally
occurring VIP sequence. In some embodiments, the VIP analog is a
fragment that comprises between about 1 to about 23 amino acids of
the naturally occurring VIP sequence. In some embodiments, the VIP
analog is a fragment that comprises between about 1 to about 22
amino acids of the naturally occurring VIP sequence. In some
embodiments, the VIP analog is a fragment that comprises between
about 1 to about 21 amino acids of the naturally occurring VIP
sequence. In some embodiments, the VIP analog is a fragment that
comprises between about 1 to about 20 amino acids of the naturally
occurring VIP sequence. In some embodiments, the VIP analog is a
fragment that comprises between about 1 to about 19 amino acids of
the naturally occurring VIP sequence. In some embodiments, the VIP
analog is a fragment that comprises between about 1 to about 18
amino acids of the naturally occurring VIP sequence. In some
embodiments, the VIP analog is a fragment that comprises between
about 1 to about 19 amino acids of the naturally occurring VIP
sequence. In some embodiments, the VIP analog is a fragment that
comprises between about 1 to about 17 amino acids of the naturally
occurring VIP sequence. In some embodiments, the VIP analog is a
fragment that comprises between about 1 to about 16 amino acids of
the naturally occurring VIP sequence. In some embodiments, the VIP
analog is a fragment that comprises between about 1 to about 15
amino acids of the naturally occurring VIP sequence. In some
embodiments, the VIP analog is a fragment that comprises between
about 1 to about 14 amino acids of the naturally occurring VIP
sequence. In some embodiments, the VIP analog is a fragment that
comprises between about 1 to about .beta. amino acids of the
naturally occurring VIP sequence. In some embodiments, the VIP
analog is a fragment that comprises between about 1 to about 12
amino acids of the naturally occurring VIP sequence. In some
embodiments, the VIP analog is a fragment that comprises between
about 1 to about 11 amino acids of the naturally occurring VIP
sequence. In some embodiments, the VIP analog is a fragment that
comprises between about 1 to about 10 amino acids of the naturally
occurring VIP sequence. In some embodiments, the VIP analog is a
fragment that comprises between about 1 to about 9 amino acids of
the naturally occurring VIP sequence. In some embodiments, the VIP
analog is a fragment of VIP that comprises between about 1 to about
8 amino acids of the naturally occurring VIP sequence. In some
embodiments, the VIP analog is a fragment that comprises between
about 1 to about 7 amino acids of the naturally occurring VIP
sequence. In some embodiments, the VIP analog is a fragment that
comprises between about 1 to about 6 amino acids of the naturally
occurring VIP sequence. In some embodiments, the VIP analog is a
fragment that comprises between about 1 to about 5 amino acids of
the naturally occurring
[0273] VIP sequence. In some embodiments, the VIP analog is a
fragment that comprises between about 1 to about 4 amino acids of
the naturally occurring VIP sequence. In some embodiments, the
analog is modified with at least one PEG molecule on at least one
of the non-natural amino acids.
[0274] The term "halo" or "halogen" refers to fluorine, chlorine,
bromine or iodine or a radical thereof.
[0275] The term "alkyl" refers to a hydrocarbon chain that is a
straight chain or branched chain, containing the indicated number
of carbon atoms. For example, C.sub.1-C.sub.10 indicates that the
group has from 1 to 10 (inclusive) carbon atoms in it. In the
absence of any numerical designation, "alkyl" is a chain (straight
or branched) having 1 to 20 (inclusive) carbon atoms in it. In some
embodiments the alkyl group is chosen from: C.sub.1-C.sub.10,
C.sub.2-C.sub.10, C.sub.3-C.sub.10, C.sub.4-C.sub.10,
C.sub.5-C.sub.10, C.sub.6-C.sub.10, C.sub.8-C.sub.10,
C.sub.9-C.sub.10, C.sub.1-C.sub.10, C.sub.1-C.sub.2,
C.sub.1-C.sub.3, C.sub.1-C.sub.4, C.sub.1-C.sub.5, C.sub.1-C.sub.6,
C.sub.1-C.sub.8, or C.sub.1-C.sub.9,
[0276] The term "alkylene" refers to a divalent alkyl (i.e.,
--R--).
[0277] The term "alkenyl" refers to a hydrocarbon chain that is a
straight chain or branched chain having one or more carbon-carbon
double bonds. The alkenyl moiety contains the indicated number of
carbon atoms. For example, C.sub.2-C.sub.10 indicates that the
group has from 2 to 10 (inclusive) carbon atoms in it. The term
"lower alkenyl" refers to a C.sub.2-C.sub.6 alkenyl chain. In the
absence of any numerical designation, "alkenyl" is a chain
(straight or branched) having 2 to 20 (inclusive) carbon atoms in
it.
[0278] The term "alkynyl" refers to a hydrocarbon chain that is a
straight chain or branched chain having one or more carbon-carbon
triple bonds. The alkynyl moiety contains the indicated number of
carbon atoms. For example, C.sub.2-C.sub.10 indicates that the
group has from 2 to 10 (inclusive) carbon atoms in it. The term
"lower alkynyl" refers to a C.sub.2-C.sub.6 alkynyl chain. In the
absence of any numerical designation, "alkynyl" is a chain
(straight or branched) having about 2 to about 20 (inclusive)
carbon atoms in it.
[0279] The term "aryl" refers to an aromatic ring system. In some
embodiments, the aryl group of the analog include substituents,
wherein 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 atoms of each ring are
substituted by a substituent. In some embodiments, the aryl group
refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring
system wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted
by a substituent. Examples of aryl groups include phenyl, naphthyl
and the like. The term "arylalkyl" or the term "aralkyl" refers to
alkyl substituted with an aryl. The term "arylalkoxy" refers to an
alkoxy substituted with aryl. "Arylalkyl" refers to an aryl group,
as defined above, wherein one of the aryl group's hydrogen atoms
has been replaced with an alkyl group, as defined above.
Representative examples of an arylalkyl group include, but are not
limited to, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,
2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl,
3-propylphenyl, 4-propylphenyl, 2-butylphenyl, 3-butylphenyl,
4-butylphenyl, 2-pentylphenyl, 3-pentylphenyl, 4-pentylphenyl,
2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl,
2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl,
2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl,
2-t-butylphenyl, 3-t-butylphenyl and 4-t-butylphenyl.
[0280] "Arylamido" refers to an aryl group, as defined above,
wherein one of the aryl group's hydrogen atoms has been replaced
with one or more --C(O)NH.sub.2 groups. Representative examples of
an arylamido group include 2-C(O)NH.sub.2-phenyl,
3-C(O)NH.sub.2-phenyl, 4-C(O)NH.sub.2-phenyl,
2-C(O)NH.sub.2-pyridyl, 3-C(O)NH.sub.2-pyridyl, and
4-C(O)NH.sub.2-pyridyl.
[0281] "Alkylheterocycle" refers to an alkyl group, as defined
above, wherein one of the alkyl group's hydrogen atoms has been
replaced with a heterocycle. Representative examples of an
alkylheterocyclo group include, but are not limited to,
--CH.sub.2CH.sub.2-morpholine, --CH.sub.2CH.sub.2piperidine,
--CH.sub.2CH.sub.2CH.sub.2-morpholine, and
--CH.sub.2CH.sub.2CH.sub.2-imidazole.
[0282] "Alkylamido" refers to an alkyl group, as defined above,
wherein one of the alkyl group's hydrogen atoms has been replaced
with a --C(O)NH.sub.2 group. Representative examples of an
alkylamido group include, but are not limited to,
--CH.sub.2C(O)NH.sub.2, --CH.sub.2CH.sub.2C(O)NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2C(O)NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)NH.sub.2,
--CH.sub.2CH(C(O)NH.sub.2)CH.sub.3,
--CH.sub.2CH(C(O)NH.sub.2)CH.sub.2CH.sub.3,
--CH(C(O)NH.sub.2)CH.sub.2CH.sub.3,
--C(CH.sub.3).sub.2CH.sub.2C(O)NH.sub.2,
--CH.sub.2CH.sub.2NHC(O)CH.sub.3,
--CH.sub.2CH.sub.2NHC(O)CH.sub.2CH.sub.3, and
--CH.sub.2CH.sub.2NHC(O)CH.dbd.CH.sub.2.
[0283] "Alkylamino" refers to an alkyl group, as defined above,
wherein one of the alkyl group's hydrogen atoms has been replaced
with a --NH.sub.2 group. Representative examples of an alkylamido
group include, but are not limited to --CH.sub.2NH.sub.2,
CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2.
[0284] "Alkylguanidino" refers to an alkyl group, as defined above,
wherein one of the alkyl group's hydrogen atoms has been replaced
with a --NH.sub.2(C.dbd.NH)NH.sub.2 group. Representative examples
of an alkylamido group include, but are not limited to
--CH.sub.2NH.sub.2(C.dbd.NH)NH.sub.2, CH.sub.2CH.sub.2
NH.sub.2(C.dbd.NH)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2
NH.sub.2(C.dbd.NH)NH.sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2
NH.sub.2(C.dbd.NH)NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2
NH.sub.2(C.dbd.NH)NH.sub.2. In some embodiments alkyl units can be
found on the N atom(s) of the alkylamino or alkylguanidino groups
(for example, --CH.sub.2NH(CH.sub.3),
CH.sub.2N(CH.sub.3).sub.2).
[0285] "Alkanol" refers to an alkyl group, as defined above,
wherein one of the alkyl group's hydrogen atoms has been replaced
with a hydroxyl group. Representative examples of an alkanol group
include, but are not limited to, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH(OH)CH.sub.3, --CH.sub.2CH(OH)CH.sub.2CH.sub.3,
--CH(OH)CH.sub.3 and --C(CH.sub.3).sub.2CH.sub.2OH.
[0286] "Alkylcarboxy" refers to an alkyl group, as defined above,
wherein one of the alkyl group's hydrogen atoms has been replaced
with a --COOH group. Representative examples of an alkylcarboxy
group include, but are not limited to, --CH.sub.2COOH,
--CH.sub.2CH.sub.2COOH, --CH.sub.2CH.sub.2CH.sub.2COOH,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2COOH, --CH.sub.2CH(COOH)CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2COOH,
--CH.sub.2CH(COOH)CH.sub.2CH.sub.3, --CH(COOH)CH.sub.2CH.sub.3 and
--C(CH.sub.3).sub.2CH.sub.2COOH.
[0287] The term "cycloalkyl" as employed herein includes saturated
and partially unsaturated cyclic hydrocarbon groups having 3 to 12
carbons, 3 to 8 carbons, or 3 to 6 carbons, wherein the cycloalkyl
group additionally is optionally substituted. Some cycloalkyl
groups include, without limitation, cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
and cyclooctyl.
[0288] The term "heteroaryl" refers to an aromatic 5-10 membered
monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic
ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms
if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms
selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9
heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic,
respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring are
substituted by a substituent. Examples of heteroaryl groups
include, but are not limited to, pyridyl, furyl or furanyl,
imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl,
quinolinyl, indolyl, thiazolyl, and the like.
[0289] The term "heteroarylalkyl" or the term "heteroaralkyl"
refers to an alkyl substituted with a heteroaryl. The term
"heteroarylalkoxy" refers to an alkoxy substituted with
heteroaryl.
[0290] The term "heterocyclyl" refers to a nonaromatic 5-8 membered
monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic
ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms
if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms
selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9
heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic,
respectively), wherein 0, 1, 2 or 3 atoms of each ring are
substituted by a substituent. Examples of heterocyclyl groups
include, but are not limited to, piperazinyl, pyrrolidinyl,
dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.
[0291] The term "substituent" refers to a group replacing a second
atom or group such as a hydrogen atom on any molecule, compound or
moiety. Suitable substituents include, without limitation, halo,
hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl,
aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido,
carboxy, alkanesulfonyl, alkylcarbonyl, and cyano groups.
[0292] In some embodiments, the composition comprises an analog
comprises one or more asymmetric centers and thus occur as
racemates and racemic mixtures, single enantiomers, individual
diastereomers and diastereomeric mixtures. Preparation of pure
enantiomers or mixtures of desired enantiomeric excess (ee) or
enantiomeric purity are accomplished by one or more of the many
methods of (a) separation or resolution of enantiomers, or (b)
enantioselective synthesis known to those of skill in the art, or a
combination thereof. These resolution methods generally rely on
chiral recognition and include, for example, chromatography using
chiral stationary phases, enantioselective host-guest complexation,
resolution or synthesis using chiral auxiliaries, enantioselective
synthesis, enzymatic and nonenzymatic kinetic resolution, or
spontaneous enantioselective crystallization. Such methods are
disclosed generally in Chiral Separation Techniques: A Practical
Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T. E.
Beesley and R. P. W. Scott, Chiral Chromatography, John Wiley &
Sons, 1999; and Satinder Ahuja, Chiral Separations by
Chromatography, Am. Chem. Soc., 2000. Furthermore, there are
equally well-known methods for the quantitation of enantiomeric
excess or purity, for example, GC, HPLC, CE, or NMR, and assignment
of absolute configuration and conformation, for example, CD ORD,
X-ray crystallography, or NMR.
[0293] All tautomeric forms and isomeric forms and mixtures,
whether individual geometric isomers or stereoisomers or racemic or
non-racemic mixtures, of a chemical structure or entire analog is
intended, unless the specific stereochemistry or isomeric form is
specifically indicated in the analog name, chemical name or
structure. All such isomeric forms of these compositions are
included in the present invention unless expressly provided
otherwise. In some embodiments, the analogs of this invention are
also represented in multiple tautomeric forms, in such instances,
the invention includes all tautomeric forms of the analogs
described herein (e.g., if alkylation of a ring system results in
alkylation at multiple sites, the invention includes all such
reaction products). All such isomeric forms of such analogs are
included in the present invention unless expressly provided
otherwise. All crystal forms of the analogs described herein are
included in the present invention unless expressly provided
otherwise. All deuterated form of the analogs described herein are
included in the present invention. In some embodiments as least one
hydrogen atom of the analog is replace with a deuterium atom. In
some embodiments at least one hydrogen atom that is involved with a
hydrogen-bond is replaced with a deuterium atom. In some
embodiments at least one solvent exchangeable hydrogen atom is
replaced with a deuterium atom. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 1% to about 100% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 90% to about 100% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 80% to about 90% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 70% to about 80% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 60% to about 70% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 50% to about 60% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 40% to about 50% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 30% to about 40% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 20% to about 30% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 10% to about 20% of their hydrogen
replaced with deuterium atoms. In some embodiments, the
compositions, pharmaceutical compositions, and analogs contained
therein comprise from about 5% to about 10% of their hydrogen
replaced with deuterium atoms. If the analog of the claimed
invention includes a methyl group, a deuterated analog may have
one, two, or three of the hydrogens replaced by deuterium atoms. In
some embodiments, the analog may contain one or more radioisotopes.
In some embodiments, as least one hydrogen atom of the analog is
replace with a tritium atom. In some embodiments, the compositions,
pharmaceutical compositions, and analogs contained therein comprise
from about 1% to about 5% of their hydrogens are replaced with
tritium atoms.
[0294] As used herein, the terms "increase" and "decrease" mean,
respectively, to cause a statistically significantly (i.e.,
p<0.15) increase or decrease of at least 1%, 2%, or 5%.
[0295] As used herein, the recitation of a numerical range for a
variable is intended to convey that the invention may be practiced
with the variable equal to any of the values within that range.
Thus, for a variable which is inherently discrete, the variable is
equal to any integer value within the numerical range, including
the end-points of the range. Similarly, for a variable which is
inherently continuous, the variable is equal to any real value
within the numerical range, including the end-points of the range.
As an example, and without limitation, a variable which is
described as having values between 0 and 2 takes the values 0, 1 or
2 if the variable is inherently discrete, and takes the values 0.0,
0.1, 0.01, 0.001, 10.sup.-12, 10.sup.-11, 10.sup.-10, 10.sup.-9,
10-.sup.8, 10.sup.-7, 10.sup.-6, 10.sup.-5, 10.sup.-4 or any other
real values .gtoreq.0 and .ltoreq.2 if the variable is inherently
continuous.
[0296] As used herein, unless specifically indicated otherwise, the
word "or" is used in the inclusive sense of "and/or" and not the
exclusive sense of "either/or."
[0297] The term "biological activity" encompasses structural and
functional properties of a macrocycle of the invention. Biological
activity is, for example, structural stability, alpha-helicity,
affinity for a target, resistance to proteolytic degradation, cell
penetrability, intracellular stability, in vivo stability, or any
combination thereof.
[0298] The terms "prodrug" or "prodrug derivative" mean a
covalently-bonded derivative or carrier of the analog of the
claimed invention or active drug substance which undergoes at least
some biotransformation prior to exhibiting its pharmacological
effect(s). In general, such prodrugs have metabolically cleavable
groups and are rapidly transformed in vivo to yield the analog of
the claimed invention, for example, by hydrolysis in blood, and
generally include esters and amide analogs of the analogs. The
prodrug is formulated with the objectives of improved chemical
stability, improved patient acceptance and compliance, improved
bioavailability, prolonged duration of action, improved organ
selectivity, improved formulation (e.g., increased
hydrosolubility), and/or decreased side effects (e.g., toxicity).
In general, prodrugs themselves have weak or no biological activity
and are stable under ordinary conditions. Prodrugs can be readily
prepared from the analogs using methods known in the art, such as
those described in A Textbook of Drug Design and Development,
Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach,
1991, particularly Chapter 5: "Design and Applications of
Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985;
Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.),
Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al.
(eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396;
Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff
(ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp.
172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T.
Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; and
Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,
1987, each of which is incorporated herein by reference in their
entireties. In some embodiments, the analog may be a prodrug that,
when administered to the subject becomes biologically active.
[0299] In some embodiments, the invention relates to a composition
or pharmaceutical composition comprising a pharmaceutically
acceptable prodrug that, when administered to the subject becomes
biologically active. The term "pharmaceutically acceptable prodrug"
as used herein means a prodrug of a compound of the invention which
is, within the scope of sound medical judgment, suitable for use in
contact with the tissues of humans and lower animals without undue
toxicity, irritation, allergic response, and the like, commensurate
with a reasonable benefit/risk ratio, and effective for their
intended use, as well as the zwitterionic forms, where
possible.
[0300] In some embodiments, the analog of the claimed invention is
a pharmaceutically-acceptable acid addition salt. The term
"pharmaceutically-acceptable acid addition salt" means those salts
which retain the biological effectiveness and properties of the
free bases and which are not biologically or otherwise undesirable,
formed with inorganic acids such as hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid,
phosphoric acid, and the like, and organic acids such as acetic
acid, trichloroacetic acid, trifluoroacetic acid, adipic acid,
alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid,
benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid,
camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid,
ethanesulfonic acid, glutamic acid, glycolic acid,
glycerophosphoric acid, hemisulfic acid, heptanoic acid, hexanoic
acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid
(isethionic acid), lactic acid, maleic acid, hydroxymaleic acid,
malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid,
methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid,
2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic
acid, phenylacetic acid, 3-phenylpropionic acid, picric acid,
pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic
acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid,
p-toluenesulfonic acid, undecanoic acid, and the like. In some
embodiments, the analog of the claimed invention is a
pharmaceutically-acceptable base addition salt. The term
"pharmaceutically-acceptable base addition salt" means those salts
which retain the biological effectiveness and properties of the
free acids and which are not biologically or otherwise undesirable,
formed with inorganic bases such as ammonia or hydroxide,
carbonate, or bicarbonate of ammonium or a metal cation such as
sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper,
manganese, aluminum, and the like. Suitable salts include the
ammonium, potassium, sodium, calcium, and magnesium salts. Salts
derived from pharmaceutically-acceptable organic nontoxic bases
include salts of primary, secondary, and tertiary amines,
quaternary amine compounds, substituted amines including naturally
occurring substituted amines, cyclic amines and basic ion-exchange
resins, such as methylamine, dimethylamine, trimethylamine,
ethylamine, diethylamine, triethylamine, isopropylamine,
tripropylamine, tributylamine, ethanolamine, diethanolamine,
2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,
lysine, arginine, histidine, caffeine, hydrabamine, choline,
betaine, ethylenediamine, glucosamine, methylglucamine,
theobromine, purines, piperazine, piperidine, N-ethylpiperidine,
tetramethylammonium compounds, tetraethylammonium compounds,
pyridine, N,N-dimethylaniline, N-methylpiperidine,
N-methylmorpholine, dicyclohexylamine, dibenzylamine,
N,N-dibenzylphenethylamine, 1-ephenamine,
N,N'-dibenzylethylenediamine, polyamine resins, and the like. In
some embodiments, the composition of the claimed invention
comprises at least one organic nontoxic bases chosen from
isopropylamine, diethylamine, ethanolamine, trimethylamine,
dicyclohexylamine, choline, and caffeine.
[0301] The term "solvate" means a physical association of a
compound with one or more solvent molecules or a complex of
variable stoichiometry formed by a solute (the analog of the
claimed invention) and a solvent, for example, water, ethanol, or
acetic acid. This physical association may involve varying degrees
of ionic and covalent bonding, including hydrogen bonding. In
certain instances, the solvate will be capable of isolation, for
example, when one or more solvent molecules are incorporated in the
crystal lattice of the crystalline solid. In general, the solvents
selected do not interfere with the biological activity of the
solute. Solvates encompasses both solution-phase and isolatable
solvates. Representative solvates include hydrates, ethanolates,
and methanolates.
[0302] The invention relates to compositions comprising an analog
of a naturally occurring polypeptide sequence. In some embodiments
the invention relates to a composition comprising an analog of a
naturally occurring polypeptide sequence wherein the analog is from
about 80% to 99% homologous to a naturally occurring polypeptide
sequence. In some embodiments the invention relates to a
composition comprising an analog of a naturally occurring
polypeptide sequence wherein the analog is from about 80% to 85%
homologous to a naturally occurring polypeptide sequence. In some
embodiments the invention relates to a composition comprising an
analog of a naturally occurring polypeptide sequence wherein the
analog is from about 85% to 90% homologous to a naturally occurring
polypeptide sequence. In some embodiments the invention relates to
a composition comprising an analog of a naturally occurring
polypeptide sequence wherein the analog is from about 90% to 95%
homologous to a naturally occurring polypeptide sequence. In some
embodiments the invention relates to a composition comprising an
analog of a naturally occurring polypeptide sequence wherein the
analog is from about 95% to 99% homologous to a naturally occurring
polypeptide sequence. In some embodiments the invention relates to
a composition comprising an analog of a naturally occurring
polypeptide sequence wherein the analog is about 95%, 96%, 97%,
98%, or 99% homologous to a naturally occurring polypeptide
sequence. In some embodiments the analog is derived from the
naturally occurring polypeptide of the secretin family In some
embodiments, the analog is derived from the naturally occurring
polypeptide of the secretin family and has at least one
.beta.-amino acid residue and/or at least one modified amino acid
residue comprising APC or ACPC. Table 1 below illustrates the known
wild-type sequences of each naturally occurring human secretin
family members:
TABLE-US-00002 TABLE 1 Amino Acid Sequences for Peptides of the
Secretin Family GHRF YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQER GARARL
(SEQ ID NO: 1) GIP YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKH NITQ (SEQ
ID NO: 2) GLP-1 HDEFERHAEGTFTSDVSSYLEGQAAQGFIAWLVKGRG (SEQ ID NO:
3) Glucagon HSQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO: 4) PACAP-27
HSDGIFTDSYSRYRKQMAVKKYLAAVL (SEQ ID NO: 5) PACAP-38
HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK (SEQ ID NO: 6) PHM
HADGVFTSDFSKLLGQLSAKKYLESLM (SEQ ID NO: 7) PrP
DVAHGILNEAYRKVLGQLSAGKHLQSLVA (SEQ ID NO: 8) Secretin
HSDGTFTSELSRLREGARLQRLLQGLV (SEQ ID NO: 9) VIP
HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10)
TABLE-US-00003 TABLE 2 Amino Acid Sequences for Interleukins IL-10
>gi|10835141|ref|NP_000563.1|interleukin-10 precursor {Homo
sapiens} MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLRDAFSR
VKTFFQMKDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAEN
QDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQ
EKGIYKAMSEFDIFINYIEAYMTMKIRN (SEQ ID NO: 11) IL-4
>gi|4504669|ref|NP_000580.1|interleukin-4 isoform 1 precursor
{Homo sapiens} MGLTSQLLPPLFFLLACAGNFVHGHKCDITLQEIIKTLNSLTEQKTLCTE
LTVTDIFAASKNTTEKETFCRAATVLRQFYSHHEKDTRCLGATAQQFHRH
KQLIRFLKRLDRNLWGLAGLNSCPVKEANQSTLENFLERLKTIMREKYSK CSS (SEQ ID NO:
12) >gi|27477092|ref|NP_758858.1|interleukin-4 isoform 2
precursor {Homo sapiens}
MGLTSQLLPPLFFLLACAGNFVHGHKCDITLQEIIKTLNSLTEQKNTTEK
ETFCRAATVLRQFYSHHEKDTRCLGATAQQFHRHKQLIRFLKRLDRNLWG
LAGLNSCPVKEANQSTLENFLERLKMREKYSKCSS (SEQ ID NO: 13) IL-5
>gi|4504671|ref|NP_000870.1|interleukin 5 precursor {Homo
sapiens} MRMLLHLSLLALGAAYVYAIPTEIPTSALVKETLALLSTHRTLLIANETL
RIPVPVHKNHQLCTEEIFQGIGTLESQTVQGGTVERLFKNLSLIKKYIDG
QKKKCGEERRRVNQFLDYLQEFLGVMNTEWIIES(SEQ ID NO: 14) IL-8
>gi|10834978|ref|NP_000575.1|interleukin-8 precursor {Homo
sapiens} MTSKLAVALLAAFLISAALCEGAVLPRSAKELRCQCIKTYSKPFHPKFIK
ELRVIESGPHCANTEIIVKLSDGRELCLDPKENWVQRVVEKFLKRAENS (SEQ ID NO: 15)
IL-12A >gi|24430219|ref|NP_000873.2|interleukin-12 subunit alpha
precursor {Homo sapiens}
MWPPGSASQPPPSPAAATGLHPAARPVSLQCRLSMCPARSLLLVATLVLL
DHLSLARNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTS
EEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKT
SFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDEL
MQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYL NAS (SEQ ID NO:
16) IL-12B >gi|24497438|ref|NP_002178. 2|interleukin-12 subunit
beta precursor {Homo sapiens}
MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGEMVVLTC
DTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHS
LLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTIST
DLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACP
AAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSR
QVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVIC
RKNASISVRAQDRYYSSSWSEWASVPCS (SEQ ID NO: 17) IL-2
>gi|28178861|ref|NP_000577.2|interleukin 2 precursor {Homo
sapiens} MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINN
YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHL
RPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIIS TLT (SEQ ID NO:
18) IL-15 gi|26787984|ref|NP_751914.1|interleukin 15 preproprotein
{Homo sapiens} MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANW
VNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISL
ESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQS FVHIVQMFINTS
(SEQ ID NO: 19) gi|10835153|ref|NP_000576.1|interleukin 15
preproprotein {Homo sapiens}
MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANW
VNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISL
ESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQS FVHIVQMFINTS
(SEQ ID NO: 20) IL-17 >gi|4504651|ref|NP_002181.1|interleukin
17A precursor {Homo sapiens}
MTPGKTSLVSLLLLLSLEAIVKAGITIPRNPGCPNSEDKNFPRTVMVNLN
IHNRNTNTNPKRSSDYYNRSTSPWNLHRNEDPERYPSVIWEAKCRHLGCI
NADGNVDYHMNSVPIQQEILVLRREPPHCPNSFRLEKILVSVGCTCVTPI VHHVA (SEQ ID
NO: 21) IL-18 >gi|4504653|ref|NP_001553.1|interleukin-18
proprotein {Homo sapiens}
MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLSVIRN
LNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTI
SVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQ
FESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 22)
interleukin-18-binding protein isoform a precursor {Homo sapiens}
>gi|89111125|ref|NP_001034748.1|interleukin-18- binding protein
isoform a precursor {Homo sapiens}
MTMRHNWTPDLSPLWVLLLCAHVVTLLVRATPVSQTTTAATASVRSTKDP
CPSQPPVFPAAKQCPALEVTWPEVEVPLNGTLSLSCVACSRFPNFSILYW
LGNGSFIEHLPGRLWEGSTSRERGSTGTQLCKALVLEQLTPALHSTNFSC
VLVDPEQVVQRHVVLAQLWAGLRATLPPTQEALPSSHSSPQQQ (SEQ ID NO: 23) IL-21
>gi|11141875|ref|NP_068575.1|interleukin-21 {Homo sapiens}
MRSSPGNMERIVICLMVIFLGTLVHKSSSQGQDRHMIRMRQLIDIVDQLK
NYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSI
KKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQ HLSSRTHGSEDS(SEQ
ID NO: 24) IL-22 >gi|10092625|ref|NP_065386.1|interleukin-22
precursor {Homo sapiens}
MAALQKSVSSFLMGTLATSCLLLLALLVQGGAAAPISSHCRLDKSNFQQP
YITNRTFMLAKEASLADNNTDVRLIGEKLFHGVSMSERCYLMKQVLNFTL
EEVLFPQSDRFQPYMQEVVPFLARLSNRLSTCHIEGDDLHIQRNVQKLKD
TVKKLGESGEIKAIGELDLLFMSLRNACI (SEQ ID NO: 25) IL-24
>gi|5803086|ref|NP_006841.1|interleukin 24 isoform 1 precursor
{Homo sapiens} MNFQQRLQSLWTLARPFCPPLLATASQMQMVVLPCLGFTLLLWSQVSGAQ
GQEFHFGPCQVKGVVPQKLWEAFWAVKDTMQAQDNITSARLLQQEVLQNV
SDAESCYLVHTLLEFYLKTVFKNYHNRTVEVRTLKSFSTLANNFVLIVSQ
LQPSQENEMFSIRDSAHRRFLLFRRAFKQLDVEAALTKALGEVDILLTWM QKFYKL (SEQ ID
NO: 26) >gi|31317246|ref|NP_851936.1|interleukin-24 isoform 2
{Homo sapiens} MFSIRDSAHRRFLLFRRAFKQLDVEAALTKALGEVDILLTWMQKFYKL
(SEQ ID NO: 27) IL-26 >gi|8923756|ref|NP_060872.1|interleukin-26
precursor {Homo sapiens}
MLVNFILRCGLLLVTLSLAIAKHKQSSFTKSCYPRGTLSQAVDALYIKAA
WLKATIPEDRIKNIRLLKKKTKKQFMKNCQFQEQLLSFFMEDVFGQLQLQ
GCKKIRFVEDFHSLRQKLSHCISCASSAREMKSITRMKRIFYRIGNKGIY
KAISELDILLSWIKKLLESSQ (SEQ ID NO: 28)
TABLE-US-00004 TABLE 3 Amino Acid Sequences for Anti-inflammatory
Neuropeptides pro-opiomelanocortin preproprotein {Homo sapiens}
>gi|4505949|ref|NP_000930.1|pro-opiomelanocortin preproprotein
{Homo sapiens} MPRSCCSRSGALLLALLLQASMEVRGWCLESSQCQDLTTESNLLECIRAC
KPDLSAETPMFPGNGDEQPLTENPRKYVMGHFRWDRFGRRNSSSSGSSGA
GQKREDVSAGEDCGPLPEGGPEPRSDGAKPGPREGKRSYSMEHFRWGKPV
GKKRRPVKVYPNGAEDESAEAFPLEFKRELTGQRLREGDGPDGPADDGAG
AQADLEHSLLVAAEKKDEGPYRMEHFRWGSPPKDKRYGGFMTSEKSQTPL
VTLFKNAIIKNAYKKGE (SEQ ID NO: 29) Active form: oc-MSH
SYSMEHFRWGKPV-NH2 (SEQ ID NO: 581)
>gi|490074|emb|CAA00890.1|ACTH {Homo sapiens}
GPSYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF urocortin preproprotein
{Homo sapiens} >gi|4507803|ref|NP_003344.1|urocortin
preproprotein {Homo sapiens}
MRQAGRAALLAALLLLVQLCPGSSQRSPEAAGVQDPSLRWSPGARNQGGG
ARALLLLLAERFPRRAGPGRLGLGTAGERPRRDNPSLSIDLTFHLLRTLL ELARTQSQRERA(SEQ
ID NO: 30) EQNRIIFDSVGK Active form: Urocortin
DNPSLSIDLTFHLLRTLLELADTQSQRERAQNRIIFDSV- NH2 (SEQ ID NO: 1336)
urocortin-2 preproprotein {Homo sapiens}
>gi|15082240|ref|NP_149976.1|urocortin-2 preproprotein {Homo
sapiens} MTRCALLLLMVLMLGRVLVVPVTPIPTFQLRPQNSPQTTPRPAASESPSA
APTWPWAAQSHCSPTRHPGSRIVLSLDVPIGLLQILLEQARARAAREQAT TNARILARVGHC
(SEQ ID NO: 31) nrocortin-3 preproprotein {Homo sapiens}
>gi|45238845|ref|NP_444277.2|urocortin-3 preproprotein {Homo
sapiens} MLMPVHFLLLLLLLLGGPRTGLPHKFYKAKPIFSCLNTALSEAEKGQWED
ASLLSKRSFHYLRSRDASSGEEEEGKEKKTFPISGARGGARGTRYRYVSQ
AQPRGKPRQDTAKSPHRTKFTLSLDVPTNIMNLLFNIAKAKNLRAQAAAN AHLMAQIGRKK (SEQ
ID NO: 32) adrenomedullin precursor {Homo sapiens}
>gi|4501945|ref|NP_001115.1|adrenomedullin precursor {Homo
sapiens} MKLVSVALMYLGSLAFLGADTARLDVASEFRKKWNKWALSRGKRELRMSS
SYPTGLADVKAGPAQTLIRPQDMKGASRSPEDSSPDAARIRVKRYRQSMN
NFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGYGRRR
RRSLPEAGPGRTLVSSKPQAHGAPAPPSGSAPHFL (SEQ ID NO: 33)
gi|41152110|ref|NP_079142.2|adrenomedullin 2 precursor {Homo
sapiens} MARIPTAALGCISLLCLQLPGSLSRSLGGDPRPVKPREPPARSPSSSLQP
RHPAPRPVVWKLHRALQAQRGAGLAPVMGQPLRDGGRQHSGPRRHSGPRR
TQAQLLRVGCVLGTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSYG (SEQ ID NO: 1337)
Active portion: Adrenomeclullin
YRQSMNNFQGLRFG{CRFGTC}TVQKLAHQIYQFTDKDKDNVAPRNKISP QGY-NH2 (SEQ ID
NO: 1338) eortistatin preproprotein {Homo sapiens}
>gi|41327683|ref|NP_001293.2|cortistatin preproprotein {Homo
sapiens} MYRHKNSWRLGLKYPPSSKEETQVPKTLISGLPGRKSSSRVGEKLQSAHK
MPLSPGLLLLLLSGATATAALPLEGGPTGRDSEHMQEAAGIRKSSLLTFL
AWWFEWTSQASAGPLIGEEAREVARRQEGAPPQQSARRDRMPCRNFFWKT FSSCK (SEQ ID
NO: 34) Active form: Cortistatin DRMP{CKNFFWKTFSSC}K-NH2 (SEQ ID
NO: 1339) somatostatin preproprotein {Homo sapiens}
>gi|4507243|ref|NP_001039.1|somatostatin preproprotein {Homo
sapiens} MLSCRLQCALAALSIVLALGCVTGAPSDPRLRQFLQKSLAAAAGKQELAK
YFLAELLSEPNQTENDALEPEDLSQAAEQDEMRLELQRSANSNPAMAPRE RKAGCKNFFWKTFTSC
(SEQ ID NO: 35) appetite-regulating hormone isoforml preproprotein
{Homo sapiens} >gi|7706519|ref|NP_057446.1|appetite-regulating
hormone isoform 1 preproprotein {Homo sapiens}
MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQQRKESKKPPAKLQP
RALAGWLRPEDGGQAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGK
FLQDILWEEAKEAPADK (SEQ ID NO: 36) appetite-regulating hormone
isoform 2 preproprotein {Homo sapiens}
>gi|201860279|ref|NP_001128413.1|appetite- regulating hormone
isoform 2 preproprotein {Homo sapiens}
MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQRKESKKPPAKLQPR
ALAGWLRPEDGGQAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKF LQDILWEEAKEAPADK
(SEQ ID NO: 37) appetite-regulating hormone isoform 3 preproprotein
{Homo sapiens} >gi|201860281|ref|NP_001128416.1|appetite-
regulating hormone isoform 3 preproprotein {Homo sapiens}
MFTCWWSYLRSTLAAVPGEASRVQQRKESKKPPAKLQPRALAGWLRPEDG
GQAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKFLQDILWEEAKE APADK (SEQ ID
NO: 38) appetite-regulating hormone isoform 4 preproprotein {Homo
sapiens} >gi|201860283|ref|NP_001128417.1|appetite- regulating
hormone isoform 4 preproprotein {Homo sapiens}
MFTCWWSYLRSTLAAVPGEASRVQRKESKKPPAKLQPRALAGWLRPEDGG
QAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKFLQDILWEEAKEA PADK (SEQ ID NO:
39) appetite-regulating hormone isoform 5 preproprotein {Homo
sapiens} >gi|201860285|ref|NP_001128418.1|appetite- regulating
hormone isoform 5 preproprotein {Homo sapiens}
MFTCWWSYLRSTLAAVPGEASRVQFNAPFDVGIKLSGVQYQQHSQALGKF LQDILWEEAKEAPADK
(SEQ ID NO: 40) ghrelin {Homo sapiens}
>gi|53794041|gb|AAU93610.1|ghrelin {Homo sapiens}
MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQ (SEQ ID NO: 41) Active form:
Ghrelin GSSFLSPEHQRVQQRKESKKPPAKLPQ R-NH2 (SEQ ID NO: 567) (Expert
Opin. Biol. Tiler. (2007) 7(4): 461-478)
[0303] In some embodiments, the composition comprises a VIP analog.
In some embodiments, the composition comprises a Secretin analog.
In some embodiments, the composition comprises a PrP analog. In
some embodiments, the composition comprises a PrP analog. In some
embodiments, the composition comprises a PHM analog. In some
embodiments, the composition comprises a PACAP-27 analog. In some
embodiments, the composition comprises a PACAP-38 analog. In some
embodiments, the composition comprises a Glucagon analog. In some
embodiments, the composition comprises a GLP-1 analog. In some
embodiments, the composition comprises a GIP analog. In some
embodiments, the composition comprises a GHRF analog. In some
embodiments, the composition comprises a secretin family analog
that is derived from mammalian amino acid sequences of secretin
family polypeptides other than humans In some embodiments, the
secretin family analog may be selective for one particular receptor
versus another. In some embodiments, the composition comprises a
secretin analog wherein the secretin analog is selective for, or
preferentially binds to, VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. In
some embodiments, the composition comprises a secretin analog
wherein the secretin analog is selective for, or preferentially
binds, VPAC1. In some embodiments, the composition comprises a
secretin analog wherein the secretin analog is selective for, or
preferentially binds, VPAC2. In some embodiments, the composition
comprises a secretin analog wherein the secretin analog is
selective for, or preferentially binds, PAC1. In some embodiments,
the composition comprises a secretin analog wherein the secretin
analog is selective for, or preferentially binds, VIPR1. In some
embodiments, the composition comprises a secretin analog wherein
the secretin analog is selective for, or preferentially binds,
VIPR2. In some embodiments, the secretin analog is an agonist of at
least one of the following: VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. In
some embodiments, the the secretin analog is an antagonist of at
least one of the following: VPAC1, VPAC2, PAC1, VIPR1, or
VIPR2.
[0304] In some embodiments, the composition comprises a
apolipoprotein A-1 analog. In some embodiments the apoA-1 analog is
from about 80% to about 99% homologous to the human sequence of
apolipoprotein A-1. In some embodiments the apoA-1 analog is from
about 80% to about 85% homologous to the human sequence of
apolipoprotein A-1. In some embodiments the apoA-1 analog is from
about 85% to about 90% homologous to the human sequence of
apolipoprotein A-1. In some embodiments the apoA-1 analog is from
about 90% to about 95% homologous to the human sequence of
apolipoprotein A-1. In some embodiments the apoA-1 analog is from
about 95% to about 99% homologous to the human sequence of
apolipoprotein A-1. In some embodiments the apoA-1 analog is about
95%, 96%, 97%, 98%, or 99% homologous to the human sequence of
apolipoprotein A-1. In some embodiments the apoA-1 analog is from
about 80% to about 85% homologous to the following of
apolipoprotein A-1 analog: DWFKAFYDKVAEKFKEAF (SEQ ID NO:533).
[0305] In some embodiments, the composition comprises a cytokine or
interleukin analog. In some embodiments the cytokine or interleukin
analog is from about 80% to about 99% homologous to the human
sequence of cytokine or interleukin. In some embodiments the
cytokine or interleukin analog is from about 80% to about 85%
homologous to the human sequence of a cytokine or interleukin. In
some embodiments the cytokine or interleukin analog is from about
85% to about 90% homologous to the human sequence of a cytokine or
interleukin. In some embodiments the cytokine or interleukin analog
is from about 90% to about 95% homologous to the human sequence of
a cytokine or interleukin. In some embodiments the cytokine or
interleukin analog is from about 95% to about 99% homologous to the
human sequence of a cytokine or interleukin. In some embodiments
the cytokine or interleukin analog is about 95%, 96%, 97%, 98%, or
99% homologous to the human sequence of a cytokine or interleukin.
In some embodiments the cytokine or interleukin analog is from
about 80% to about 99% homologous to a cytokine or interleukin
chosen from IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-15,
IL-17, IL-18, IL-21,IL-22, IL-23, IL-24, IL-26, IFN-.gamma.,
TNF-.alpha., and TNF-.beta.. In some embodiments, the cytokine or
interleukin analog comprises at least one non-natural amino acid
within the structure that corresponds to helix F in the naturally
occurring polypeptide sequence upon which the analog is based or
derived. In some embodiments, the cytokine or interleukin analog
comprises at least one non-natural amino acid within the structure
that corresponds to AB loop in the naturally occurring polypeptide
sequence upon which the analog is based or derived.
[0306] The invention relates to the manufacturing of a synthetic
polypeptide which is an amino acid sequence that corresponds to the
sequence of a biologically active polypeptide or fragment thereof.
In the synthetic polypeptide, from about 14% to about 50% of the
.alpha.-amino acid residues found in the biologically active
polypeptide or fragment are replaced with .beta.-amino acid
residues. In another embodiment of the invention, the .alpha.-amino
acid residues and the .beta.-amino acid residues are distributed in
a repeating pattern. Human cells are then contacted with the
synthetic polypeptide to induce the biochemical pathway or
biological activity ordinarily induced by the naturally occurring
polypeptide upon which the analog is based.
[0307] The compositions of the invention may be prepared by the
synthetic chemical procedures described herein, as well as other
procedures similar to those which may be used for making
.beta.-amino acid peptides. Such procedures include both solution
and solid phase procedures, e.g., using either Boc and Fmoc
methodologies. The compounds of the invention may be synthesized
using solid phase synthesis techniques. Fmoc-N-Protected
.beta.-amino acids can be used to synthesize
poly-.alpha./.beta.-peptides by conventional manual solid-phase
synthesis procedures under standard conditions on any number of
solid supports, including ortho-chloro-trityl chloride resin.
Esterification of Fmoc-.beta.-amino acids with the
ortho-chloro-trityl resin can be performed according to the method
of Barbs et. al., Tetrahedron Lett., 1989, 30, 3943. The resin (150
mg, 1.05 mmol Cl) is swelled in 2 ml CH.sub.2Cl.sub.2 for 10 min A
solution of the Fmoc-protected .beta.-amino acid in
CH.sub.2Cl.sub.2 and iPr.sub.2EtN are then added successively and
the suspension is mixed under argon for 4 h. Subsequently, the
resin is filtered and washed with
CH.sub.2Cl.sub.2/MeOH/iPr.sub.2EtN (17:2:1, 3.times.3 min),
CH.sub.2Cl.sub.2 (3.times.3 min), DMF (2.times.3 min),
CH.sub.2Cl.sub.2 (3.times.3 min), and MeOH (2.times.3 min). The
substitution of the resin is determined on a 3 mg sample by
measuring the absorbance of the dibenzofulvene adduct at 300 nm.
The Fmoc group is removed using 20% piperidine in DMF (4 ml,
2.times.20 min) under Ar bubbling. The resin is then filtered and
washed with DMF (6.times.3 min). For each coupling step, a solution
of the .beta.-amino acid (3 equiv.), BOP (3 equiv.) and HOBT (3
equiv.) in DMF (2 ml) and iPr.sub.2EtN (9 eq) are added
successively to the resin and the suspension is mixed for 1 h under
Ar. Monitoring of the coupling reaction is performed with
2,4,6-trinitrobenzene-sulfonic acid (TNBS) (W. S. Hancock and J. E.
Battersby, Anal. Biochem. (1976), 71, 260). In the case of a
positive TNBS test (indicating incomplete coupling), the suspension
is allowed to react for a further 1 h. The resin is then filtered
and washed with DMF (3.times.3 min) prior to the following Fmoc
deprotection step. After the removal of the last Fmoc protecting
group, the resin is washed with DMF (6.times.3 min),
CH.sub.2Cl.sub.2 (3.times.3 min), Et.sub.2O (3.times.3 min) and
dried under vacuum for 3 h. Finally the peptides are cleaved from
the resin using 2% TFA in CH.sub.2Cl.sub.2 (2 ml, 5.times.15 min)
under Ar. The solvent is removed and the oily residues are
triturated in ether to give the crude .alpha.-/.beta.-polypeptides.
The compounds are further purified by HPLC.
[0308] The compositions of the invention may be prepared by the
synthetic chemical procedures described herein, as well as other
procedures similar to those which may be used for making
.beta.-amino acid peptides. Such procedures include both solution
and solid phase procedures, e.g., using either Boc or Fmoc
methodologies. The compounds of the invention may be synthesized
using solid phase synthesis techniques. Fmoc-N-Protected
.beta.-amino acids can be used to synthesize
poly-.alpha./.beta.-peptides by conventional manual solid-phase
synthesis procedures under standard conditions on any number of
solid supports, including ortho-chloro-trityl chloride resin, Wang
resin (NovaBiochem 0.75 mmol substitution) and Rink amid resin
(NovaBiochem 0.55 mmol substitution). Resin is typically swelled in
100% DMF for 30 minutes then deprotected using 20% piperidine in
DMF for 2 minutes at 80.degree. (3.times.). Fmoc protected amino
acids (natural or non-natural) can then be coupled to the resin
using a cocktail of AA:HATU:DIEA:Resin (3:2.5:4:1, LiCL 0.8M final
concentration) in DMF for 2 minutes at 70.degree. (3.times.). The
resin is then washed (3.times.) with DMF, DCM (dichloromethane)
(3.times.) and again with DMF (3.times.) between deprotection and
coupling steps. Monitoring of the coupling reaction is performed
with 2,4,6-trinitrobenzene-sulfonic acid (TNBS) (W. S. Hancock and
J. E. Battersby, Anal. Biochem. (1976), 71, 260). In the case of a
positive TNBS test (indicating incomplete coupling), the suspension
is allowed to react for another three times. This process is
repeated until the desired product has been achieved. After the
removal of the last Fmoc protecting group, the resin is washed with
DMF (3.times.), CH.sub.2Cl.sub.2 (3.times.) and DMF again
(3.times.). The remaining free-amine group is then acetylated using
a cocktail of DIEA:Ac.sub.2O (1:1) for 5 minutes at room
temperature. Full-length peptides were then cleaved from solid
support using TFA:TIS:H.sub.2O (95:2.5:2.5) for 150 minutes,
precipitated in cold ethyl ether and lyophilized The polymer was
reconstituted in a 1:1 solution of A:B (A: H.sub.20, 0.1% TFA) (B:
90:10:0.1 acetonitrile/H.sub.2O/TFA).
[0309] The compositions described herein may be prepared by
successive amide bond-forming procedures in which amide bonds are
formed between the .beta.-amino group of a first .beta.-amino acid
residue or a precursor thereof and the .alpha.-carboxyl group of a
second .beta.-amino acid residue or .alpha.-amino acid residue or a
precursor thereof. The amide bond-forming step may be repeated as
many times, and with specific .alpha.-amino acid residues and/or
.beta.-amino acid residues and/or precursors thereof, as required
to give the desired .alpha./.beta.-polypeptide. Also analogs
comprising two, three, or more amino acid residues (.alpha.- or
.beta.-) may be joined together to yield larger analogs comprising
any combination of .alpha.-, or .beta.-amino acids. Cyclic
compounds may be prepared by forming peptide bonds between the
N-terminal and C-terminal ends of a previously synthesized linear
polypeptide or through the disulfide crosslinking of sidechains of
non-adjacent residues. .beta..sup.3-amino acids may be produced
enantioselectively from corresponding .beta.-amino acids. For
instance, by Arndt-Eisert homologation of N-protected .alpha.-amino
acids. Homologation may be followed by coupling of the reactive
diazoketone intermediate of the Wolff rearrangement with a
.beta.-amino acid residue.
[0310] In some embodiments, the analog of the invention comprises a
repeating pattern of the .beta.-amino acid residues in alignment on
a longitudinal axis of the analog in order to constrain the
conformation of the analog in an active state or to avoid
disruption of the active site. That is, in the folded structure
adopted by the analogs of the present invention, the repeating
pattern of .alpha.- or .beta.-amino acids residues disposes the
synthetic non-natural amino acid residues in alignment along one
longitudinal axis of the folded molecular structure from N-terminus
to C-terminus when the unnatural polypeptides adopt a helical
conformation. In some embodiments, the analog of the invention
comprises the alignment of .beta.-amino acids or ACPC or APC along
a longitudinal axis of the folded molecular structure from
N-terminus to C-terminus when the polypeptide adopts a helical
conformation chosen from any of the conformations shown in FIG. 5,
wherein the residue positions in a solid dot represent non-natural
amino acid residues. In some embodiments, the analog of the
invention comprises the alignment along a longitudinal axis of the
folded molecular structure from N-terminus to C-terminus when the
polypeptide adopts a helical conformation chosen from any of the
conformations shown in FIG. 5, wherein the positions with solid
dots represent .beta..sup.3-amino acid residues. In some
embodiments, the analog of the invention comprises the alignment
along a longitudinal axis of the folded molecular structure from
N-terminus to C-terminus when the polypeptide adopts a helical
conformation chosen from any of the conformations shown in FIG. 5,
wherein the positions with solid dots represent .beta.-amino acid
residues.
[0311] The repeating pattern of .beta.-amino acid residues and
.alpha.-amino acid residues may be a pattern of from about two to
about seven residues in length, such as
(.beta..alpha..alpha..alpha..alpha..alpha..alpha.),
(.beta..alpha..alpha..alpha..beta..alpha..alpha.),
(.alpha..alpha..alpha..alpha..alpha..alpha..beta.),
(.alpha..alpha..alpha..alpha..beta.),
(.alpha..alpha..alpha..beta.), (.alpha..alpha..beta.),
(.alpha..alpha..beta..alpha..alpha..alpha..beta.),
(.alpha..alpha..beta..alpha..beta..alpha..beta.), and
(.alpha..beta.). All unique patterns of .alpha.- or .beta.-amino
acids residues from about two to about fourteen residues in length
are explicitly within the scope of the invention. All unique
patterns of .alpha.- or .beta.-amino acids residues from about two
to about seven residues in length are explicitly within the scope
of the invention. In some embodiments, the composition comprises an
analog, wherein the analog wherein the analog comprises a
repetitive pattern of sequential .beta.-amino acids from the
amino-terminus to the carboxy-terminus, and wherein the analog is
an agonist or antagonist of the receptor to which it selectively
binds or associates. For instance, in some embodiments, the analog
is a VIP analog or a functional fragment thereof that selectivity
binds to VPAC1, VPAC2, or PAC1 and wherein the VIP analog of
functional fragment thereof is an agonist or antagonist of at least
one receptor chosen from: VPAC1, VPAC2, and PAC1. In some
embodiments, the methods of treatment or prevention include
administration of VIP analogs, wherein the VIP analog is an an
agonist or antagonist of at least one receptor chosen from: VPAC1,
VPAC2, and PAC1. In some embodiments, the composition comprises an
analog, wherein the analog wherein the analog comprises a
repetitive pattern of sequential .beta.-amino acids from the
amino-terminus to the carboxy-terminus chosen from the following:
.alpha..alpha..alpha..alpha..alpha..alpha..beta.,
.alpha..alpha..alpha..alpha..alpha..beta..alpha.,
.alpha..alpha..alpha..alpha..beta..alpha..alpha.,
.alpha..alpha..alpha..beta..alpha..alpha..alpha.,
.alpha..alpha..beta..alpha..alpha..alpha..alpha.,
.alpha..beta..alpha..alpha..alpha..alpha..alpha.,
.beta..alpha..alpha..alpha..alpha..alpha..alpha.,
.alpha..alpha..alpha..alpha..alpha..beta..beta.,
.alpha..alpha..alpha..alpha..beta..beta..alpha.,
.alpha..alpha..alpha..beta..beta..alpha..alpha.,
.alpha..alpha..beta..beta..alpha..alpha..alpha.,
.alpha..beta..beta..alpha..alpha..alpha..alpha.,
.beta..beta..alpha..alpha..alpha..alpha..alpha.,
.beta..alpha..alpha..alpha..alpha..alpha..beta.,
.beta..alpha..alpha..alpha..alpha..beta..alpha.,
.beta..alpha..alpha..alpha..beta..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha., .beta.
.beta..alpha..alpha..alpha..alpha.,
.alpha..beta..alpha..alpha..alpha..alpha..beta.,
.alpha..beta..alpha..alpha..alpha..beta..alpha.,
.alpha..beta..alpha..alpha..beta..alpha..alpha.,
.alpha..beta..alpha..beta..alpha..alpha..alpha.,
.alpha..alpha..beta..alpha..alpha..alpha..beta.,
.alpha..alpha..beta..alpha..alpha..beta..alpha.,
.alpha..alpha..beta..alpha..beta..alpha..alpha.,
.alpha..alpha..alpha..beta..alpha..alpha..beta.,
.alpha..alpha..alpha..beta..alpha..beta..alpha., and
.alpha..alpha..alpha..alpha..beta..alpha..beta.. In some
embodiments, the composition comprises an analog, wherein the
analog comprises a repetitive pattern of sequential .beta.-amino
acids from the amino-terminus to the carboxy-terminus chosen from
the following:
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..alpha..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..beta..alpha., and
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..beta..beta.. In some embodiments,
the composition comprises an analog, wherein the analog comprises a
repetitive pattern of sequential .beta.-amino acids from the
amino-terminus to the carboxy-terminus chosen from the following:
.beta..beta..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..beta..beta..alpha..alpha..alpha..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..beta..alpha..alpha..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..beta..alpha..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..alpha..beta..beta..alpha..alpha..beta..-
alpha..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..beta..alpha..beta..-
alpha..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..beta..beta..-
alpha..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.beta..alpha..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..beta..alpha..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..beta..beta..alpha..alpha..beta.;
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..alpha..beta.; and
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..alpha..beta..beta.. In some
embodiments, the composition comprises an analog, wherein the
analog comprises a repetitive pattern of sequential .beta.-amino
acids from the amino-terminus to the carboxy-terminus chosen from
the following:
.beta..beta..alpha..alpha..beta..alpha..alpha..beta..alpha..alpha..alpha.-
.beta..alpha..alpha..beta..alpha..alpha..alpha.;
.beta..alpha..beta..alpha..beta..alpha..alpha..beta..alpha..alpha..alpha.-
.beta..alpha..alpha..beta..alpha..alpha..alpha.;
.beta..alpha..alpha..beta..beta..alpha..alpha..beta..alpha..alpha..alpha.-
.beta..alpha..alpha..beta..alpha..alpha..alpha.;
.beta..alpha..alpha..alpha..beta..beta..alpha..beta..alpha..alpha..alpha.-
.beta..alpha..alpha..beta..alpha..alpha..alpha.;
.beta..alpha..alpha..alpha..beta..alpha..beta..beta..alpha..alpha..alpha.-
.beta..alpha..alpha..beta..alpha..alpha..alpha.;
.beta..alpha..alpha..alpha..beta..alpha..alpha..beta..beta..alpha..alpha.-
.beta..alpha..alpha..beta..alpha..alpha..alpha.;
.beta..alpha..alpha..alpha..beta..alpha..alpha..beta..alpha..beta..alpha.-
.beta..alpha..alpha..beta..alpha..alpha..alpha.;
.beta..alpha..alpha..alpha..beta..alpha..alpha..beta..alpha..alpha..beta.-
.beta..alpha..alpha..beta..alpha..alpha..alpha.;
.beta..alpha..alpha..alpha..beta..alpha..alpha..beta..alpha..alpha..alpha-
..beta..beta..alpha..beta..alpha..alpha..alpha.;
.beta..alpha..alpha..alpha..beta..alpha..alpha..beta..alpha..alpha..alpha-
..beta..alpha..beta..beta..alpha..alpha..alpha.;
.beta..alpha..alpha..alpha..beta..alpha..alpha..beta..alpha..alpha..alpha-
..beta..alpha..alpha..beta..beta..alpha..alpha.;
.beta..alpha..alpha..alpha..beta..alpha..alpha..beta..alpha..alpha..alpha-
..beta..alpha..alpha..beta..alpha..beta..alpha.; and
.beta..alpha..alpha..alpha..beta..alpha..alpha..beta..alpha..alpha..alpha-
..beta..alpha..alpha..beta..alpha..alpha..beta..
[0312] In some embodiments, the composition comprises an analog,
wherein the analog comprises a repetitive pattern of sequential
.beta.-amino acids from the amino-terminus to the carboxy-terminus
chosen from the following:
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..alpha..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..beta..alpha.,
and.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..be-
ta..alpha..alpha..alpha..beta..beta..beta..beta., wherein any
.alpha.-amino acid residue may be a non-natural amino acid. In some
embodiments, the composition comprises an analog, wherein the
analog comprises a repetitive pattern of sequential .beta.-amino
acids from the amino-terminus to the carboxy-terminus chosen from
the following:
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..alpha..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..beta..alpha., and
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..beta..beta., wherein at least one
.alpha.-amino acid residue may be a non-natural amino acid. In some
embodiments, the composition comprises an analog, wherein the
analog comprises a repetitive pattern of sequential .beta.-amino
acids from the amino-terminus to the carboxy-terminus chosen from
the following:
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..alpha..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..alpha..alpha.,
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..beta..beta..alpha.,
and.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..be-
ta..alpha..alpha..alpha..beta..beta..beta..beta., wherein from
about 1 to about 10 .alpha.-amino acid residues may be a
non-natural amino acid. In any of the above-mentioned patterns one
or more of the .beta.-amino acid residues may be replaced or
modified with cyclic .beta.-amino acid (cyclically-constrained beta
amino acid), such as APC or ACPC.
[0313] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus to the
carboxy-terminus:
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..alpha..alpha..beta.. In some
embodiments, the composition comprises a VIP analog, wherein the
analog comprises the following repetitive pattern of sequential
.beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid.
[0314] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta-3, beta-2, cyclic or
heterocyclic beta-amino acid; .alpha..sub.1=any alpha amino acid;
.alpha..sub.2=any alpha amino acid; .beta..sub.2=any beta-3,
beta-2, cyclic or heterocyclic beta-amino acid; .alpha..sub.3=any
alpha amino acid; .alpha..sub.4=any alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta-3,
beta-2, cyclic or heterocyclic beta-amino acid; .alpha..sub.6=any
alpha amino acid; .alpha..sub.7=any alpha amino acid;
.beta..sub.4=any beta-3, beta-2, cyclic or heterocyclic beta-amino
acid; .alpha..sub.8=any alpha amino acid; .alpha..sub.9=any alpha
amino acid; .alpha..sub.10=any alpha amino acid; .beta..sub.5=any
beta-3, beta-2, cyclic or heterocyclic beta-amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta-3, beta-2, cyclic or heterocyclic
beta-amino acid.
[0315] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4
.alpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha.-
.sub.12.beta..sub.6, wherein .beta..sub.1=any beta-3 amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta-3 amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta-3 amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta-3 amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta-3 amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta-3 amino acid.
[0316] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4
.alpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha.-
.sub.12.beta..sub.6, wherein .beta..sub.1=any beta-2 amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta-2 amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta-2 amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta-2 amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta-2 amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta-2 amino acid.
[0317] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4
.alpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha.-
.sub.12.beta..sub.6, wherein .beta..sub.1=any cyclic or
heterocyclic beta-amino acid; .alpha..sub.1=any alpha amino acid;
.alpha..sub.2=any alpha amino acid; .beta..sub.2=any cyclic or
heterocyclic beta-amino acid; .alpha..sub.3=any alpha amino acid;
.alpha..sub.4=any alpha amino acid; .alpha..sub.5=any alpha amino
acid; .beta..sub.3=cyclic or heterocyclic beta-amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=cyclic or heterocyclic beta-amino acid;
.alpha..sub.8=any alpha amino acid; .alpha..sub.9=any alpha amino
acid; .alpha..sub.10=any alpha amino acid; .beta..sub.5=cyclic or
heterocyclic beta-amino acid; .alpha..sub.11=any alpha amino acid;
.alpha..sub.12=any alpha amino acid; .beta..sub.6=cyclic or
heterocyclic beta-amino acid
[0318] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta-3 amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta-3 amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta-3 amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta-3 amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=a beta-3 alanine; .alpha..sub.11=any
alpha amino acid; .alpha..sub.12=any alpha amino acid;
.beta..sub.6=any beta-3 amino acid.
[0319] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta-3 amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta-3 amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha leucine; .beta..sub.3=any beta-3 amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta-3 amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=a beta-3 alanine.alpha..sub.11=any
alpha amino acid; .alpha..sub.12=any alpha amino acid;
.beta..sub.6=any beta-3 amino acid.
[0320] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta-3 amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta-3 amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha leucine; .beta..sub.3=any beta-3 amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta-3 amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=a beta-3 amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta-3 amino acid.
[0321] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta 3-threonine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=a beta-3 arginine; .alpha..sub.3=any alpha amino
acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=a beta-3 alanine; .alpha..sub.6=any alpha
amino acid; .alpha..sub.7=any alpha amino acid; .beta..sub.4=a
beta-3 lysine; .alpha..sub.8=any alpha amino acid;
.alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha amino
acid; .beta..sub.5=a beta-3 alanine; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .beta..sub.6=a beta-3
asparagine.
[0322] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta 3-threonine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=a beta-3 arginine; .alpha..sub.3=any alpha amino
acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an alpha
leucine; .beta..sub.3=a beta-3 alanine; .alpha..sub.6=any alpha
amino acid; .alpha..sub.7=any alpha amino acid; .beta..sub.4=a
beta-3 lysine; .alpha..sub.8=any alpha amino acid;
.alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha amino
acid; .beta..sub.5=a beta-3 alanine; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .beta..sub.6=a beta-3
asparagine.
[0323] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.beta..sub.2=any beta amino acid; .alpha..sub.3=an alpha lysine;
.alpha..sub.4=an alpha glutamine; .alpha..sub.5=an alpha-leucine;
.beta..sub.3=any beta amino acid; .alpha..sub.6=an alpha valine;
.alpha..sub.7=an alpha lysine; .beta..sub.4=any beta amino acid;
.alpha..sub.8=an alpha tyrosine; .alpha..sub.9=an alpha leucine;
.alpha..sub.10=an alpha asparagine; .beta..sub.5=a beta-3 alanine;
.alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .beta..sub.6=any beta amino acid.
[0324] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta-3 amino acid;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.beta..sub.2=any beta-3 amino acid; .alpha..sub.3=an alpha lysine;
.alpha..sub.4=an alpha glutamine; .alpha..sub.5=an alpha leucine;
.beta..sub.3=any beta-3 amino acid; .alpha..sub.6=an alpha valine;
.alpha..sub.7=an alpha lysine; .beta..sub.4=any beta-3 amino acid;
.alpha..sub.8=an alpha tyrosine; .alpha..sub.9=an alpha leucine;
.alpha..sub.10=an alpha asparagine; .beta..sub.5=any beta-3 amino
acid; .alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .beta..sub.6=any beta amino acid.
[0325] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta-2 threonine;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.beta..sub.2=a beta-2 arginine; .alpha..sub.3=an alpha lysine;
.alpha..sub.4=an alpha glutamine; .alpha..sub.5=an alpha leucine;
.beta..sub.3=a beta-2 alanine; .alpha..sub.6=an alpha valine;
.alpha..sub.7=an alpha lysine; .beta..sub.4=a beta-2 lysine,
.alpha..sub.8=an alpha tyrosine; .alpha..sub.9=an alpha leucine;
.alpha..sub.10=an alpha asparagine; .beta..sub.5=a beta-2 alanine;
.alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .beta..sub.6=a beta-2 asparagine.
[0326] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta-3 threonine or ACPC;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.beta..sub.2=a beta-3 arginine or APC; .alpha..sub.3=an alpha
lysine; .alpha..sub.4=an alpha glutamine; .alpha..sub.5=an
alpha-leucine; .beta..sub.3=a beta-3 alanine or ACPC;
.alpha..sub.6=an alpha valine; .alpha..sub.7=an alpha lysine;
.beta..sub.4=a beta-3 lysine or APC; .alpha..sub.8=an alpha
tyrosine; .alpha..sub.9=an alpha leucine; .alpha..sub.10=an alpha
asparagine; .beta..sub.5=a beta-3 alanine or ACPC;
.alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .beta..sub.6=a beta-3 asparagine.
[0327] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any beta
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .alpha..sub.13=any alpha amino acid.
[0328] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=any beta-3, beta-2, cyclic or
heterocyclic beta-amino acid; .alpha..sub.1=any alpha amino acid;
.alpha..sub.2=any alpha amino acid; .alpha..sub.3=any alpha amino
acid; .beta..sub.2=any beta-3, beta-2, cyclic or heterocyclic
beta-amino acid; .alpha..sub.4=any alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta-3,
beta-2, cyclic or heterocyclic beta-amino acid; .alpha..sub.6=any
alpha amino acid; .alpha..sub.7=any alpha amino acid; .alpha.8=any
alpha amino acid; .beta..sub.4=any beta-3, beta-2, cyclic or
heterocyclic beta-amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta-3,
beta-2, cyclic or heterocyclic beta-amino acid; .alpha..sub.11=any
alpha amino acid; .alpha..sub.12=any alpha amino acid;
.alpha..sub.13=any alpha amino acid.
[0329] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=any beta-3 amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta-3
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta-3 amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta-3 amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta-3 amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid.
[0330] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=any beta-2 amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta-2
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta-2 amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta-2 amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta-2 amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid.
[0331] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=any cyclic or heterocyclic
beta-amino acid; .alpha..sub.1=any alpha amino acid;
.alpha..sub.2=any alpha amino acid; .alpha..sub.3=any alpha amino
acid, .beta..sub.2=any cyclic or heterocyclic beta-amino acid;
.alpha..sub.4=any alpha amino acid; .alpha..sub.5=any alpha amino
acid; .beta..sub.3=any cyclic or heterocyclic beta-amino acid;
.alpha.6=any alpha amino acid, .alpha.7=any alpha amino acid;
.alpha.8=any alpha amino acid, .beta..sub.4=any cyclic or
heterocyclic beta-amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any cyclic or
heterocyclic beta-amino acid; .alpha..sub.11=any alpha amino acid;
.alpha..sub.12=any alpha amino acid, .alpha..sub.13=any alpha amino
acid.
[0332] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=a beta-3 threonine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=a beta-3
lysine; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=a beta-3 alanine; .alpha.6=any alpha amino
acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha amino acid;
.beta..sub.4=a beta-3 tyrosine; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=a beta-3 alanine;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .alpha..sub.13=any alpha amino acid.
[0333] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13; wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.beta..sub.3=an alpha arginine; .beta..sub.2=any beta amino acid;
.alpha..sub.4=an alpha glutamine; .alpha..sub.5=an alpha leucine;
.beta..sub.3=any beta amino acid; .alpha..sub.6=an alpha valine
acid; .alpha..sub.7=an alpha lysine, .alpha..sub.8=an alpha lysine,
.beta..sub.4=any beta amino acid; .alpha..sub.9=an alpha leucine;
.alpha..sub.10=an alpha asparagine, .beta..sub.5=any beta amino
acid; .alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .alpha..sub.13=an alpha asparagine.
[0334] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13; wherein .beta..sub.1=any beta-3 amino acid;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.beta..sub.3=an alpha arginine; .beta..sub.2=any beta-3 amino acid;
.alpha..sub.4=an alpha glutamine; .alpha..sub.5=an alpha leucine;
=any beta-3 amino acid; .alpha..sub.6=an alpha valine acid;
.alpha..sub.7=an alpha lysine, .alpha..sub.8=an alpha lysine,
.beta..sub.4=any beta-3 amino acid; .alpha..sub.9=an alpha leucine;
.alpha..sub.10=an alpha asparagine, .beta..sub.5=any beta-3 amino
acid; .alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .alpha..sub.13=an alpha asparagine.
[0335] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13; wherein .beta..sub.1=any beta-2 amino acid;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.beta..sub.3=an alpha arginine; .beta..sub.2=any beta-2 amino acid;
.alpha..sub.7=an alpha glutamine; .alpha..sub.8=an alpha leucine;
.beta..sub.3=any beta-2 amino acid; .alpha..sub.6=an alpha valine
acid; .alpha..sub.7=an alpha lysine, .alpha..sub.8=an alpha lysine,
.beta..sub.4=any beta-2 amino acid; .alpha..sub.9=an alpha leucine;
.alpha..sub.10=an alpha asparagine; .beta..sub.5=any beta-2 amino
acid; .alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .alpha..sub.13=an alpha asparagine.
[0336] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13; wherein .beta..sub.1=any cyclic and heterocyclic beta
amino acid; .alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha
leucine; .alpha..sub.3=an alpha arginine; .beta..sub.2=any cyclic
and heterocyclic beta amino acid; .alpha..sub.4=an alpha glutamine;
.alpha..sub.5=an alpha leucine; .beta..sub.3=any cyclic and
heterocyclic beta amino acid; .alpha..sub.6=an alpha valine acid;
.alpha..sub.7=an alpha lysine; .alpha..sub.8=an alpha lysine;
.beta..sub.4=any cyclic and heterocyclic beta amino acid;
.alpha..sub.9=an alpha leucine; .alpha..sub.10=an alpha asparagine;
.beta..sub.5=any cyclic and heterocyclic beta amino acid;
.alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .alpha..sub.13=an alpha asparagine.
[0337] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=a beta-3 threonine or an ACPC;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.alpha..sub.3=an alpha arginine; .beta..sub.2=a beta-3 lysine or
APC; .alpha..sub.4=an alpha glutamine; .alpha..sub.5=an alpha
leucine; .beta..sub.3=a beta-3 alanine or ACPC; .alpha..sub.6=an
alpha valine acid; .alpha..sub.7=an alpha lysine; .alpha..sub.8=an
alpha lysine; .beta..sub.4=a beta-3 tyrosine or; .alpha..sub.9=an
alpha leucine; .alpha..sub.10=an alpha asparagine; .beta..sub.5=a
beta-3 alanine or ACPC; .alpha..sub.11=an alpha isoleucine;
.alpha..sub.12=an alpha leucine; .alpha..sub.13=an alpha
asparagine.
[0338] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any beta
amino acid; .beta..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid.
[0339] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta-3, beta-2,
cyclic or heterocyclic beta-amino acid; .alpha..sub.1=any alpha
amino acid; .alpha..sub.2=any alpha amino acid; .alpha..sub.3=an
alpha amino acid; .beta..sub.2=any beta-3, beta-2, cyclic or
heterocyclic beta-amino acid; .alpha..sub.4=an alpha alpha amino
acid; .alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta-3,
beta-2, cyclic or heterocyclic beta-amino acid; .alpha..sub.6=any
alpha amino acid; .alpha..sub.7=any alpha amino acid;
.alpha..sub.8=any alpha amino acid; .beta..sub.4=any beta-3,
beta-2, cyclic or heterocyclic beta-amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta-3, beta-2, cyclic or heterocyclic beta-amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta-3, beta-2, cyclic or heterocyclic beta-amino
acid.
[0340] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta-3 amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta-3 amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta-3 amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta-3 amino acid; .alpha..sub.9=any alpha amino acid,
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta-3 amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta-3 amino acid.
[0341] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta-2 amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta-2 amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta-2 amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta-2 amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta-2 amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta-2 amino acid.
[0342] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any cyclic or
heterocyclic beta-amino acid; .alpha..sub.1=any alpha amino acid;
.alpha..sub.2=any alpha amino acid; .alpha..sub.3=an alpha amino
acid; .beta..sub.2=any cyclic or heterocyclic beta-amino acid;
.alpha..sub.4=an alpha alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=any cyclic or heterocyclic beta-amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
cyclic or heterocyclic beta-amino acid; .alpha..sub.9=any alpha
amino acid; .alpha..sub.10=any alpha amino acid; .beta..sub.5=any
cyclic or heterocyclic beta-amino acid; .alpha..sub.11=any alpha
amino acid, .alpha..sub.12=any alpha amino acid, .alpha..sub.13=any
alpha amino acid; and .beta..sub.6=any cyclic or heterocyclic
beta-amino acid.
[0343] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=a beta-2 tyrosine;
.alpha..sub.1=any alpha amino acid, .alpha..sub.2=any alpha amino
acid, .alpha..sub.3=an alpha amino acid; .beta..sub.2=a beta-2
arginine; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=a beta-2 leucine;
.alpha..sub.6=any alpha amino acid, .alpha..sub.7=any alpha amino
acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=a beta-2
lysine; .alpha..sub.9=any alpha amino acid, .alpha..sub.10=any
alpha amino acid; .beta..sub.5=a beta-2 asparagine;
.alpha..sub.11=any alpha amino acid, .alpha..sub.12=any alpha amino
acid, .alpha..sub.13=any alpha amino acid; and .beta..sub.6=a
beta-2 asparagine.
[0344] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=a beta-3 tyrosine;
.alpha..sub.1=any alpha amino acid, .alpha..sub.2=any alpha amino
acid, .alpha..sub.3=an alpha amino acid, .beta..sub.2=a beta-3
arginine; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=a beta-3 leucine;
.alpha..sub.6=any alpha amino acid, .alpha..sub.7=any alpha amino
acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=a beta-3
lysine; .alpha..sub.9=any alpha amino acid, .alpha..sub.10=any
alpha amino acid; .beta..sub.5=a beta-3 asparagine;
.alpha..sub.11=any alpha amino acid, .alpha..sub.12=any alpha amino
acid, .alpha..sub.13=any alpha amino acid; and .beta..sub.6=a
beta-3 asparagine.
[0345] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=an alpha threonine; .alpha..sub.2=an alpha arginine;
.alpha..sub.3=an alpha leucine; .beta..sub.2=any beta amino acid;
.alpha..sub.4=an alpha lysine, .alpha..sub.5=an alpha glutamine,
.beta..sub.3=any beta amino acid; .alpha..sub.6=an alpha alanine;
.alpha..sub.7=an alpha valine; .alpha..sub.8=an alpha lysine,
.beta..sub.4=any beta amino acid; .alpha..sub.9=an alpha tyrosine;
.alpha..sub.10=an alpha leucine; .beta..sub.5=any beta amino acid;
.alpha..sub.11=an alpha alanine, .alpha..sub.12=an alpha
isoleucine; .alpha..sub.13=an alpha leucine; and .beta..sub.6=any
beta amino acid.
[0346] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta-3 amino
acid; .alpha..sub.1=an alpha threonine; .alpha..sub.2=an alpha
arginine; .alpha..sub.3=an alpha leucine; .beta..sub.2=any beta-3
amino acid; .alpha..sub.4=an alpha lysine; .alpha..sub.5=an alpha
glutamine; .beta..sub.3=any beta-3 amino acid; .alpha..sub.6=an
alpha alanine; .alpha..sub.7=an alpha valine; .alpha..sub.8=an
alpha lysine; .beta..sub.4=any beta-3 amino acid; .alpha..sub.9=an
alpha tyrosine; .alpha..sub.10=an alpha leucine; .beta..sub.5=any
beta-3 amino acid; .alpha..sub.11=an alpha alanine;
.alpha..sub.12=an alpha isoleucine; .alpha..sub.13=an alpha
leucine; and .beta..sub.6=any beta-3 amino acid.
[0347] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta-2 amino
acid; .alpha..sub.1=an alpha threonine; .alpha..sub.2=an alpha
arginine; .alpha..sub.3=an alpha leucine; .beta..sub.2=any beta-2
amino acid; .alpha..sub.4=an alpha lysine; .alpha..sub.5=an alpha
glutamine; .beta..sub.3=any beta-2 amino acid; .alpha..sub.6=an
alpha alanine; .alpha..sub.7=an alpha valine; .alpha..sub.8=an
alpha lysine; .beta..sub.4=any beta-2 amino acid; .alpha..sub.9=an
alpha tyrosine; .alpha..sub.10=an alpha leucine; .beta..sub.5=any
beta-2 amino acid; .alpha..sub.11=an alpha alanine;
.alpha..sub.12=an alpha isoleucine; .alpha..sub.13=an alpha
leucine; and .beta..sub.6=any beta-2 amino acid.
[0348] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any cyclic or
heterocyclic beta amino acid; .alpha..sub.1=an alpha threonine;
.alpha..sub.2=an alpha arginine; .alpha..sub.3=an alpha leucine;
.beta..sub.2=any cyclic or heterocyclic beta amino acid;
.alpha..sub.4=an alpha lysine; .alpha..sub.5=an alpha glutamine;
.beta..sub.3=any cyclic or heterocyclic beta amino acid;
.alpha..sub.6=an alpha alanine; .alpha..sub.7=an alpha valine;
.alpha..sub.8=an alpha lysine; .beta..sub.4=any cyclic or
heterocyclic beta amino acid; .alpha..sub.9=an alpha tyrosine;
.alpha..sub.10=an alpha leucine; .beta..sub.5=any cyclic or
heterocyclic beta amino acid; .alpha..sub.11=an alpha alanine;
.alpha..sub.12=an alpha isoleucine; .alpha..sub.13=an alpha
leucine; and .beta..sub.6=any cyclic or heterocyclic beta amino
acid.
[0349] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=an alpha threonine; .alpha..sub.2=an alpha arginine;
.alpha..sub.3=an alpha leucine; .beta..sub.2=a beta-2 arginine or
APC; .alpha..sub.4=an alpha lysine; .alpha..sub.5=an alpha
glutamine; .beta..sub.3=any beta-2 amino acid; .alpha..sub.6=an
alpha alanine; .alpha..sub.7=an alpha valine; .alpha..sub.8=an
alpha lysine; .beta..sub.4=any beta-2 amino acid; .alpha..sub.9=an
alpha tyrosine; .alpha..sub.10=an alpha leucine; .beta..sub.5=any
beta-2 amino acid; .alpha..sub.11=an alpha alanine;
.alpha..sub.12=an alpha isoleucine; .alpha..sub.13=an alpha
leucine; and .beta..sub.6=any beta-2 amino acid.
[0350] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=a beta-3 tyrosine;
.alpha..sub.1=an alpha threonine; .alpha..sub.2=an alpha arginine;
.alpha..sub.3=an alpha leucine; .beta..sub.2=a beta-3 arginine or
APC; .alpha..sub.4=an alpha lysine, .alpha..sub.5=an alpha
glutamine; .beta..sub.3=a beta-3 leucine or ACPC; .alpha..sub.6=an
alpha alanine; .alpha..sub.7=an alpha valine; .alpha..sub.5=an
alpha lysine, .beta..sub.4=a beta-3 lysine or APC; .alpha..sub.9=an
alpha tyrosine; .alpha..sub.10=an alpha leucine; .beta..sub.5=a
beta-3 asparagine or ACPC; .alpha..sub.11=an alpha alanine;
.alpha..sub.12=an alpha isoleucine; .alpha..sub.13=an alpha
leucine; and .beta..sub.6=a beta-3 asparagine.
[0351] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0352]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and
[0353]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid; and
[0354] wherein the repetitive pattern is, optionally, preceded
by:
[0355] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and
[0356] wherein the C-terminus is optionally amidated; and
[0357] wherein the N-terminus is optionally acylated;
[0358] or functional fragments thereof.
[0359] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0360]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6, wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=any alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha.6=any alpha amino acid; .alpha.7=any alpha amino acid;
.alpha.8=any alpha amino acid; .beta..sub.4=any beta amino acid;
.alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha amino
acid; .beta..sub.5=any beta amino acid; .alpha..sub.11=any alpha
amino acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any
alpha amino acid;
[0361]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid,
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and
[0362]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid; and
[0363] wherein the repetitive pattern is, optionally, preceded
by:
[0364] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and
[0365] wherein the C-terminus is optionally amidated; and
[0366] wherein the N-terminus is optionally acylated;
[0367] or functional fragments thereof.
[0368] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0369]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid;
[0370]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha leucine; .beta..sub.3=any beta amino acid; .alpha..sub.6=any
alpha amino acid; .alpha..sub.7=any alpha amino acid;
.beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha amino
acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha
amino acid; .beta..sub.5=a beta-3 alanine or an ACPC;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and
[0371]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid; and
[0372] wherein the repetitive pattern is, optionally, preceded
by:
[0373] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and
[0374] wherein the C-terminus is optionally amidated; and
[0375] wherein the N-terminus is optionally acylated;
[0376] or functional fragments thereof.
[0377] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0378]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid;
[0379]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.8=an
alpha leucine; .beta..sub.3=any beta amino acid; .alpha..sub.6=any
alpha amino acid; .alpha..sub.7=any alpha amino acid;
.beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha amino
acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha
amino acid; .beta..sub.5=any beta amino acid; .alpha..sub.11=any
alpha amino acid; .alpha..sub.12=any alpha amino acid;
.beta..sub.6=any beta amino acid; and
[0380]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid;
[0381] wherein the repetitive pattern is, optionally, preceded
by:
[0382] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..alpha..sub.8.-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; or a fragment thereof; and wherein at
least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340)
or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a non-natural
amino acid.
[0383] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0384]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid;
[0385]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha leucine; .beta..sub.3=any beta amino acid; .alpha..sub.6=any
alpha amino acid; .alpha..sub.7=any alpha amino acid;
.beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha amino
acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha
amino acid; .beta..sub.5=a beta-3 alanine or an ACPC;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and
[0386]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid;
[0387] wherein the repetitive pattern is, optionally, preceded
by:
[0388] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..beta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the
composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2-
.alpha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..su-
b.8.beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha-
..sub.12.alpha..sub.13.beta..sub.6; or a fragment thereof; and
wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID
NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a
non-natural amino acid.
[0389] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0390]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid;
[0391]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha leucine; .beta..sub.3=any beta amino acid; .alpha..sub.6=any
alpha amino acid; .alpha..sub.7=any alpha amino acid;
.beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha amino
acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha
amino acid; .beta..sub.5=any beta amino acid; .alpha..sub.11=any
alpha amino acid; .alpha..sub.12=any alpha amino acid;
.beta..sub.6=any beta amino acid; and
[0392]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid;
[0393] wherein the repetitive pattern is, optionally, preceded
by:
[0394] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and wherein at least one or more of the
amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO:
1341) is substituted with a beta amino acid selected from the group
chosen from: a beta-3 homolog of the wild-type amino acid
sequence.
[0395] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0396]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid;
[0397]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha leucine; .beta..sub.3=any beta amino acid; .alpha..sub.6=any
alpha amino acid; .alpha..sub.7=any alpha amino acid;
.beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha amino
acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha
amino acid; .beta..sub.5=any beta amino acid; .alpha..sub.11=any
alpha amino acid; .alpha..sub.12=any alpha amino acid;
.beta..sub.6=any beta amino acid; and
[0398]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid;
[0399] wherein the repetitive pattern is, optionally, preceded
by:
[0400] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and wherein at least one or more of the
amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO:
1341) is substituted with a beta amino acid selected from the group
chosen from: APC, ACPC, a beta-2 homolog of a wild-type amino acid,
or a beta-3 homolog of a wild-type amino acid.
[0401] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0402]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6, wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=any alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid, .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.6=any alpha amino acid;
[0403]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and
[0404]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid;
[0405] wherein the repetitive pattern is, optionally, preceded
by:
[0406] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and wherein at least one or more of the
amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO:
1341) is substituted with a beta amino acid selected from the group
chosen from: a beta-3 homolog of the wild-type amino acid sequence,
a beta-2 homolog of the wild-type amino acid sequence, ACPC, or
APC.
[0407] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0408]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid;
[0409]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and
[0410]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid;
[0411] wherein the repetitive pattern is, optionally, preceded
by:
[0412] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and wherein the D at position 8 of
HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid
selected from the group chosen from: a beta-3 homolog of the
wild-type amino acid sequence, a beta-2 homolog of the wild-type
amino acid sequence, ACPC, or APC.
[0413] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0414]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid;
[0415]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and
[0416]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .beta..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid;
[0417] wherein the repetitive pattern is, optionally, preceded
by:
[0418] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and wherein the T at position 7 of p
HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid
selected from the group chosen from: a beta-3 homolog of the
wild-type amino acid sequence, a beta-2 homolog of the wild-type
amino acid sequence, ACPC, or APC.
[0419] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0420]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid; .alpha.6=any
alpha amino acid; .alpha.7=any alpha amino acid; .alpha.8=any alpha
amino acid; .beta..sub.4=any beta amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid,
.beta..sub.5=any beta amino acid; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha
amino acid;
[0421]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and
[0422]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid;
[0423] wherein the repetitive pattern is, optionally, preceded
by:
[0424] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and wherein the D at position 8 of
HSDAVFTDNY (SEQ ID NO: 1340) and, optionally, the T at position 7
of HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino
acid selected from the group chosen from: a beta-3 homolog of the
wild-type amino acid sequence, a beta-2 homolog of the wild-type
amino acid sequence, ACPC, or APC.
[0425] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus selected from
the following:
[0426]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any beta
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid, .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .alpha..sub.13=any alpha amino acid;
[0427]
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.a-
lpha..sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and
[0428]
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alp-
ha..sub.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.alpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino
acid; .alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha
amino acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any
beta amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid;
[0429] wherein the repetitive pattern is, optionally, preceded
by:
[0430] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13 or
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition
comprises
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; and wherein the T at position 7 of
[0431] HSDAVFTDNY (SEQ ID NO: 1340) and, optionally, the D at
position 8 of HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a
beta amino acid selected from the group chosen from: a beta-3
homolog of the wild-type amino acid sequence, a beta-2 homolog of
the wild-type amino acid sequence ACPC, or APC.
[0432] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus to the
carboxy-terminus:
.beta..alpha..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta.-
.alpha..alpha..alpha..beta..alpha..alpha..beta.. In some
embodiments, the composition comprises a VIP analog, wherein the
analog comprises the following repetitive pattern of sequential
.beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; wherein the repetitive
pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340)
if the composition comprises; and
[0433] wherein the C-terminus is, optionally, amidated; and
[0434] wherein the N-terminus is, optionally, acylated;
[0435] or functional fragments thereof.
[0436] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta 3-threonine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=a beta-3 arginine; .alpha..sub.3=any alpha amino
acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=a beta-3 alanine; .alpha..sub.6=any alpha
amino acid; .alpha..sub.7=any alpha amino acid; .beta..sub.4=a
beta-3 lysine; .alpha..sub.5=any alpha amino acid;
.alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha amino
acid; .beta..sub.5=a beta-3 asparagine; .alpha..sub.11=any alpha
amino acid; .alpha..sub.12=any alpha amino acid; .beta..sub.6=any
beta amino acid; wherein the repetitive pattern is, optionally,
preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition
comprises; and
[0437] wherein the C-terminus is, optionally, amidated; and
[0438] wherein the N-terminus is, optionally, acylated;
[0439] or functional fragments thereof.
[0440] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta 3-threonine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=a beta-3 arginine; .alpha..sub.3=any alpha amino
acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=a beta-3 alanine; .alpha..sub.6=any alpha
amino acid; .alpha..sub.7=any alpha amino acid; .beta..sub.4=a
beta-3 lysine; .alpha..sub.5=any alpha amino acid;
.alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha amino
acid; .beta..sub.5=a beta-3 alanine; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .beta..sub.6=a beta-3
asparagine; wherein the repetitive pattern is, optionally, preceded
by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises;
and
[0441] wherein the C-terminus is, optionally, amidated; and
[0442] wherein the N-terminus is, optionally, acylated;
[0443] or functional fragments thereof.
[0444] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta 3-threonine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=a beta-3 arginine; .alpha..sub.3=any alpha amino
acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an alpha
leucine; .beta..sub.3=a beta-3 alanine; .alpha..sub.6=any alpha
amino acid; .alpha..sub.7=any alpha amino acid; .beta..sub.4=a
beta-3 lysine; .alpha..sub.8=any alpha amino acid;
.alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha amino
acid; .beta..sub.5=a beta-3 alanine; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .beta..sub.6=a beta-3
asparagine; wherein the repetitive pattern is, optionally, preceded
by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises;
and
[0445] wherein the C-terminus is, optionally, amidated; and
[0446] wherein the N-terminus is, optionally, acylated;
[0447] or functional fragments thereof.
[0448] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.5=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=a beta-3 alanine; .alpha..sub.11=any
alpha amino acid; .alpha..sub.12=any alpha amino acid;
.beta..sub.6=a beta-3 asparagine; wherein the repetitive pattern
is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the
composition comprises; and
[0449] wherein the C-terminus is, optionally, amidated; and
[0450] wherein the N-terminus is, optionally, acylated;
[0451] or functional fragments thereof.
[0452] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=an alpha arginine; .alpha..sub.5=an alpha leucine;
.beta..sub.2=any beta amino acid; .alpha..sub.3=an alpha lysine,
.alpha..sub.4=an alpha glutamine; .alpha..sub.5=an alpha leucine;
.beta..sub.3=any beta amino acid; .alpha..sub.6=an alpha valine;
.alpha..sub.7=an alpha lysine; .beta..sub.4=any beta amino acid;
.alpha..sub.8=an alpha tyrosine; .alpha..sub.9=an alpha leucine;
.alpha..sub.10=an alpha asparagine; .beta..sub.5=any beta amino
acid; .alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .beta..sub.6=any beta amino acid; wherein the repetitive
pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340)
if the composition comprises, and
[0453] wherein the C-terminus is, optionally, amidated; and
[0454] wherein the N-terminus is, optionally, acylated;
[0455] or functional fragments thereof.
[0456] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta-3 threonine or ACPC;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.beta..sub.2=a beta-3 arginine or APC; .alpha..sub.3=an alpha
lysine; .alpha..sub.4=an alpha glutamine; .alpha..sub.5=an alpha
leucine; .beta..sub.3=a beta-3 alanine or ACPC; .alpha..sub.6=an
alpha valine; .alpha..sub.7=an alpha lysine; .beta..sub.4=a beta-3
lysine or APC; .alpha..sub.s=an alpha tyrosine; .alpha..sub.9=an
alpha leucine; .alpha..sub.10=an alpha asparagine; .beta..sub.5=a
beta-3 alanine or ACPC; .alpha..sub.11=an alpha isoleucine;
.alpha..sub.12=an alpha leucine; .beta..sub.6=a beta-3 asparagine;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
[0457] wherein the C-terminus is, optionally, amidated; and
[0458] wherein the N-terminus is, optionally, acylated;
[0459] or functional fragments thereof.
[0460] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any beta
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .alpha..sub.13=any alpha amino acid; wherein the repetitive
pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340)
if the composition comprises; and
[0461] wherein the C-terminus is, optionally, amidated; and
[0462] wherein the N-terminus is, optionally, acylated;
[0463] or functional fragments thereof.
[0464] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=a beta-3 threonine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=any alpha amino acid; .beta..sub.2=a beta-3
lysine; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=a beta-3 alanine; .alpha..sub.6=any alpha
amino acid; .alpha..sub.7=any alpha amino acid; .alpha..sub.8=any
alpha amino acid; .beta..sub.4=a beta-3 tyrosine; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=a beta-3 alanine; .alpha..sub.11=any alpha amino acid;
.alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha amino
acid; wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
[0465] wherein the C-terminus is, optionally, amidated; and
[0466] wherein the N-terminus is, optionally, acylated;
[0467] or functional fragments thereof.
[0468] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13; wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=an alpha arginine; .alpha..sub.2=an alpha leucine;
.beta..sub.3=an alpha arginine; .beta..sub.2=any beta amino acid;
.alpha..sub.4=an alpha glutamine; .alpha..sub.5=an alpha leucine;
.beta..sub.3=any beta amino acid; .alpha..sub.6=an alpha valine
acid; .alpha..sub.7=an alpha lysine; .alpha..sub.8=an alpha lysine,
.beta..sub.4=any beta amino acid; .alpha..sub.9=an alpha leucine;
.alpha..sub.10=an alpha asparagine; .beta..sub.5=any beta amino
acid; .alpha..sub.11=an alpha isoleucine; .alpha..sub.12=an alpha
leucine; .alpha..sub.13=an alpha asparagine; wherein the repetitive
pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340)
if the composition comprises; and
[0469] wherein the C-terminus is, optionally, amidated; and
[0470] wherein the N-terminus is, optionally, acylated;
[0471] or functional fragments thereof.
[0472] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13, wherein .beta..sub.1=a beta-3 threonine or an ACPC;
.alpha..sub.1=an alpha arginine, .alpha..sub.2=an alpha leucine;
.alpha..sub.3=an alpha arginine; .beta..sub.2=a beta-3 lysine or
APC; .alpha..sub.1=an alpha glutamine; .alpha..sub.5=an alpha
leucine; .beta..sub.3=a beta-3 alanine or ACPC; .alpha..sub.6=an
alpha valine acid, .alpha..sub.7=an alpha lysine; .alpha..sub.8=an
alpha lysine; .beta..sub.4=a beta-3 tyrosine or; .alpha..sub.9=an
alpha leucine; .alpha..sub.10=an alpha asparagine; .beta..sub.5=a
beta-3 alanine or ACPC; .alpha..sub.11=an alpha isoleucine;
.alpha..sub.12=an alpha leucine; .alpha..sub.13=an alpha
asparagine; wherein the repetitive pattern is, optionally, preceded
by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises;
and
[0473] wherein the C-terminus is, optionally, amidated; and
[0474] wherein the N-terminus is, optionally, acylated;
[0475] or functional fragments thereof.
[0476] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid; wherein the repetitive pattern
is, optionally, preceded by: HSDAVFTDN (SEQ ID NO: 1341), and
[0477] wherein the C-terminus is, optionally, amidated; and
[0478] wherein the N-terminus is, optionally, acylated;
[0479] or functional fragments thereof.
[0480] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=a beta-3 tyrosine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=a beta-3
arginine; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=a beta-3 leucine;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=a beta-3
lysine; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=a beta-3 asparagine;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .alpha..sub.13=any alpha amino acid; and .beta..sub.6=a
beta-3 asparagine; wherein the repetitive pattern is, optionally,
preceded by: HSDAVFTDN (SEQ ID NO: 1341), and
[0481] wherein the C-terminus is, optionally, amidated; and
[0482] wherein the N-terminus is, optionally, acylated;
[0483] or functional fragments thereof.
[0484] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=a beta-3 tyrosine;
.alpha..sub.1=an alpha threonine; .alpha..sub.2=an alpha arginine;
.alpha..sub.3=an alpha leucine; .beta..sub.2=a beta-3 arginine or
APC; .alpha..sub.4=an alpha lysine; .alpha..sub.5=an alpha
glutamine; .beta..sub.3=a beta-3 leucine or ACPC; .alpha..sub.6=an
alpha alanine; .alpha..sub.7=an alpha valine; .alpha..sub.8=an
alpha lysine; .beta..sub.4=a beta-3 lysine or APC; .alpha..sub.9=an
alpha tyrosine; .alpha..sub.10=an alpha leucine; .beta..sub.5=a
beta-3 asparagine or ACPC; .alpha..sub.11=an alpha alanine;
.alpha..sub.12=an alpha isoleucine; .alpha..sub.13=an alpha
leucine; and .beta..sub.6=a beta-3 asparagine; wherein the
repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID
NO: 1341), and
[0485] wherein the C-terminus is, optionally, amidated; and
[0486] wherein the N-terminus is, optionally, acylated;
[0487] or functional fragments thereof.
[0488] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=a beta-3 tyrosine;
.alpha..sub.1=an alpha threonine; .alpha..sub.2=an alpha arginine;
.alpha..sub.3=an alpha leucine; .beta..sub.2=a beta-3 arginine or
APC; .alpha..sub.4=an alpha lysine; .alpha..sub.5=an alpha
glutamine; .beta..sub.3=a beta-3 leucine or ACPC; .alpha..sub.6=an
alpha alanine; .alpha..sub.7=an alpha valine; .alpha..sub.8=an
alpha lysine; .beta..sub.4=a beta-3 lysine or APC; .alpha..sub.9=an
alpha tyrosine; .alpha..sub.10=an alpha leucine, .beta..sub.5=a
beta-3 asparagine or ACPC; .alpha..sub.11=an alpha alanine;
.alpha..sub.12=an alpha isoleucine, .alpha..sub.13=an alpha
leucine; and .beta..sub.6=a beta-3 asparagine; wherein the
repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID
NO: 1341); and
[0489] wherein the C-terminus is, optionally, amidated; and
[0490] wherein the N-terminus is, optionally, acylated;
[0491] or functional fragments thereof
[0492] In some embodiments, the composition comprises HSDAVFTDN
(SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein at least
one of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or
HSDAVFTDNY (SEQ ID NO: 1340) are non-natural or beta amino acids.
In some embodiments, the composition comprises HSDAVFTDN (SEQ ID
NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein at least one of
the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ
ID NO: 1340) is a beta-3, beta-2, cyclic, or heterocyclic beta
amino acids. In some embodiments, the C-terminus is not amidated.
In some embodiments, the N-terminus is not acylated. In some
embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341)
or HSDAVFTDNY (SEQ ID NO: 1340), wherein the the amino acids from
HSDAVFTDN or HSDAVFTDNY (SEQ ID NO: 1340) are alpha amino acids. In
some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO:
1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein the the amino acids
from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340)
are not alpha amino acids. In some embodiments, the composition
comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO:
1340), wherein none of the amino acids from HSDAVFTDN (SEQ ID NO:
1341) or HSDAVFTDNY (SEQ ID NO: 1340) are beta-3 amino acids. In
some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO:
1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino
acids from HSDAVFTDN or HSDAVFTDNY (SEQ ID NO: 1340) are beta-2
amino acids. In some embodiments, the composition comprises
HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340),
wherein none of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or
HSDAVFTDNY (SEQ ID NO: 1340) are ACPC or APC. In some embodiments,
the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY
(SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN
(SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are cyclic. In
some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO:
1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino
acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO:
1340) are heterocyclic.
[0493] "Selective" or "Selectivity" means that the analog of the
present invention has a binding preference for one protein as
compared to another protein. In some embodiments, the binding
preference may be measured as an affinity for a protein in terms of
half maximal inhibitory concentration (IC50). In some embodiments,
the binding preference may be measured as an affinity for a protein
in terms of half maximal effective concentration (EC50). For
example, an analog selective to VPAC2 receptor with a selectivity
to VPAC2 means that the analog may bind to VPAC1 receptor but has a
higher binding affinity for a domain of the VPAC2 receptor if the
analog is exposed to both VPAC1 and VPAC2 at similar or equivalent
concentrations. As used herein, an analog that selectively binds to
VPAC2 refers to an analog with increased selectivity for the VPAC2
receptor compared to other known receptors or proteins to which the
peptide may bind. In some embodiments, the analog selective for
VPAC2 may be an agonist of the VPAC2 receptor peptide. In some
embodiments, the analog selective for VPAC2 may be an antagonist of
VPAC2 receptor. In some embodiments, an analog selective to VPAC2
receptor means that the analog may bind to VPAC1 receptor but has a
higher binding affinity for a domain of the VPAC2 receptor if the
analog is exposed to PAC1, VPAC1 receptor and VPAC2 receptors at
similar or equivalent concentrations. In some embodiments, an
analog selective to VPAC1 receptor means that the analog may bind
to a domain of VPAC2 or PAC1 receptor but has a higher binding
affinity for a domain of the VPAC1 receptor if the analog is
exposed to to PAC1, VPAC1 receptor and VPAC2 receptors at similar
or equivalent concentrations. As used herein, an analog that
selectively binds to VPAC1 refers to an analog with increased
selectivity for the VPAC1 receptor compared to other known
receptors or proteins to which the peptide may bind. In some
embodiments, the analog selective for VPAC1 may be an agonist of
the VPAC1 receptor peptide. In some embodiments, the analog
selective for VPAC1 may be an antagonist of VPAC1 receptor. In some
embodiments, an analog selective to VPAC1 receptor means that the
analog may bind to VPAC2 receptor but has a higher binding affinity
for a domain of the VPAC1 receptor if the analog is exposed to both
VPAC1 receptor and VPAC2 receptor at similar or equivalent
concentrations. As used herein, an analog that selectively binds to
PAC1 refers to an analog with increased selectivity for the PAC1
receptor as compared to other known receptors or proteins to which
the peptide may bind. In some embodiments, the analog selective for
PAC1 may be an agonist of the PAC1 receptor peptide. In some
embodiments, the analog selective for PAC1 may be an antagonist of
PAC1 receptor. In some embodiments, an analog selective to PAC1
receptor means that the analog may bind to VPAC2 or VPAC1 receptors
but has a higher binding affinity for a domain of the PAC1 receptor
if the analog is exposed to to PAC1, VPAC1 receptor and VPAC2
receptors at similar or equivalent concentrations. The degree of
selectivity may be determined by a ratio of VPAC2 receptor binding
affinity to VPAC1 receptor binding affinity or by a ratio of VPAC2
receptor binding affinity to PAC1 receptor binding affinity.
Binding affinity is determined as described below in Example 1.
[0494] In any of the embodiments described below wherein the
polypeptide comprises a residue designated f, the residue
designated f is D-Phe or L-Phe or S. In some embodiments, the
invention relates to compositions or pharmaceutical compositions
comprising a VIP analog, wherein the analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid, and wherein
the analog is between 75% and 99% homologous to
HfDAVFTNSYRKVLKRLSARKLLQDIL; where residue designated f (position
2) is D-Phe, and wherein the analog interferes with the VPAC1
receptor signaling pathway. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
VIP analog, wherein the analog comprises an .alpha.-amino acid and
at least one .beta.-amino acid, and wherein the analog is between
75% and 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where
residue designated f (position 2) is D-Phe, and wherein the analog
is an antagonist of the VPAC1 receptor. In some embodiments, the
composition comprises a VIP analog is from about 80% to about 99%
homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated
f (position 2) is D-Phe. In some embodiments the VIP analog is from
about 80% to about 85% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL,
where residue designated f (position 2) is D-Phe. In some
embodiments the VIP analog is from about 85% to about 90%
homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated
f (position 2) is D-Phe. In some embodiments the VIP analog is from
about 90% to about 95% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL,
where residue designated f (position 2) is D-Phe. In some
embodiments the VIP analog is from about 95% to about 99%
homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated
f (position 2) is D-Phe. In some embodiments the VIP analog is
about 95%, 96%, 97%, 98%, or 99% homologous to
HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position
2) is D-Phe. In some embodiments, the composition or pharmaceutical
compositions comprise a VIP analog, wherein the analog is either:
(a) an antagonist of VPAC1 receptor; or (b) interferes with VPAC1
receptor signaling pathway and comprises the following repetitive
pattern of sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5, wherein
.beta..sub.1=any beta amino acid; .alpha..sub.1=any alpha amino
acid; .alpha..sub.2=any alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.3=any alpha amino acid; .alpha..sub.4=any
alpha amino acid; .alpha..sub.5=any alpha amino acid;
.beta..sub.3=any beta amino acid; .alpha..sub.6=any alpha amino
acid; .alpha..sub.7=any alpha amino acid; .beta..sub.4=any beta
amino acid; .alpha..sub.8=any alpha amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta amino acid; wherein the repetitive pattern
is, optionally, preceded by: HfDAV FTNSY; and
[0495] wherein residue designated f (position 2) is D-Phe
[0496] wherein the C-terminus is, optionally, amidated; and
[0497] wherein the N-terminus is, optionally, acylated;
[0498] or functional fragments thereof.
In some embodiments, the composition or pharmaceutical compositions
comprise a VIP analog, wherein the analog is either: (a) an
antagonist of VPAC1 receptor; or (b) interferes with VPAC1 receptor
signaling pathway and comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5, wherein
.beta..sub.1=any beta 3 amino acid; .alpha..sub.1=any alpha amino
acid; .alpha..sub.2=any alpha amino acid; .beta..sub.2=any beta 3
amino acid; .alpha..sub.3=any alpha amino acid; .alpha..sub.4=any
alpha amino acid; .alpha..sub.5=any alpha amino acid;
.beta..sub.3=any beta 3 amino acid; .alpha..sub.6=any alpha amino
acid; .alpha..sub.7=any alpha amino acid; .beta..sub.4=any beta 3
amino acid; .alpha..sub.8=any alpha amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta 3 amino acid; wherein the repetitive pattern
is, optionally, preceded by: HfDAV FTNSY, and
[0499] wherein residue designated f (position 2) is D-Phe
[0500] wherein the C-terminus is, optionally, amidated; and
[0501] wherein the N-terminus is, optionally, acylated;
[0502] or functional fragments thereof.
In some embodiments, the composition or pharmaceutical compositions
comprise a VIP analog, wherein the analog is either: (a) an
antagonist of VPAC1 receptor; or (b) interferes with VPAC1 receptor
signaling pathway and comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5, wherein
.beta..sub.1=a beta-3 arginine; .alpha..sub.1=any alpha amino acid;
.alpha..sub.2=any alpha amino acid; .beta..sub.2=a beta-3 leucine;
.alpha..sub.3=any alpha amino acid; .alpha..sub.4=any alpha amino
acid; .alpha..sub.5=any alpha amino acid; .beta..sub.3=a beta-3
serine; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .beta..sub.4=a beta-3 lysine; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=a beta-3 aspartic acid; wherein the
repetitive pattern is, optionally, preceded by: HfDAV FTNSY;
and
[0503] wherein residue designated f (position 2) is D-Phe
[0504] wherein the C-terminus is, optionally, amidated; and
[0505] wherein the N-terminus is, optionally, acylated;
[0506] or functional fragments thereof.
In some embodiments, the composition comprises HfDAVFTDN or
HfDAVFTDNY, wherein at least one of the amino acids from HfDAVFTDN
or HfDAVFTDNY are non-natural or beta amino acids, wherein residue
designated f (position 2) is D-Phe. In some embodiments, the
composition comprises HfDAVFTDN or HfDAVFTDNY, wherein at least one
of the amino acids from HfDAVFTDN or HfDAVFTDNY is a beta-3,
beta-2, cyclic, or heterocyclic beta amino acids, and wherein
residue designated f (position 2) is D-Phe. In some embodiments,
the C-terminus is not amidated. In some embodiments, the N-terminus
is not acylated. In some embodiments, the composition comprises
HfDAVFTDN or HfDAVFTDNY, wherein the the amino acids from HfDAVFTDN
or HfDAVFTDNY are alpha amino acids, and wherein residue designated
f (position 2) is D-Phe. In some embodiments, the composition
comprises HfDAVFTDN or HfDAVFTDNY, wherein the the amino acids from
HfDAVFTDN or HfDAVFTDNY are not alpha amino acids, and wherein
residue designated f (position 2) is D-Phe. In some embodiments,
the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of
the amino acids from HfDAVFTDN or HfDAVFTDNY are beta-3 amino
acids, and wherein residue designated f (position 2) is D-Phe. In
some embodiments, the composition comprises HfDAVFTDN or
HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or
HfDAVFTDNY are beta-2 amino acids, and wherein residue designated f
(position 2) is D-Phe. In some embodiments, the composition
comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids
from HfDAVFTDN or HfDAVFTDNY are ACPC or APC, and wherein residue
designated f (position 2) is D-Phe. In some embodiments, the
composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the
amino acids from HfDAVFTDN or HfDAVFTDNY are cyclic, wherein
residue designated f (position 2) is D-Phe. In some embodiments,
the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of
the amino acids from HfDAVFTDN or HfDAVFTDNY are heterocyclic, and
wherein residue designated f (position 2) is D-Phe.
[0507] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5; wherein
.beta..sub.1=any beta amino acid; .alpha..sub.1=any alpha amino
acid; .alpha..sub.2=any alpha amino acid; .alpha..sub.3=an alpha
amino acid; .beta..sub.2=any beta amino acid; .alpha..sub.4=an
alpha alpha amino acid; .alpha..sub.5=any alpha amino acid;
.beta..sub.3=any beta amino acid; .alpha..sub.6=any alpha amino
acid; .alpha..sub.7=any alpha amino acid; .alpha..sub.8=any alpha
amino acid; .beta..sub.4=any beta amino acid; .alpha..sub.9=any
alpha amino acid; .alpha..sub.10=any alpha amino acid;
.beta..sub.5=any beta amino acid; wherein the repetitive pattern
is, optionally, preceded by: HfDAV FTNSY or HfDAV FTNS; and
[0508] wherein the C-terminus is, optionally, amidated; and
[0509] wherein the N-terminus is, optionally, acylated;
[0510] or functional fragments thereof; and wherein residue
designated f (position 2) is D-Phe.
[0511] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5; wherein
.beta..sub.1=a beta-3 arginine or beta-3 tyrosine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=a beta-3
lysine or beta-3 leucine; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=a beta-3 serine or
a beta-3 leucine; .alpha..sub.6=any alpha amino acid;
.alpha..sub.7=any alpha amino acid; .alpha..sub.8=any alpha amino
acid; .beta..sub.4=a beta-3 leucine or beta-3 lysine;
.alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha amino
acid; .beta..sub.5=a beta-3 aspartic acid or beta-3 glutamine;
wherein the repetitive pattern is, optionally, preceded by: HfDAV
FTNSY or HfDAV FTNS; and
[0512] wherein the C-terminus is, optionally, amidated; and
[0513] wherein the N-terminus is, optionally, acylated;
[0514] or functional fragments thereof, and wherein residue
designated f (position 2) is D-Phe.
[0515] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5; wherein
.beta..sub.1=a beta-3 arginine, beta-3 tyrosine, or APC;
.alpha..sub.1=any alpha amino acid, .alpha..sub.2=any alpha amino
acid, .alpha..sub.3=an alpha amino acid; .beta..sub.2=ACPC or APC;
.alpha..sub.4=an alpha alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=ACPC or a beta-3 leucine;
.alpha..sub.6=any alpha amino acid, .alpha..sub.7=any alpha amino
acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=a beta-3
leucine, beta-3 lysine, or APC; .alpha..sub.9=any alpha amino acid,
.alpha..sub.10=any alpha amino acid; .beta..sub.5=a beta-3 aspartic
acid or ACPC; wherein the repetitive pattern is, optionally,
preceded by: HfDAV FTNSY or HfDAV FTNS; and
[0516] wherein the C-terminus is, optionally, amidated; and
[0517] wherein the N-terminus is, optionally, acylated;
[0518] or functional fragments thereof, and wherein residue
designated f (position 2) is D-Phe.
[0519] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 100%
homologous to one or more of the following sequences:
TABLE-US-00005 HfDAV FTNSY ZKVXK RLXAR KLLQD IL HfDAV FTNSY RKVXK
RLXAR ZLLQD IL HfDAV FTNSY RKVXK RLXAR KLLQX IL HfDAV FTNSY ZKVXK
RLXAR ZLLQX IL HfDAV FTNSY RKVLZ RLXAR KLLQX IL HfDAV FTNSY ZKVLZ
RLXAR KLLQX IL HfDAV FTNSY RKVXK RLSAR ZLLXD IL HfDAV FTNSY RKVXK
RXSAR KLLXD IL HfDAV FTNSY RKVXK RXSAR ZLLXD IL
wherein residue designated f (position 2) is D-Phe, wherein each
underlined residue is a beta amino acid, wherein X is a ACPC,
wherein Z is APC, and wherein the analog interferes with the VPAC1
receptor signaling pathway. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
VIP analog, wherein the analog comprises an .alpha.-amino acid and
at least one .beta.-amino acid, and wherein the analog is between
75% and 100% homologous to one or more of the following
sequences:
TABLE-US-00006 HfDAV FTNSY ZKVXK RLXAR KLLQD IL HfDAV FTNSY RKVXK
RLXAR ZLLQD IL HfDAV FTNSY RKVXK RLXAR KLLQX IL HfDAV FTNSY ZKVXK
RLXAR ZLLQX IL HfDAV FTNSY RKVLZ RLXAR KLLQX IL HfDAV FTNSY ZKVLZ
RLXAR KLLQX IL HfDAV FTNSY RKVXK RLSAR ZLLXD IL HfDAV FTNSY RKVXK
RXSAR KLLXD IL HfDAV FTNSY RKVXK RXSAR ZLLXD IL
wherein residue designated f (position 2) is D-Phe, wherein each
underlined residue is a beta amino acid, wherein X is a ACPC,
wherein Z is APC, and wherein the analog is an antagonist of the
VPAC1 receptor; or functional fragments thereof.
[0520] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 100%
homologous to one or more of the following sequences:
TABLE-US-00007 (SEQ ID NO: 1342) HSDAV FTDNY TRLRK QlAVK KYLNa ILN
(SEQ ID NO: 1342) HSDAV FTDNY tRLrK QLaVK kYLNa Iln (SEQ ID NO:
1342) HSDAV FTDNY tRLRk QLaVK KyLNa ILN (SEQ ID NO: 1342) HSDAV
FTDNy TRLrK QlAVK kYLnA Iln (SEQ ID NO: 1343) HSDAV FTDNY tRLzK
QLxVK kYLNx ILn (SEQ ID NO: 1344) HSDAV FTDNY tRLzK QLxVK zYLNx Iln
(SEQ ID NO: 1345) HSDAV FTDNY xRLzK QLxVK kYLNx Iln (SEQ ID NO:
1346) HSDAV FTDNY xRLzK QLxVK zYLNx Iln (SEQ ID NO: 1347) HSDAV
FTDNY tRLRz QLxVK KyLNx ILN (SEQ ID NO: 1348) HSDAV FTDNY xRLRz
QLxVK KyLNx ILN (SEQ ID NO: 1349) HSDAV FTDNy TRLzK QlAVK zYLxA Iln
(SEQ ID NO: 1350) HSDAV FTDNy TRLzK QxAVK kYLxA Iln (SEQ ID NO:
1351) HSDAV FTDNy TRLzK OxAVK zYLxA Iln
wherein each underlined residue is a beta amino acid corresponding
to the single code amino acid upon which it is based, wherein X is
a ACPC, and wherein Z is APC; or functional fragments thereof.
[0521] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 99%
homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433), and
wherein the analog stimulates the VPAC2 receptor signaling pathway.
In some embodiments, the invention relates to compositions or
pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 99%
homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433),
wherein the analog is an agonist of the VPAC2 receptor. In some
embodiments, the composition comprises a VIP analog is from about
80% to about 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ
ID NO:433). In some embodiments the VIP analog is from about 80% to
about 85% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID
NO:433). In some embodiments the VIP analog is from about 85% to
about 90% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID
NO:433). In some embodiments the VIP analog is from about 90% to
about 95% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID
NO:433). In some embodiments the VIP analog is from about 95% to
about 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID
NO:433). In some embodiments the VIP analog is about 95%, 96%, 97%,
98%, or 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID
NO:433). In some embodiments the VIP analog is
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433).
[0522] In some embodiments, the composition or pharmaceutical
composition comprises a VIP analog, wherein the analog comprises
the following repetitive pattern of sequential .beta.-amino acids
from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .beta..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid; .beta..sub.6=any beta amino acid; and wherein the repetitive
pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340)
or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern
is, optionally, succeeded by: K, KR, or KRY
[0523] wherein the C-terminus is, optionally, amidated; and
[0524] wherein the N-terminus is unmodified or modified; or
functional fragments thereof.
[0525] In some embodiments, the composition or pharmaceutical
composition comprises a VIP analog, wherein the analog comprises
the following repetitive pattern of sequential .beta.-amino acids
from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta-3 threonine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=a beta-3 arginine; .alpha..sub.3=any alpha amino
acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=an alpha
leucine; .beta..sub.3=a beta-3 alanine; .alpha..sub.6=any alpha
amino acid; .alpha..sub.7=any alpha amino acid; .beta..sub.4=a
beta-3 lysine; .alpha..sub.8=any alpha amino acid;
.alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha amino
acid; .beta..sub.5=a beta-3 serine; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .beta..sub.6=a beta-3
asparagine; and wherein the repetitive pattern is, optionally,
preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID
NO: 1341); and wherein the repetitive pattern is, optionally,
succeeded by: K, KR, or KRY
[0526] wherein the C-terminus is, optionally, amidated; and
[0527] wherein the N-terminus is unmodified or modified; or
functional fragments thereof,
[0528] wherein the VIP analog or functional fragment thereof is a
VPAC2 agonist.
[0529] In some embodiments, the composition or pharmaceutical
composition comprises a VIP analog, wherein the analog comprises
the following repetitive pattern of sequential .beta.-amino acids
from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=any beta amino acid; .alpha..sub.3=any alpha
amino acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any
alpha amino acid; .beta..sub.3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .alpha..sub.4=any beta amino acid; .alpha..sub.8=any alpha
amino acid; .alpha..sub.9=any alpha amino acid; .alpha..sub.10=any
alpha amino acid; .beta..sub.5=any beta amino acid;
.alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha amino
acid, .beta..sub.6=any beta amino acid; and wherein the repetitive
pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340)
or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern
is, optionally, succeeded by: K, KR, or KRY
[0530] wherein the C-terminus is, optionally, amidated; and
[0531] wherein the N-terminus is unmodified or modified; or
functional fragments thereof; and wherein the analog or functional
fragment thereof is a VPAC2 agonist.
[0532] In some embodiments, the composition or pharmaceutical
composition comprises a VIP analog, wherein the analog comprises
the following repetitive pattern of sequential .beta.-amino acids
from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.beta..sub.2.alpha..sub.3.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.beta..sub.4.alpha..-
sub.8.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.6, wherein .beta..sub.1=a beta-3 threonine;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .beta..sub.2=a beta-3 arginine; .alpha..sub.3=any alpha amino
acid; .alpha..sub.4=any alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=a beta-3 alanine; .alpha..sub.6=any alpha
amino acid; .alpha..sub.7=any alpha amino acid; .beta..sub.4=a
beta-3 lysine; .alpha..sub.8=any alpha amino acid;
.alpha..sub.9=any alpha amino acid; .alpha..sub.10=any alpha amino
acid; .beta..sub.5=a beta-3 serine; .alpha..sub.11=any alpha amino
acid; .alpha..sub.12=any alpha amino acid; .beta..sub.6=a beta-3
asparagine; and wherein the repetitive pattern is, optionally,
preceded by: HSDAVFTDNY CSEQ ID NO: 1340); and wherein the
repetitive pattern is, optionally, succeeded by: K, KR, or KRY
[0533] wherein the C-terminus is, optionally, amidated; and
[0534] wherein the N-terminus is unmodified or modified; or
functional fragments thereof.
[0535] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=any beta amino acid;
.alpha..sub.1=any alpha amino acid; .alpha..sub.2=any alpha amino
acid; .alpha..sub.3=an alpha amino acid; .beta..sub.2=any beta
amino acid; .alpha..sub.4=an alpha alpha amino acid;
.alpha..sub.5=any alpha amino acid; .beta..sub.3=any beta amino
acid; .alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha
amino acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=any
beta amino acid; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid, .beta..sub.5=any beta amino
acid; .alpha..sub.11=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.13=any alpha amino acid; and
.beta..sub.6=any beta amino acid; and wherein the repetitive
pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340)
or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern
is, optionally, succeeded by: K, KR, or KRY
[0536] wherein the C-terminus is, optionally, amidated; and
[0537] wherein the N-terminus is unmodified or modified; or
functional fragments thereof.
[0538] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=a beta-3 threonine
or a beta-3 tyrosine; .alpha..sub.1=any alpha amino acid;
.alpha..sub.2=any alpha amino acid; .alpha..sub.3=an alpha amino
acid; .beta..sub.2=a beta-3 lysine or a beta-3 arginine;
.alpha..sub.4=an alpha alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=a beta-3 alanine or a beta-3 valine;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .alpha..sub.8=any alpha amino acid; .beta..sub.4=a beta-3
tyrosine or a beta-3 lysine; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=a beta-3 serine
or a beta-3 glutamine; .alpha..sub.11=any alpha amino acid;
.alpha..sub.12=any alpha amino acid; .alpha..sub.13=any alpha amino
acid; and .beta..sub.6=a beta-3 lysine or a beta-3 asparagine; and
wherein the repetitive pattern is, optionally, preceded by: HSDAV
FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and
wherein the repetitive pattern is, optionally, succeeded by: K, KR,
or KRY
[0539] wherein the C-terminus is, optionally, amidated; and
[0540] wherein the N-terminus is unmodified or modified; or
functional fragments thereof.
[0541] In some embodiments, the composition comprises a VIP analog,
wherein the analog comprises the following repetitive pattern of
sequential .beta.-amino acids from the amino-terminus:
.beta..sub.1.alpha..sub.1.alpha..sub.2.alpha..sub.3.beta..sub.2.alpha..su-
b.4.alpha..sub.5.beta..sub.3.alpha..sub.6.alpha..sub.7.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.a-
lpha..sub.13.beta..sub.6; wherein .beta..sub.1=a beta-3 threonine
or a beta-3 tyrosine; .alpha..sub.1=any alpha amino acid;
.alpha..sub.2=any alpha amino acid; .alpha..sub.3=an alpha amino
acid; .beta..sub.2=a beta-3 lysine or a beta-3 arginine;
.alpha..sub.4=an alpha alpha amino acid; .alpha..sub.5=any alpha
amino acid; .beta..sub.3=a beta-3 alanine or a beta-3 valine;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .alpha..sub.8=any alpha amino acid, .alpha..sub.4=a beta-3
tyrosine or a beta-3 lysine; .alpha..sub.9=any alpha amino acid;
.alpha..sub.10=any alpha amino acid; .beta..sub.5=a beta-3 serine
or a beta-3 glutamine; .alpha..sub.11=any alpha amino acid,
.alpha..sub.12=any alpha amino acid, .alpha..sub.13=any alpha amino
acid; and .beta..sub.6=a beta-3 lysine or a beta-3 asparagine; and
wherein the repetitive pattern is, optionally, preceded by: HSDAV
FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and
wherein the repetitive pattern is, optionally, succeeded by: K, KR,
or KRY.
[0542] wherein the C-terminus is, optionally, amidated; and
[0543] wherein the N-terminus is unmodified or modified; or
functional fragments thereof;
[0544] and wherein the analog or functional fragment thereof is a
VPAC2 agonist.
[0545] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 100%
homologous to one or more of the following sequences:
TABLE-US-00008 (SEQ ID NO: 1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY
(SEQ ID NO: 1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQ ID NO: 1355)
HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQ ID NO: 1356)
HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQ ID NO: 1357)
HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1358)
HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1359)
HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQ ID NO: 1360)
HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQ ID NO: 1361)
HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta amino acid corresponding
to the single code amino acid upon which it is based, wherein X is
a ACPC, and wherein Z is APC; or functional fragments thereof;
wherein the C-terminus is, optionally, amidated; and wherein the
N-terminus is unmodified.
[0546] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 100%
homologous to one or more of the following sequences:
TABLE-US-00009 (SEQ ID NO: 1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY
(SEQ ID NO: 1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQ ID NO: 1355)
HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQ ID NO: 1356)
HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQ ID NO: 1357)
HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1358)
HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1359)
HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQ ID NO: 1360)
HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQ ID NO: 1361)
HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta amino acid corresponding
to the single code amino acid upon which it is based, wherein X is
a ACPC, and wherein Z is APC; or functional fragments thereof;
wherein the C-terminus is, optionally, amidated; and wherein the
N-terminus is, optionally, modified.
[0547] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 100%
homologous to one or more of the following sequences:
TABLE-US-00010 (SEQ ID NO: 1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY
(SEQ ID NO: 1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQ ID NO: 1355)
HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQ ID NO: 1356)
HSDAVFTDNYXRLZKQVXXAKZYLQXIKXKRY (SEQ ID NO: 1357)
HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1358)
HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1359)
HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQ ID NO: 1360)
HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQ ID NO: 1361)
HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta amino acid corresponding
to the single code amino acid upon which it is based, wherein X is
a ACPC, and wherein Z is APC; or functional fragments thereof;
wherein the C-terminus is, optionally, amidated; wherein the
N-terminus is, optionally, modified; and wherein the VIP analog or
functional fragment thereof is a VPAC2 agonist.
[0548] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 100%
homologous to one or more of the following sequences:
TABLE-US-00011 (SEQ ID NO: 433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y
(SEQ ID NO: 433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y (SEQ ID NO: 433)
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y (SEQ ID NO: 1353)
HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQ ID NO: 1354)
HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQ ID NO: 1355)
HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQ ID NO: 1356)
HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQ ID NO: 1357)
HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1358)
HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1359)
HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQ ID NO: 1360)
HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQ ID NO: 1361)
HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is an unnatural amino acid
corresponding to the single code amino acid upon which it is based,
wherein X is a ACPC, and wherein Z is APC; or functional fragments
thereof; wherein the C-terminus is, optionally, amidated; wherein
the N-terminus is, optionally, modified; and wherein the VIP analog
or functional fragment thereof is a VPAC1 agonist.
[0549] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 100%
homologous to one or more of the following sequences:
TABLE-US-00012 (SEQ ID NO: 433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y
(SEQ ID NO: 433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y (SEQ ID NO: 433)
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y (SEQ ID NO: 1353)
HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQ ID NO: 1354)
HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQ ID NO: 1355)
HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQ ID NO: 1356)
HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQ ID NO: 1357)
HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1358)
HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1359)
HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQ ID NO: 1360)
HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQ ID NO: 1361)
HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta amino acid corresponding
to the single code amino acid upon which it is based, wherein X is
a ACPC, and wherein Z is APC; or functional fragments thereof;
wherein the C-terminus is, optionally, amidated; wherein the
N-terminus is, optionally, modified; and wherein the VIP analog or
functional fragment thereof is a VPAC1 agonist.
[0550] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 75% and 100%
homologous to one or more of the following sequences:
TABLE-US-00013 (SEQ ID NO: 433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y
(SEQ ID NO: 433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y (SEQ ID NO: 433)
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y (SEQ ID NO: 1353)
HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQ ID NO: 1354)
HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQ ID NO: 1355)
HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQ ID NO: 1356)
HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQ ID NO: 1357)
HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1358)
HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1359)
HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQ ID NO: 1360)
HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQ ID NO: 1361)
HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta-3 homo amino acid
corresponding to the single code amino acid upon which it is based,
wherein X is a ACPC, and wherein Z is APC; or functional fragments
thereof; wherein the C-terminus is, optionally, amidated; wherein
the N-terminus is, optionally, modified; and wherein the VIP analog
or functional fragment thereof is a VPAC1 agonist.
[0551] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog comprises an amino acid
sequence that is between 75% and 100% homologous to one or more of
the following sequences:
TABLE-US-00014 (SEQ ID NO: 433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y
(SEQ ID NO: 433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y (SEQ ID NO: 433)
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKR Y (SEQ ID NO: 1353)
HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQ ID NO: 1354)
HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQ ID NO: 1355)
HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQ ID NO: 1356)
HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQ ID NO: 1357)
HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1358)
HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQ ID NO: 1359)
HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQ ID NO: 1360)
HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQ ID NO: 1361)
HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is any unnatural amino acid; any
beta-2 amino acid; any beta-3 amino acid; or a beta-3 homo amino
acid corresponding to the single code amino acid upon which it is
based; wherein X is a ACPC, and wherein Z is APC; or functional
fragments thereof; wherein the C-terminus is, optionally, amidated;
wherein the N-terminus is, optionally, modified; and wherein the
VIP analog or functional fragment thereof is a VPAC1 or VPAC2
agonist.
[0552] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog comprises an amino acid
sequence that is between 75% and 100% homologous to:
TABLE-US-00015 (SEQ ID NO: 433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY
or functional fragments thereof; and wherein the VIP analog or
functional fragment thereof is a VPAC2 agonist.
[0553] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a VIP analog, wherein the
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog comprises an amino acid
sequence that is between 75% and 100% homologous to any of the
amino acid sequence provided in this application.
[0554] The invention relates to methods of manufacturing a
composition comprising an analog, wherein the analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid. In some
embodiments, the invention relates to methods of manufacturing a
composition comprising an analog, wherein the analog comprises an
.alpha.-amino acid, at least one .beta.-amino acid, and at least
one modified amino acid residue comprising ACPC or APC. The
invention relates to methods of manufacturing a composition
comprising a secretin family analog, wherein the secretin family
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid. The invention relates to methods of
manufacturing a composition comprising a VIP analog, wherein the
VIP analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid. The method used to fabricate polypeptide
compounds may be any means of polypeptide synthesis. Using methods
of peptide synthesis, polypeptides fabricated according to the
present method are generally less than about 100 residues long. In
some embodiments, the invention relates to a method of
manufacturing an analog (or fragments herein) comprising
non-natural amino acids from from about 5 total residues to about
50 total residues, from about 10 total residues to about 20 total
residues, from about 20 total residues to about 30 total residues,
from about 30 total residues to about 40 total residues, from about
40 total residues to about 50 total residues, from about 50 to
about 60 total residues, from about 60 to about 70 total residues
from about 70 to about 80 total residues, from about 80 to about 90
total residues, and from about 90 to about 100 total residues.
Ranges above and below these stated ranges are within the scope of
the invention. Many commercial services, such as Abgent (San Diego,
Calif., USA) offer peptide synthesis services up to about 100
residues. In some embodiments, the invention relates to a method of
manufacturing an analog comprising no more than 100 non-natural
amino acids. In some embodiments, the invention relates to a method
of manufacturing an analog comprising no more than 90 non-natural
amino acids. In some embodiments, the invention relates to a method
of manufacturing an analog comprising no more than 80 non-natural
amino acids. In some embodiments, the invention relates to a method
of manufacturing an analog comprising no more than 70 non-natural
amino acids. In some embodiments, the invention relates to a method
of manufacturing an analog comprising no more than 60 non-natural
amino acids. In some embodiments, the invention relates to a method
of manufacturing an analog comprising no more than 50 non-natural
amino acids. In some embodiments, the invention relates to a method
of manufacturing an analog comprising no more than 40 non-natural
amino acids. In some embodiments, the invention relates to a method
of manufacturing an analog comprising no more than 30 non-natural
amino acids. In some embodiments, the invention relates to a method
of manufacturing an analog comprising no more than 20 non-natural
amino acids. In some embodiments, the invention relates to a method
of manufacturing an analog comprising no more than 10 non-natural
amino acids. In some embodiments, the method of manufacturing the
analog comprises synthesizing the analog using at least one, and,
in some embodiments, a plurality of the following non-naturally
occurring amino acid residues:
(2S,3R)-3-(amino)-2-hydroxy-4-(4-nitrophenyl)butyric acid,
(2R,3R)-3-(amino)-2-hydroxy-4-phenylbutyric acid,
(R)-3-(amino)-5-phenylpentanoic acid,
(R)-3-(amino)-4-(2-naphthyl)butyric acid,
(R)-2-methyl-.beta.-Phe-OH, (R)-3,4-dimethoxy-.beta.-Phe-OH,
(R)-(3-pyridyl)-.beta.-Ala-OH,
(R)-3-(trifluoromethyl)-.beta.-Phe-OH, (R)-3-cyano-.beta.-Phe-OH,
(R)-3-methoxy-.beta.-Phe-OH, (R)-3-methyl-.beta.-Phe-OH,
(R)-4-(4-pyridyl)-.beta.-HomoAla-OH,
(R)-4-(trifluoromethyl)-.beta.-HomoPhe-OH,
(R)-4-(trifluoromethyl)-.beta.-Phe-OH, (R)-4-bromo-.beta.-Phe-OH,
(R)-4-chloro-.beta.-HomoPhe-OH, (R)-4-chloro-.beta.-Phe-OH,
(R)-4-cyano-.beta.-HomoPhe-OH, (R)-4-cyano-.beta.-Phe-OH,
(R)-4-fluoro-.beta.-Phe-OH, (R)-4-methoxy-.beta.-Phe-OH,
(R)-4-methyl-.beta.-Phe-OH, (R)-.beta.-Tyr-OH,
(R)-4-(3-pyridyl)-.beta.-HomoAla-OH,
(R)-4-fluoro-.beta.-HomoPhe-OH, (S)-5-phenylpentanoic acid,
(S)-5-hexenoic acid, (S)-5-phenyl-pentanoic acid,
(S)-6-phenyl-5-hexenoic acid,
(S)-2-(trifluoromethyl)-.beta.-HomoPhe-OH,
(S)-2-(trifluoromethyl)-.beta.-Phe-OH,
(S)-2-cyano-.beta.-HomoPhe-OH, (S)-2-methyl-.beta.-Phe-OH,
(S)-3,4-dimethoxy-.beta.-Phe-OH,
(S)-3-(trifluoromethyl)-.beta.-HomoPhe-OH,
(S)-3-(trifluoromethyl)-.beta.-Phe-OH, (S)-3-cyano-.beta.-Phe-OH,
(S)-3-methoxy-.beta.-Phe-OH, (S)-3-methyl-.beta.-Phe-OH,
(S)-4-(4-pyridyl)-.beta.-HomoAla-OH,
(S)-4-(trifluoromethyl)-.beta.-Phe-OH, (S)-4-bromo-.beta.-Phe-OH,
(S)-4-chloro-.beta.-HomoPhe-OH, (S)-4-chloro-.beta.-Phe-OH,
(S)-4-cyano-.beta.-HomoPhe-OH, (S)-4-cyano-.beta.-Phe-OH,
(S)-4-fluoro-.beta.-Phe-OH, (S)-4-iodo-.beta.-HomoPhe-OH,
(S)-4-methyl-.beta.-HomoPhe-OH, (S)-4-methyl-.beta.-Phe-OH,
(S)-(3-Tyr-OH, (S)-.gamma.,.gamma.-diphenyl-.beta.-HomoAla-OH,
(S)-2-methyl-.beta.-Homophe-OH, (S)-3,4-difluoro-.beta.-HomoPhe-OH,
(S)-3-(trifluoromethyl)-.beta.-HomoPhe-OH,
(S)-3-cyano-.beta.-HomoPhe-OH, (S)-3-methyl-.beta.-HomoPhe-OH,
(S)-.gamma.,.gamma.-diphenyl-.beta.-HomoAla-OH,
3-Amino-3-(3-bromophenyl)propionic acid, and
3-Amino-4,4,4-trifluorobutyric acid.
[0555] In some embodiments, the fragment comprises 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 30,
31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids of the wild
type protein sequence. In some embodiments, the fragment comprises
any of the above-mentioned numbers of amino acids located anywhere
within the peptide. Thus, one skilled in the art understands that a
fragment of any of these lengths can be walked along the length of
the peptide, thus providing any fragment of the peptide with the
same or similar function as the native or wild-type amino acid
sequence.
[0556] One of ordinary skill in the art would readily appreciate
that the protecting groups would be removed from the final chemical
structure of the analog which becomes administered to a subject.
One of ordinary skill would be able to predict the final chemical
structure of the analog by using the protecting groups selectively
to create a polypeptide with a desirable chirality or secondary
structure. For instance, if the analog of the composition is
manufactured using (S)-Fmoc-3-methyl-.beta.-HomoPhe-OH, the final
yielded product should comprise at least one .beta.-amino acid
residue of a 3-methyl-.beta.-homophenylalanine.
[0557] In some embodiments, the method of manufacturing the analog
comprises synthesizing the analog using at least one, and in some
embodiments, a plurality of cyclic amino acid residues. In some
embodiments, the VIP analog of the claimed invention comprises the
cyclic amino acid residues. In some embodiments, the VIP analog of
the claimed invention comprises at least one disulfide bridge that
forms a cyclic chain of atoms along a side chain of two amino acid
residues.
[0558] In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00016 (SEQ ID NO: 10) HSDAVFTDNYTRLRKQMAVKKYLNSILN;
wherein at least one of the amino acid residues is a .beta.-amino
acid residue, and at least one of the amino acid residues is an
.alpha.-amino acid residue. In some embodiments, the at least one
.alpha.-amino acid residue is a non-natural amino acid residue. In
some embodiments, the amino acid residues at positions 1, 3, 6, 7,
10, and 23 of the VIP analog are not alanine, glycine, or any
.beta. amino acid residue with a methyl side chain.
[0559] In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00017 (SEQ ID NO: 1362) HSDAVF NYTRLR A YLN
wherein any of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5,
X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 may be a beta-amino
acid. In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00018 (SEQ ID NO: 1362)
HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8-
IX.sub.9X.sub.10
wherein any of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5,
X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 are a
.beta..sup.3-amino acid residue. In some embodiments, at least one
of the .beta..sup.3-amino acid residues is substituted with a
residue chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC),
(S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC),
(R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or
(R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC,
(RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the
amino acid is basic. In some embodiments, at least one of the
.beta..sup.3-amino acid residues is substituted with a residue
chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if
the residue is basic.
[0560] In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00019 (SEQ ID NO: 1362)
HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8-
IX.sub.9X.sub.10
wherein any one or more of X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 is a
beta-amino acid, and wherein X.sub.1=T; X.sub.2=D; X.sub.3=R or K;
X.sub.4=M or L; X.sub.5=A or V; X.sub.6=R or K; X.sub.7=R or K;
X.sub.8=S or A; X.sub.9=L or K; and X.sub.10=N or K. In some
embodiments, the VIP analog of the claimed invention comprises the
following sequence:
TABLE-US-00020 (SEQ ID NO: 1362)
HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8-
IX.sub.9X.sub.10
wherein any one of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5,
X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 is a
.beta..sup.3-amino acid residue. In some embodiments, at least one
of the .beta..sup.3-amino acid residues is substituted with a
residue chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC),
(S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC),
(R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or
(R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC,
(RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the
amino acid is basic. In some embodiments, at least one of the
.beta..sup.3-amino acid residues is substituted with a residue
chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if
the residue is basic.
[0561] In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00021 (SEQ ID NO: 1362)
HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8-
IX.sub.9X.sub.10
wherein any one or more of X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 is a
beta-amino acid, and wherein X.sub.1=T; X.sub.2=D; X.sub.3=R or K;
X.sub.4=M or L; X.sub.5=A or V; X.sub.6=R or K; X.sub.7=R or K;
X.sub.8=S or A; X.sub.9=L or K; and X.sub.10=N or K. In some
embodiments, the VIP analog of the claimed invention comprises the
following sequence:
TABLE-US-00022 (SEQ ID NO: 1362)
HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8-
IX.sub.9X.sub.10
wherein any one or more of X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 is a
.beta..sup.3-amino acid residue. In some embodiments, at least one
of the .beta..sup.3-amino acid residues is substituted with a
residue chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC),
(S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC),
(R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or
(R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC,
(RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the
amino acid is basic. In some embodiments, at least one of the
.beta..sup.3-amino acid residues is substituted with a residue
chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if
the residue is basic.
[0562] In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00023 (SEQ ID NO: 1363)
HSDAVFX.sub.1X.sub.2NYX.sub.3RLX.sub.4X.sub.5QX.sub.6X.sub.7X.sub.8X.sub.-
9X.sub.10YLNX.sub.11IX.sub.12X.sub.13
wherein X.sub.3, X.sub.4, X.sub.7, X.sub.10, and X.sub.11 are
beta-amino acid residues derived from the naturally occurring
.alpha.-amino acid residue at that position, and wherein X.sub.1=T;
X.sub.2=D; X.sub.5=R or K; X.sub.6=M or L; X.sub.8=A or V;
X.sub.9=R or K; X.sub.10=R or K; X.sub.1=S or A; X.sub.12=L or K;
and X.sub.13=N or K.
HSDAVFX.sub.1X.sub.2NYX.sub.3RLX.sub.4X.sub.5QX.sub.6X.sub.7X.sub.8X.sub.-
9X.sub.10YLNX.sub.11IX.sub.12X.sub.13 (SEQ ID NO: 1363) wherein
X.sub.3, X.sub.4, X.sub.7, X.sub.10, and X.sub.11 are
.beta..sup.3-amino acid residues derived from the naturally
occurring .alpha.-amino acid residue at that position. In some
embodiments, at least one of the .beta..sup.3-amino acid residues
is substituted with a residue chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC),
(S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC),
(R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or
(R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC,
(RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the
amino acid is basic. In some embodiments, at least one of the
.beta..sup.3-amino acid residues is substituted with a residue
chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if
the residue is basic.
[0563] In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00024 (SEQ ID NO: 1363)
HSDAVFX.sub.1X.sub.2NYX.sub.3RLX.sub.4X.sub.5QX.sub.6X.sub.7X.sub.8X.sub.-
9X.sub.10YLNX.sub.11IX.sub.12X.sub.13
wherein at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10, X.sub.11,
X.sub.12, or X.sub.13 is a beta-amino acid, and wherein X.sub.1=T;
X.sub.2=D; X.sub.5=R or K; X.sub.6=M or L; X.sub.8=A or V;
X.sub.9=R or K; X.sub.10=R or K; X.sub.11=S or A; X.sub.12=L or K;
and X.sub.13=N or K. In some embodiments, the VIP analog of the
claimed invention comprises the following sequence:
TABLE-US-00025 (SEQ ID NO: 1363)
HSDAVFX.sub.1X.sub.2NYX.sub.3RLX.sub.4X.sub.5QX.sub.6X.sub.7X.sub.8X.sub.-
9X.sub.10YLNX.sub.11IX.sub.12X.sub.13
wherein at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10, X.sub.11,
X.sub.12, or X.sub.13 is a .beta..sup.3-amino acid residue, and
wherein X.sub.1=T; X.sub.2=D; X.sub.5=R or K; X.sub.6=M or L;
X.sub.8=A or V; X.sub.9=R or K; X.sub.10=R or K; X.sub.11=S or A;
X.sub.12=L or K; and X.sub.13=N or K. In some embodiments, at least
one of the .beta..sup.3-amino acid residues is substituted with a
residue chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC),
(S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC),
(R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or
(R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC,
(RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the
amino acid is basic. In some embodiments, at least one of the
.beta..sup.3-amino acid residues is substituted with a residue
chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if
the residue is basic.
[0564] In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00026 (SEQ ID NO: 1364)
X.sub.1TX.sub.2LRX.sub.3QLX.sub.4AX.sub.5X.sub.6YLQSIX.sub.7X.sub.8;
wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6,
X.sub.7, X.sub.8 are non-natural amino acids and wherein the
underlined residues are .beta.-amino acid residues. In some
embodiments, the VIP analog of the claimed invention comprises the
following sequence:
TABLE-US-00027 (SEQ ID NO: 1364)
X.sub.1TX.sub.2LRX.sub.3QLX.sub.4AX.sub.5X.sub.6YLQSIX.sub.7X.sub.8;
wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6,
X.sub.7, X.sub.8 are non-natural amino acids and wherein the
underlined residues are .beta..sup.3-amino acid residues. In some
embodiments, at least one of the .beta..sup.3-amino acid residues
is substituted with a residue chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC),
(S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC),
(R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or
(R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC,
(RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the
amino acid is basic. In some embodiments, at least one of the
.beta..sup.3-amino acid residues is substituted with a residue
chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if
the residue is basic.
[0565] In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00028 (SEQ ID NO: 1365)
Y(OMe)TOrnLRAibQLUAAibOrnYLQSIOrnOrn,
wherein Orn=ornithine, Y(OMe)=O-methylated Tyrosine,
Aib=.alpha.-aminoisobutyric acid, U=amino butyric acid (i.e., side
chain=ethyl), and wherein each underlined position is a
.beta.-amino acid residue. In some embodiments at least one of the
.beta.-amino acid residue are .beta..sup.3-amino acid residues. In
some embodiments, at least one of the .beta..sup.3-amino acid
residues is substituted with a residue chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC),
(S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC),
(R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or
(R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC,
(RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the
amino acid is basic. In some embodiments, at least one of the
.beta..sup.3-amino acid residues is substituted with a residue
chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if
the residue is basic.
[0566] In some embodiments, the VIP analog of the claimed invention
comprises at least 17% .beta.-amino acid residues. In some
embodiments, the VIP analog of the claimed invention comprises from
about 15% to about 30% .beta.-amino acid residues. In some
embodiments, the VIP analog of the claimed invention comprises from
about 15% to about 30% .beta.-amino acid residues wherein the first
ten amino acids of the amino acid sequence are alpha amino acids.
In some embodiments, the VIP analog of the claimed invention
comprises from about 16% to about 29% .beta.-amino acid residues.
In some embodiments, the VIP analog of the claimed invention
comprises from about 17% to about 29% .beta.-amino acid residues.
In some embodiments, the VIP analog of the claimed invention
comprises from about 18% to about 29% .beta.-amino acid residues.
In some embodiments, the VIP analog of the claimed invention
comprises from about 19% to about 29% .beta.-amino acid residues.
In some embodiments, the VIP analog of the claimed invention
comprises from about 20% to about 29% .beta.-amino acid
residues.
[0567] In some embodiments, the VIP analog of the claimed invention
comprises .beta.-amino acid residues at residue positions 11, 14,
18, 21, and 25 of HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10). In
some embodiments, the VIP analog of the claimed invention comprises
.beta.-amino acid residues at positions 11, 14, 18, 21, and 25 of
HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10), wherein the position
11 is .beta..sup.3-homothreonine, position 14 is
.beta..sup.3-homoarginine, position 18 is .beta..sup.3-homoalanine,
position 21 is .beta..sup.3-homolysine, and position 25 is
.beta..sup.3-homoserine. In some embodiments, at least one of the
.beta..sup.3-amino acid residues is substituted with a residue
chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC),
(S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC),
(R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or
(R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC,
(RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the
amino acid is basic. In some embodiments, at least one of the
.beta..sup.3-amino acid residues is substituted with a residue
chosen from the following:
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the
amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if
the residue is basic.
[0568] In some embodiments, the VIP analog of the claimed invention
comprises the following sequence:
TABLE-US-00029 (SEQ ID NO: 1352)
HSDAVFTDNYX.sub.1RLX.sub.2KQLX.sub.3VKX.sub.4YLNX.sub.5ILN
wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, and X.sub.5 are
.beta.-amino acid residues and wherein all other .alpha.-amino
residues are naturally-occurring or non-naturally occurring amino
acid residues. In some embodiments, the VIP analog comprises a
cyclic amino acid residue covalently bonded to one or more
contiguous or non-contiguous amino acid sidechain residues via a
lactam ring. In some embodiments, the VIP analog comprises a cyclic
amino acid residue covalently bonded to one or more contiguous or
non-contiguous amino acid sidechain residues via an amide bond. In
some embodiments, the VIP analog of the claimed invention comprises
one of the following sequences:
TABLE-US-00030 (SEQ ID NO: 435) HSDAV FTDNY ARLRK QMAVK KALNS ILA
(SEQ ID NO: 435) HSDAV FTDNY ARLRK QMAVK KALNS ILA (SEQ ID NO: 435)
HSDAV FTDNY ARLRK QMAVK KALNS ILA (SEQ ID NO: 435) HSDAV FTDNY
ARLRK QMAVK KALNS ILA (SEQ ID NO: 435) HSDAV FTDNY ARLRKQ MAVK
KALNS ILA (SEQ ID NO: 435) HSDAV FTDNY ARLRKQ MAVK KALNS ILA (SEQ
ID NO: 435) HSDAV FTDNY ARLRKQ MAVK KALNS ILA (SEQ ID NO: 434)
HADAV FTAAY ARLRK QMAAK KALAA IAA (SEQ ID NO: 434) HADAV FTAAY
ARLRK QMAAK KALAA IAA (SEQ ID NO: 434) HADAV FTAAY ARLRK QMAAK
KALAA IAA) (SEQ ID NO: 434) HADAV FTAAY ARLRK QMAAK KALAA IAA (SEQ
ID NO: 434) HADAV FTAAY ARLRKQ MAAK KALAA IAA (SEQ ID NO: 434)
HADAV FTAAY ARLRKQ MAAK KALAA IAA (SEQ ID NO: 434) HADAV FTAAY
ARLRKQ MAAK KALAA IAA
wherein each underlined residue is: a .beta..sup.3-homoamino acid
residue; or, if a non-polar (e.g., A, V), the underlined residues
is/are (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC);
or, if the underlined position is basic, (such as Lys or Arg), the
underlined residue is a pyrrolidine analogue of (S,S)-ACPC, which
is designated APC. (Note: Ac=acetyl; N.sup.le=norleucine; K*---D*
indicates that the side chains of these two residues are linked via
an amide bond.) In some embodiments, the sidechains of K and D are
not linked via any bond.
[0569] a/b-Peptide analogues will be synthesized:
TABLE-US-00031 (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1374) Ac-HSDAV FTENY TKLRK RN.sup.leAAK
N.sup.leYLNN LKKGG T (SEQ ID NO: 1374) Ac-HSDAV FTENY TKLRK
RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ ID NO: 1374) Ac-HSDAV FTENY
TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ ID NO: 1374) Ac-HSDAV
FTENY TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ ID NO: 1374)
Ac-HSDAV FTENY TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ ID NO:
1374) Ac-HSDAV FTENY TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ
ID NO: 1374) Ac-HSDAV FTENY TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG
T
wherein each underlined residue is: a .beta..sup.3-homoamino acid
residue; or, if a non-polar (e.g., A, V), the underlined positions
will be replaced by (S,S)-trans-2-aminocyclopentanecarboxylic acid
((S,S)-ACPC); or if the underlined residue is basic, (such as Lys
or Arg), the underlined residue is/are the pyrrolidine analogue of
(S,S)-ACPC, which is designated APC; and wherein Ac=acetyl;
N.sup.le=norleucine; K*---D* indicates that the side chains of
these two residues are linked via an amide bond. In some
embodiments, the sidechains of K and D are not linked via any bond.
In some embodiments, the VIP analog comprises a cyclic amino acid
residue covalently bonded to one or more contiguous or
non-contiguous amino acid sidechain residues via the following
synthetic linking structures:
##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016## ##STR00017## ##STR00018## ##STR00019##
##STR00020##
[0570] In some embodiments, the analog does not comprise a cyclic
substituent in its side chain. In some embodiments, the cyclic
amino acid residues are not covalently bonded to one or more
contiguous or non-contiguous amino acid sidechain residues via the
following synthetic linking structures:
##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031##
[0571] In some embodiments, the analogs of the present invention
comprise at least one or a plurality of the following cyclic amino
acid residues, some of which being described with a protecting
group that becomes eliminated from the analog either during
synthesis or when the analog is purified after synthesis:
[0572] L-.beta.-HomohydroxyProline hydrochloride
[0573] (1R,2R)-Boc-2-aminocyclohexane carboxylic acid
{(1R,2R)-ACHC}
[0574] (1R,2R)-Fmoc-2-aminocyclohexane carboxylic acid
{(1R,2R)-ACHC}
[0575] (1R,2S)-Boc-2-aminocyclohexane carboxylic acid
{(1R,2S)-ACHC}
[0576] (1R,2S)-Fmoc-2-aminocyclohexane carboxylic acid
{(1R,2S)-ACHC}
[0577] (1S,2R)-Boc-2-aminocyclohexane carboxylic acid
{(1S,2R)-ACHC}
[0578] (1S,2R)-Fmoc-2-aminocyclohexane carboxylic acid
(1S,2R)-ACHC}
[0579] (1S,2S)-Boc-2-aminocyclohexane carboxylic acid
{(1S,2S)-ACHC}
[0580] (1S,2S)-Fmoc-2-aminocyclohexane carboxylic acid
{(1S,2S)-ACHC}
[0581] (1R,2R)-Boc-2-aminocyclopentane carboxylic acid
{(1R,2R)-ACPC}
[0582] (1R,2R)-Fmoc-2-aminocyclopentane carboxylic acid
{(1R,2R)-ACPC}
[0583] (1S,2S)-Boc-2-aminocyclopentane carboxylic acid
{(1S,2S)-ACPC}
[0584] (1S,2S)-Fmoc-2-aminocyclopentane carboxylic acid
{(1S,2S)-ACPC}
[0585] Boc-cis-2-aminocyclopentane carboxylic acid, cis-Acpc
[0586] Fmoc-cis-2-aminocyclopentane carboxylic acid, cis-Acpc
[0587] (R)-Boc-(2-carboxymethyl)-piperidine,
(R)-(1-piperidin-2-yl)-acetic acid
[0588] (R)-Fmoc-(2-carboxymethyl)-piperidine,
(R)-(1-Fmoc-piperidin-2-yl)-acetic acid
[0589] (S)-Boc-(2-carboxymethyl)-piperidine
(S)-(1-Boc-piperidin-2-yl)-acetic acid
[0590] (S)-Fmoc-(2-carboxymethyl)-piperidine
(S)-(1-Fmoc-piperidin-2-yl)-acetic acid
[0591] (R,S)-Boc-2-carboxymorpholine Boc-Cop
[0592] (R,S)-Boc-2-carboxymorpholine Fmoc-Cop
[0593] (R,S)-Boc-nipecotic acid Boc-Nip
[0594] (R,S)-Boc-nipecotic acid Fmoc-Nip
[0595] (R)-Fmoc-nipecotic acid (R)-Fmoc-Nip
[0596] (R)-Fmoc-nipecotic acid (R)-Boc-Nip
[0597] (3S)-Boc-1-pyrrolidine-3-carboxylic acid
(3S)-Boc-beta-Pro-OH
[0598] (3S)-Fmoc-1-pyrrolidine-3-carboxylic acid
(3S)-Fmoc-beta-Pro-OH
[0599] In some embodiments, the analogs of the present invention
comprise at least one or a plurality of non-natural amino acid
residues that can modified by PEGylation. In some embodiments the
analogs or fragments of the polypeptides related to this invention
comprise PEG molecules which are covalently bound to the side chain
of the .alpha., or .beta. amino acids in the polypeptide. In some
embodiments, the polypeptides of this invention comprise the
PEGylated cyclic amino acid residues or cyclic amino acid side
chains. PEG molecule(s) may be covalently attached to any Lys, Cys,
K(W) or K(CO(CH.sub.2).sub.2SH) residue at any position in the
analog or fragment of analog. In some embodiments, the analog or a
fragment thereof comprises a C-terminal extension may comprise one
or more Cys residues which may be PEGylated. In some embodiment of
the invention the polypeptides or fragments thereof may comprise
one or more PEGylated residues in either or both sequences.
[0600] In some embodiments, the analog or fragment thereof
comprises a PEG molecule covalently attached to one or all of the
.beta.-residue within the analog. In some embodiments, the analog
is at least one PEG molecule covalently attached to a residue in
the C-terminal extension of the analog or fragment thereof. In some
embodiments, the analog comprises more than one PEG molecule, there
may be a combination of Lys, Cys, K(CO(CH.sub.2).sub.2SH), K(W) and
carboxy-terminal amino acid PEGylation. For example, if there are
two PEG molecules, one may be attached to a Lys residue and one may
be attached to a Cys residue. In some embodiments, the polypeptide
comprises one or more covalently bound PEG molecules, wherein at
least one of the PEG molecules is branched. In some embodiments,
one or more of the PEG molecules are linear. In some embodiments,
the composition comprises one or more PEG molecule, wherein the PEG
molecule is between about 200 daltons and about 100,000 daltons in
molecular weight. In some embodiments, the PEG molecule is chosen
from 10,000, 20,000, 30,000, 40,000, 50,000 and 60,000 daltons. In
some embodiments, it is chosen from 20,000, 30,000, 40,000, or
60,000 daltons. Where there are two PEG molecules covalently
attached to the analog or fragment thereof, each is 1,000 to 40,000
daltons and, they have molecular weights of 20,000 and 20,000
daltons, 10,000 and 30,000 daltons, 30,000 and 30,000 daltons, or
20,000 and 40,000 daltons. In some embodiments mini-PEGs.TM. are
covalently bound to at least one residue or side chain of an a, or
.beta.-amino acid. In some embodiments, the mini-PEG.TM. is chosen
from the following list of products: 8-Amino-3,6-Dioxaoctanoic
Acid, 11-Amino-3,6,9-Trioxaundecanoic Acid,
8-Amino-3,6-Dioxaoctanoic Acid DCHA,
11-Amino-3,6,9-Trioxaundecanoic Acid DCHA.
[0601] In some embodiments the method of treatment or prevention of
a human disorder depends upon the analog being synthesized. For
instance: Peptides for triggering B and T cell activity can be used
to treat autoimmune disease, including uveitis, collagen-induced,
adjuvant and rheumatoid arthritis, thyroiditis, myasthenia gravis,
multiple sclerosis and diabetes. Examples of these peptides are
interleukins (referenced in Aulitzky, W E; Schuler, M; Peschel, C.;
Huber, C.; Interleukins. Clinical pharmacology and therapeutic use.
Drugs. 48(5):667-77, November 1994) and cytokines (referenced in
Peters, M.; Actions of cytokines on the immune response and viral
interactions: an overview. Hepatology. 23(4):909-16, April
1996).
[0602] Enkephlin analogs, agonist analogs and antagonist analogs
can be used to treat AIDS, ARC, and cancer, pain modulation,
Huntington's, Parkinson's diseases.
[0603] LHRH and analogs, agonists and antagonists can be used to
treat prostatic tumors and reproductive physiopathology, including
breast cancer, and infertility.
[0604] Peptides and peptidomimetics that target crucial enzymes,
oncogenes or oncogene products, tumor-suppressor genes and their
products, growth factors and their corresponding receptors can be
used to treat cancer. Examples of these peptides are described in
Unger, C. Current concepts of treatment in medical oncology: new
anticancer drugs. Journal of Cancer Research & Clinical
Oncology. 122(4):189-98, 1996.
[0605] Neuropeptide Y and other pancreatic polypeptides, and
analogs, agonists and antagonists can be used to treat stress,
anxiety, neurodegenerative diseases, depression and associated
vasoconstrictive activities.
[0606] Gluco-incretins, including gastric inhibitory polypeptide,
glucose-dependent insulinotropic polypeptide, PACAP/Glucagon and
glucagon-like polypeptide-1 and 2 and analogs, agonists and
antagonists can be used to treat Type II diabetic hyperglycaemia.
Atrial natriuretic factor and analogs, agonists and antagonists can
be used to treat congestive heart failure.
[0607] Integrin and analogs, agonists and antagonists can be used
to treat osteoporosis, scar formation, bone synthesis, inhibition
of vascular occlusion, and inhibition of tumor invasion and
metastasis.
[0608] Glucagon, glucagon-like peptide 1, PACAP/Glucagon, and
analogs, agonists and antagonists can be used to treat diabetes
cardiovascular emergencies.
[0609] Antithrombotic peptides and analogs, agonists and
antagonists can be used to treat cardiovascular and cerebrovascular
diseases. Examples of these peptides RGD, D-Phe-Pro-Arg and others
named are described in Ojima I.; Chakravarty S.; Dong Q.
Antithrombotic agents: from RGD to peptide mimetics. Bioorganic
& Medicinal Chemistry. 3(4):337-60, 1995.
[0610] Cytokines/interleukins and analogs, agonists and antagonists
can be used to treat inflammatory disease, immune response
dysfunction, hematopoiesis, mycosis fungoides, aplastic anemia,
thrombocytopenia, and malignant melanoma. Examples of these
peptides are Interleukins, referenced in Aulitzky et al. and Peters
et al., which is herein incorporated by reference.
[0611] Endothelin and analogs, agonists and antagonists can be used
to treat arterial hypertension, myocardial infarction, congestive
heart failure, atherosclerosis, shock conditions, renal failure,
asthma and vasospasm Natriuretic hormones and analogs, agonists and
antagonists can be used to treat cardiovasicular disease and acute
renal failure. Examples of these peptides are named and described
in Espiner, E. A.; Richards, A. M.; Yandle, T. G.; Nicholls, M. G.;
Natriuretic hormones. Endocrinology & Metabolism Clinics of
North America. 24(3):481-509, 1995.
[0612] Peptides that activate or inhibit tyrosine kinase, or bind
to TK-activating or inhibiting peptides and analogs, agonists and
antagonists can be used to treat chronic myelogenous and acute
lymphocytic leukemias, breast and ovarian cancers and other
tyrosine kinase associated diseases. Examples of these peptides are
described in Smithgall, T E.; SH2 and SH3 domains: potential
targets for anti-cancer drug design. Journal of Pharmacological
& Toxicological Methods. 34(3):125-32, 1995.
[0613] Renin inhibitors analogs, agonists and antagonists can be
used to treat cardiovascular disease, including hypertension and
congestive heart failure. Examples of these peptides are described
in Rosenberg, S. H.; Renin inhibition. Cardiovascular Drugs &
Therapy. 9(5):645-55, 1995.
[0614] Angiotensin-converting enzyme inhibitors, analogs, agonists
and antagonists can be used to treat cardiovascular disease,
including hypertension and congestive heart failure. Peptides that
activate or inhibit tyrosine phosphorylases can be used to treat
cardiovascular diseases. Examples of these peptides are described
in Srivastava, A. K.; Protein tyrosine phosphorylation in
cardiovascular system. Molecular & Cellular Biochemistry.
149-150:87-94, 1995.
[0615] Peptide based antivirals can be used to treat viral
diseases. Examples of these peptides are described in Toes, R. E.;
Feltkamp, M. C.; Ressing, M. E.; Vierboom, M. P.; Blom, R. J.;
Brandt, R. M; Hartman, M.; Offringa, R.; Melief, C. J.; Kast, W.
M.; Cellular immunity against DNA tumour viruses: possibilities for
peptide-based vaccines and immune escape. Biochemical Society
Transactions. 23(3):692-6, 1995.
[0616] Corticotropin releasing factor and peptide analogs, agonist
analogs and antagonist analogs can be used to treat disease
associated with high CRF, i.e Alzheimer's disease, anorexia
nervosa, depressive disorders, arthritis, and multiple
sclerosis.
[0617] Peptide agonist analogs and antagonist analogs of
platelet-derived wound-healing formula (PDWHF) can be used as a
therapy for donor tissue limitations and wound-healing constraints
in surgery. Examples of these peptides are described in Rudkin, G.
H.; Miller, T. A.; Growth factors in surgery. Plastic &
Reconstructive Surgery. 97(2):469-76, 1996. Fibronectin,
fibrinopeptide inhibitors and analogs, agonists and antagonists can
be used to treat metastasis (i.e. enzyme inhibition, tumor cell
migration, invasion, and metastasis).
[0618] Chemokine (types of cytokine, including interleukin-8,
RANTES, and monocyte chemotactic peptide) analogs, agonist analogs
and antagonist analogs can be used to treat arthritis,
hypersensitivity, angiogenesis, renal disease, glomerulonephritis,
inflammation, and hematopoiesis.
[0619] Neutral endopeptidase inhibitors analogs, agonist analogs
and antagonist analogs can be used to treat hypertension and
inflammation. Examples of these peptides are described in Gregoire,
J. R; Sheps, S. G; Newer antihypertensive drugs. Current Opinion in
Cardiology. 10(5):445-9, 1995.
[0620] Substance P analogs, agonist analogs and antagonist analogs
can be used to treat immune system dysfunction, pain
transmission/perception and in autonomic reflexes and behaviors.
Alpha-melanocyte-stimulating hormone analogs, agonist analogs and
antagonist analogs can be used to treat AIDS, rheumatoid arthritis,
and myocardial infarction.
[0621] Bradykinin (BK) analogs, agonist analogs and antagonist
analogs can be used to treat inflammatory diseases (edema, etc),
asthma, allergic reactions (rhinitis, etc), anesthetic uses, and
septic shock.
[0622] Secretin analogs can be used to treat cardiovascular
emergencies.
[0623] GnRH analogs, agonist analogs and antagonist analogs can be
used to treat hormone-dependent breast and prostate tumors.
[0624] Somatostatin analogs, agonist analogs and antagonist analogs
can be used to treat gut neuroendocrine tumors.
[0625] Gastrin, Gastrin Releasing Peptide analogs, agonist analogs
and antagonist analogs can be used as an adjuvant to chemotherapy
or surgery in small cell lung cancer and other malignancies, or to
treat allergic respiratory diseases, asthma and allergic
rhinitis.
[0626] Laminin analogs, agonist analogs and antagonist analogs, the
Laminin derivative antimetastatic drug YIGSR analogs,
Laminin-derived synthetic peptides analogs, agonist analogs and
antagonist analogs can be used to treat tumor cell growth,
angiogenesis, regeneration studies, vascularization of the eye with
diabetes, and ischemia. The peptides of this category can inhibit
the tumor growth and metastasis of leukemic cells and may be useful
as a potential therapeutic reagent for leukemic infiltrations.
Peptides containing this sequence also inhibit experimental
metastasis. Exemplary references include McGowan K A. Marinkovich M
P Laminins and human disease. Microscopy Research & Technique.
51(3):262-79, Nov. 1, 2000; Yoshida N. Ishii E. Nomizu M. Yamada Y.
Mohri S. Kinukawa N. Matsuzaki A. Oshima K. Hara T. Miyazaki S. The
laminin-derived peptide YIGSR (Tyr-Ile-Gly-Ser-Arg) inhibits human
pre-B leukemic cell growth and dissemination to organs in SCID
mice. British Journal of Cancer. 80(12): 1898-904, 1999. Examples
of these peptides are also described in Kleinman, H. K.; Weeks, B.
S.; Schnaper, H. W.; Kibbey, M. C.; Yamamura, K.; Grant, D. S; The
laminins: a family of basement membrane glycoproteins important in
cell differentiation and tumor metastases. Vitamins & Hormones.
47:161-86, 1993.
[0627] Defensins, corticostatins, dermaseptins, mangainins, and
other antibiotic (antibacterial and antimicrobial) peptides
analogs, agonist analogs and antagonist analogs can be used to
treat infections, tissue inflammation and endocrine regulation.
[0628] Vasopressin analogs, agonist analogs and antagonist analogs
can be used to treat neurological disorders, stress and Diabetes
insipidus.
[0629] Oxytocin analogs, agonist analogs and antagonist analogs can
be used to treat neurological disorders and to induce labor.
[0630] ACTH-related peptides and analogs, agonist analogs and
antagonist analogs can be used as neurotrophic, neuroprotective,
and peripheral demyelinating neuropathy agents. Amyloid-beta
peptide analogs, agonist analogs and antagonist analogs can be used
to treat Alzheimer's disease.
[0631] Epidermal growth factor, receptor analogs, agonist analogs
and antagonist analogs can be used to treat necrotizing
enterocolitis, Zollinger-Ellison syndrome, gastrointestinal
ulceration, colitis, and congenital microvillus
atrophycarcinomas.
[0632] Leukocyte adhesion molecule analogs, agonist analogs and
antagonist analogs can be used to treat atherosclerosis,
inflammation. Examples of these peptides are described in Barker,
J. N.; Adhesion molecules in cutaneous inflammation. Ciba
Foundation Symposium. 189:91-101.
[0633] Major histocompatibility complex (MHC) analogs, agonist
analogs and antagonist analogs can be used to treat autoimmune,
immunodysfunctional, immuno modulatory diseases and as well as used
for their corresponding therapies. Examples of these peptides are
described in Appella, E.; Padlan, E. A.; Hunt, D. F; Analysis of
the structure of naturally processed peptides bound by class I and
class II major histocompatibility complex molecules. EXS.
73:105-19, 1995.
[0634] Corticotropin releasing factor analogs can be used to treat
neurological disorders.
[0635] Neurotrophins (including brain-derived neurotrophic factor
(BDNF), nerve growth factor, and neurotrophin 3) analogs, agonist
analogs and antagonist analogs can be used to treat neurological
disorders.
[0636] Cytotoxic T-cell activating peptide analogs, agonist analogs
and antagonist analogs can be used to treat infectious diseases and
cancer. Examples of these peptides are described in: Chesnut R. W.;
Sette, A.; Celis, E.; Wentworth, P.; Kubo, R. T.; Alexander, J.;
Ishioka, G.; Vitiello, A.; Grey, H. M; Design and testing of
peptide-based cytotoxic T-cell-mediated immunotherapeutics to treat
infectious diseases and cancer. Pharmaceutical Biotechnology.
6:847-74, 1995.
[0637] Peptide immunogens for prevention of HIV-1 and HTLV-I
retroviral infections can be used to treat AIDS. Examples of these
peptides are described in Hart, M. K.; Palker, T. J.; Haynes, B F;
Design of experimental synthetic peptide immunogens for prevention
of HIV-1 and HTLV-I retroviral infections. Pharmaceutical
Biotechnology. 6:821-45, 1995.
[0638] Galanin analogs, agonist analogs and antagonist analogs can
be used to treat Alzheimer's disease, depression, eating disorders,
chronic pain, prevention of ischemic damage, and growth hormone
modulation.
[0639] Tachykinins (neurokinin A and neurokinin B) analogs, agonist
analogs and antagonist analogs can be used to treat pain
transmission/perception and in autonomic reflexes and
behaviors.
[0640] RGD containing peptide analogs can be used to treat various
diseases involved with cell adhesion, antithrombotics, and acute
renal failure.
[0641] Osteogenic growth peptide analogs, agonist analogs and
antagonist analogs can be used as treatment of systemic bone loss.
Examples of these peptides are described in Bab IA. Regulatory role
of osteogenic growth peptide in proliferation, osteogenesis, and
hemopoiesis. Clinical Orthopaedics & Related Research.
(313):64-8, 1995.
[0642] Parathyroid hormone, parathyroid hormone related-peptide
analogs, agonist analogs and antagonist analogs can be used to
treat diseases affecting calcium homeostasis (hypercalcemia), bone
metabolism, vascular disease, and atherosclerosis.
[0643] Kallidin analogs, agonist analogs and antagonist analogs can
be used to treat tissue injury or inflammation and pain signaling
pathological conditions of the CNS.
[0644] T cell receptor peptide analogs, agonist analogs and
antagonist analogs can be used in immunotherapy. Examples of these
peptides are described in Brostoff, S W; T cell receptor peptide
vaccines as immunotherapy. Agents & Actions--Supplements.
47:53-8, 1995.
[0645] Platelet-derived growth factor (PDGF) analogs, agonist
analogs and antagonist analogs can be used to treat non-neoplastic
hyperproliferative disorders, therapy for donor tissue limitations
and wound-healing constraints in surgery.
[0646] Amylin, calcitonin gene related peptides (CGRP) analogs,
agonist analogs and antagonist analogs can be used to treat
insulin-dependent diabetes.
[0647] VIP analogs, agonist analogs and antagonist analogs can be
used to treat allergic respiratory diseases, asthma and allergic
rhinitis, and nervous control of reproductive functions.
[0648] Growth hormone-releasing hormone (GHRH) analogs, agonist
analogs and antagonist analogs can be used to treat growth hormone
deficiency and immunomodulation.
[0649] HIV protease inhibiting peptide analogs, agonist analogs and
antagonist analogs can be used to treat AIDS. Examples of these
peptides are described in Bugelski, P. J.; Kirsh, R.; Hart, T. K;
HIV protease inhibitors: effects on viral maturation and
physiologic function in macrophages. Journal of Leukocyte Biology.
56(3):374-80, 1994.
[0650] Thymopoietin active fragment peptides analogs, agonist
analogs and antagonist analogs can be used to treat rheumatoid
arthritis and virus infections.
[0651] Cecropins analogs, agonist analogs and antagonist analogs
can be used as antibacterials.
[0652] Thyroid releasing hormone (TRH) analogs, agonist analogs and
antagonist analogs can be used to treat spinal cord injury and
shock.
[0653] Erythropoietin (EPO) analogs, agonist analogs and antagonist
analogs can be used to treat anemia.
[0654] Fibroblast growth factor (FGF), receptor analogs, agonist
analogs and antagonist analogs can be as stimulation of bone
formation, as well as used as a treatment for Kaposi's sarcoma,
neuron regeneration, prostate growth, tumor growth inhibition, and
angiogenesis.
[0655] Stem cell factor analogs, agonist analogs and antagonist
analogs can be used to treat anemias. GP120, GP160, CD4 fragment
peptides analogs, agonist analogs and antagonist analogs can be
used to treat HIV and AIDS.
[0656] Insulin-like growth factor (IGF) analogs, agonist analogs
and antagonist analogs, and IGF receptor analogs, agonist analogs
and antagonist analogs can be used to treat breast and other
cancers, noninsulin-dependent diabetest mellitus, cell
proliferation, apoptosis, hematopoiesis, HIV, AIDS, growth
disorders, osteoporosis, and insulin resistance.
[0657] Colony stimulating factors (granulocyte-macrophage
colony-stimulating factor (GMCSF), granulocyte colony-stimulating
factor (GCSF), and macrophage colony-stimulating factor (MCSF)
analogs, agonist analogs and antagonist analogs can be used to
treat anemias.
[0658] Kentsin analogs, agonist analogs and antagonist analogs can
be used for immunomodulation.
[0659] Lymphocyte activating peptide (LAP) analogs, agonist analogs
and antagonist analogs can be used for immunomodulation. Examples
of these peptides are described in Loleit, M.; Deres, K.;
Wiesmuller, K. H.; Jung, G.; Eckert, M.; Bessler, W. G; Biological
activity of the Escherichia coli lipoprotein: detection of novel
lymphocyte activating peptide segments of the molecule and their
conformational characterization. Biological Chemistry Hoppe-Seyler.
375(6):407-12, June 1994.
[0660] Tuftsin analogs, agonist analogs and antagonist analogs can
be used for immunomodulation.
[0661] Prolactin analogs, agonist analogs and antagonist analogs
can be used to treat rheumatic diseases, systemic lupus
erythematosus, and hyperprolactemia.
[0662] Angiotensin II analogs, agonist analogs and antagonist
analogs and Angiotensin II receptor(s) analogs, agonist analogs and
antagonist analogs can be used to treat hypertension, hemodynamic
regulation, neurological disorders, diabetic nephropathies,
aortoarterities induced RVH, hyperaldosteronism, heavy metal
induced cardiovascular effects, diabetes mellitus and thyroid
dysfunction.
[0663] Dynorphin analogs, agonist analogs and antagonist analogs
can be used to treat neurological disorders, pain management,
algesia, spinal cord injury and epilepsy.
[0664] Calcitonin analogs, agonist analogs and antagonist analogs
can be used to treat neurological disorders, immune system
dysfunction, calcium homeostasis, and osteoporosis.
[0665] Pituitary adenylate cyclase activating polypeptide analogs,
agonist analogs and antagonist analogs may modulate growth, signal
transduction vasoactivity roles.
[0666] Cholecystokinin analogs, agonist analogs and antagonist
analogs can be used to treat feeding disorders, panic disorders,
and anti-opioid properties.
[0667] Pepstatin analogs, agonist analogs and antagonist analogs
can be used as pepsin and HIV protease inhibitors (AIDS).
[0668] Bestatin analogs, agonist analogs and antagonist analogs can
be used to treat muscular dystrophy, anticancer, antileukemia,
immune response modulator, and acute non-lymphocytic leukemia.
[0669] Leupeptin analogs, agonist analogs and antagonist analogs
can be used as a protease inhibitor, exact role in diseases not
determined yet.
[0670] Luteinizing hormone and releasing hormone analogs, agonist
analogs and antagonist analogs can be used as a infertility male
contraceptive.
[0671] Neurotensin analogs, agonist analogs and antagonist analogs
can be used, e.g., as antipsychotic, analgesic, anti-cancer, and/or
neuroprotective agents, e.g., for treating stroke victims, e.g., by
inducing hypothermia so as to provide neuroprotection.
[0672] Motilin analogs, agonist analogs and antagonist analogs can
be used for the control of gastric emptying.
[0673] Insulin analogs, agonist analogs and antagonist analogs can
be used to treat diabetes.
[0674] Transforming growth factor (TGF) analogs, agonist analogs
and antagonist analogs can be used for cell proliferation and
differentiation, cancer treatment, immunoregulation, therapy for
donor tissue limitations, and wound-healing constraints in
surgery.
[0675] Bone morphogenetic proteins (BMPs) analogs, agonist analogs
and antagonist analogs can be used as therapy for donor tissue
limitations, osteogenesis, and wound-healing constraints in
surgery.
[0676] Bombesin and Enterostatin analogs, agonist analogs and
antagonist analogs can be used to prevent the proliferation of
tumor cells, modulation of feeding, and neuroendocrine functions.
These peptides fall within a supercategory of the neuromedins
described above. These peptides are described in such exemplary
references as Yamada K. Wada E. Wada K. Bombesin-like peptides:
studies on food intake and social behaviour with receptor knock-out
mice. Annals of Medicine. 32(8):519-29, November 2000;
Ohki-Hamazaki H. Neuromedin B. Progress in Neurobiology.
62(3):297-312, October 2000; Still CD. Future trends in weight
management. Journal of the American Osteopathic Association. 99(10
Su Pt 2):518-9, 1999; Martinez V. Tache Y. Bombesin and the
brain-gut axis. Peptides. 21(11):1617-25, 2000; Afferent signals
regulating food intake. Proceedings of the Nutrition Society.
59(3):373-84, 2000; Takenaka Y. Nakamura F. Jinsmaa Y. Lipkowski A
W. Yoshikawa M. Enterostatin (VPDPR) has anti-analgesic and
anti-amnesic activities. Bioscience Biotechnology &
Biochemistry. 65(1):236-8, 2001 J.
[0677] Glucagon, glucagon-like peptide 1 analogs, agonist analogs
and antagonist analogs can be used to treat diabetes cardiovascular
emergencies.
[0678] Pancreastatin, chromogranins A, B and C analogs, agonist
analogs and antagonist analogs--conditions associated with
inhibition of insulin secretion, exocrine pancreatic secretion and
gastric acid secretion, and stimulation of secretion.
[0679] Endorphins analogs, agonist analogs and antagonist analogs
can be used to treat neurological disorders, alleviating pain,
treatment of opioid abuse, obesity, and diabetes. Examples of these
peptides are named and described in Dalayeun, J. F.; Nores, J. M.;
Bergal, S.; Physiology of beta-endorphins. A close-up view and a
review of the literature. Biomedicine & Pharmacotherapy.
47(8):311-20, 1993.
[0680] Miscellaneous opioid peptides analogs, agonist analogs and
antagonist analogs, including (but not limited to) adrenal peptide
E analogs, alpha casein fragment analogs, beta casomorphin analogs,
dermorphin analogs, kyotorphin analogs, metophamide neuropeptide FF
(NPFF) analogs, melanocyte inhibiting factor analogs, agonist
analogs and antagonist analogs can be used to treat neurological
disorders, alleviating pain, as well as for the treatment of opioid
abuse.
[0681] Vasotocin analogs, agonist analogs and antagonist analogs
can be used for sleep disorders including but not limited to
insomnia.
[0682] Protein kinase C and inhibitors analogs, agonist analogs and
antagonist analogs can be used to treat cancer, apoptosis, smooth
muscle function, and Alzheimer's disease. Examples of these
peptides are named and described in Philip, P. A.; Harris, A. L;
Potential for protein kinase C inhibitors in cancer therapy. Cancer
Treatment & Research. 78:3-27, 1995.
[0683] Amyloid, amyloid fibrin, analogs, agonist analogs and
antagonist analogs can be used to treat neurodegenerative diseases
and diabetes.
[0684] Calpain and other calmodulin-inhibitory protein analogs,
agonist analogs and antagonist analogs can be used to treat
neurodegenerative disorders, cerebral ischaemia, cataracts,
myocardial ischaemia, muscular dystrophy and platelet
aggregation.
[0685] Charybdotoxin and Apamin analogs, agonist analogs and
antagonist analogs can be used for treatment of neurodegenerative
diseases and pain and cerebral ischemia.
[0686] Phospholipase A2 analogs, agonist analogs and antagonist
analogs and Phospholipase A2 receptor inhibiting/activating
peptides analogs, agonist analogs and antagonist analogs can be
used to treat acute pancreatitis, pancreatic cancer, abdominal
trauma, and inflammation, e.g., sepsis, infections, acute
pancreatitis, various forms of arthritis, cancer, complications of
pregnancy, and postoperative states.
[0687] Potassium channel activating and inhibiting analogs, agonist
analogs and antagonist analogs can be used to treat various
diseases. Examples of these peptides are described in Edwards, G.;
Weston, A. H; Pharmacology of the potassium channel openers.
Cardiovascular Drugs & Therapy. 9 Suppl 2:185-93, March
1995.
[0688] IgG activators, inhibitors analogs, agonist analogs and
antagonist analogs can be used to treat autoimmune diseases and
immune dysfunctions. Examples of these peptides are described in
Mouthon, L.; Kaveri, S. V.; Spalter, S. H.; Lacroix-Desmazes, S.;
Lefranc, C.; Desai, R.; Kazatchkine, M. D; Mechanisms of action of
intravenous immune globulin in immune-mediated diseases. Clinical
& Experimental Immunology. 104 Suppl 1:3-9, 1996.
[0689] Endotoxin and inhibitor analogs, agonist analogs and
antagonist analogs can be used for decreasing cardiac output,
systemic hypotension, decreased blood flow and O.sub.2 delivery to
tissues, intense pulmonary vasoconstriction and hypertension,
bronchoconstriction, increased permeability, pulmonary oedema,
ventilation-to-perfusion inequalities, hypoxaemia, and
haemoconcentration. Examples of these peptides are named and
described in Burrell, R; Human responses to bacterial endotoxin.
Circulatory Shock. 43(3):137-53, July 1994.
[0690] Orphan receptor ligand analogs, agonist analogs and
antagonist analogs (including but not limited to ADNF,
Adrenomedullin, Apelin, Ghrelin, Mastoparan (MCD peptides), Melanin
concentrating hormone, Nociceptin/Nocistatin, Orexin, Receptor
activity modulating protein, Urotensin) can be used to treat
obesity, weight problems, neuropathy, sleep deprivation, sleep
disorder including insomnia, and lung cell repair. These orphan
receptor ligands are described in such references as In DS. Orphan
G protein-coupled receptor s and beyond. Japanese Journal of
Pharmacology. 90(2): 101-6, 2002; Maguire J J. Discovering orphan
receptor function using human in vitro pharmacology. Current
Opinion in Pharmacology. 3(2):135-9, 2003; Szekeres P G. Functional
assays for identifying ligands at orphan G protein-coupled
receptors. Receptor s & Channels. 8(5-6):297-308, 2002; Shiau A
K. Coward P. Schwarz M. Lehmann J M. Orphan nuclear receptor s:
from new ligand discovery technologies to novel signaling pathways.
Current Opinion in Drug Discovery & Development. 4(5):575-90,
2001; Civelli O. Nothacker H P. Saito Y. Wang Z. Lin S H.
Reinscheid R K. Novel neurotransmitters as natural ligands of
orphan G-protein-coupled receptor s. Trends in Neurosciences.
24(4):230-7, 2001; Darland T. Heinricher M M. Grandy D K. Orphan in
F Q/nociceptin: a role in pain and analgesia, but so much more.
Trends in Neurosciences. 21(5):215-21, 1998, the disclosures of
which are incorporated herein by reference.
[0691] Another embodiment of the invention includes analogs of
Glycoprotein IIb/IIIa inhibitors. The central role of platelet-rich
thrombus in the pathogenesis of acute coronary syndromes (ACSs) is
well-known. Glycoprotein IIb/IIIa (Gp IIb/IIIa) receptor analogs,
agonist analogs and antagonist analogs can be used as potent
modulators of platelet function that may be expected to affect
favorably the natural history of ACSs. Exemplary references for
this category include Bhatt D L. Topol E J. Current role of
platelet glycoprotein IIb/IIIa inhibitors in acute coronary
syndromes. JAMA. 284(12):1549-58, 2000; Kereiakes D J. Oral
blockade of the platelet glycoprotein IIb/IIIa receptor: fact or
fancy?. American Heart Journal. 138(1 Pt 2):S39-46, 1999; Bassand J
P. Low-molecular-weight heparin and other antithrombotic agents in
the setting of a fast-track revascularization in unstable coronary
artery disease. Haemostasis. 30 Suppl 2:114-21; discussion 106-7,
2000.
[0692] Apo-lipoprotein A-I analogs, agonist analogs and antagonist
analogs may increase the HDL levels of subjects upon
administration. Analogs of the present invention that are
homologous to Apo-lipoprotein A-I may be useful to treat or prevent
liver disease and inflammatory diseases including but not limited
to artherosclerosis. Analogs of the present invention that are
homologous to Apo-lipoprotein A-I may be useful to increase the
amount of formation of pre-.beta.1 HDL in human plasma.
[0693] The cytokine analogs of the present invention may treat or
prevent autoimmune disease, inflammatory disease, and dysfunctional
growth or differentiation of cells such as cellular proliferative
disorders, the development of neoplasia, tumors, and cancer.
[0694] The present invention provides for the use of an antibody or
binding composition which specifically binds to a specified analog.
in some embodiments the antibody specifically binds the analog
derived from a mammalian polypeptide, e.g., a polypeptide derived
from a primate, human, cat, dog, rat, or mouse. Antibodies can be
raised to various analogs, including individual, polymorphic,
allelic, strain, or species variants, and fragments thereof, both
in their naturally occurring (full-length) forms or in their
synthetic forms. Additionally, antibodies can be raised to the
analogs in their inactive state or active state. Anti-idiotypic
antibodies may also be used.
[0695] A number of immunogens may be selected to produce antibodies
specifically reactive with ligand or receptor proteins. Synthetic
analogs may serve as an immunogen for the production of monoclonal
or polyclonal antibodies. Such antibodies may be used as
antagonists or agonists for their targets modulating the disease
state associated with the naturally occurring proteins and analogs
listed above. Synthetic polypeptides of the claimed invention may
also be used either in pure or impure form. Synthetic peptides,
made using the appropriate protein sequences, may also be used as
an immunogen for the production of antibodies. Naturally folded or
denatured material can be used, as appropriate, for producing
antibodies. Either monoclonal or polyclonal antibodies may be
generated, e.g., for subsequent use in immunoassays to measure the
protein, or for immunopurification methods. Methods of producing
polyclonal antibodies are well known to those of skill in the
art.
[0696] Typically, an immunogen, such as a purified analog of the
invention, is mixed with an adjuvant and animals are immunized with
the mixture. The animal's immune response to the immunogen
preparation is monitored by taking test bleeds and determining the
titer of reactivity to the protein of interest. For example, when
appropriately high titers of antibody to the immunogen are
obtained, usually after repeated immunizations, blood is collected
from the animal and antisera are prepared. Further fractionation of
the antisera to enrich for antibodies reactive to the protein can
be performed if desired. See, e.g., Harlow and Lane; or Coligan.
Immunization can also be performed through other methods, e.g., DNA
vector immunization. See, e.g., Wang, et al. (1997) Virology
228:278-284.
[0697] Monoclonal antibodies may be obtained by various techniques
familiar to researchers skilled in the art. Typically, spleen cells
from an animal immunized with a desired analog are immortalized,
commonly by fusion with a myeloma cell. See, Kohler and Milstein
(1976) Eur. J. Immunol. 6:511-519. Alternative methods of
immortalization include transformation with Epstein Barr Virus,
oncogenes, or retroviruses, or other methods known in the art. See,
e.g., Doyle, et al. (eds. 1994 and periodic supplements) Cell and
Tissue Culture: Laboratory Procedures, John Wiley and Sons, New
York, N.Y. Colonies arising from single immortalized cells are
screened for production of antibodies of the desired specificity
and affinity for the antigen, and yield of the monoclonal
antibodies produced by such cells may be enhanced by various
techniques, including injection into the peritoneal cavity of a
vertebrate host. Alternatively, one may isolate DNA sequences which
encode a monoclonal antibody or a binding fragment thereof by
screening a DNA library from human B cells according, e.g., to the
general protocol outlined by Huse, et al. (1989) Science
246:1275-1281.
[0698] Antibodies or binding compositions, including binding
fragments, single chain antibodies, F.sub.v, F.sub.ab, single
domain V.sub.H, disulfide-bridged F.sub.v, single-chain F.sub.v or
F(.sub.ab').sub.2 fragments of antibodies, diabodies, and
triabodies against predetermined fragments of the analogs can be
raised by immunization of animals with analogs or conjugates of
analogs or receptor proteins with carrier proteins. Monoclonal
antibodies are prepared from cells secreting the desired antibody.
These antibodies can be screened for binding to analogs described
herein. These monoclonal antibodies will usually bind with at least
a K.sub.D of about 1 mM, usually at least about 300 .mu.M,
typically at least about 10 .mu.M, at least about 30 .mu.M, at
least about 10 .mu.M, and at least about 3 .mu.M or more. These
antibodies can be screened for binding to the naturally occurring
polypeptides upon which the analogs are derived.
[0699] In some instances, it is desirable to prepare monoclonal
antibodies (mAbs) from various mammalian hosts, such as mice,
rodents, primates, humans, etc. Description of techniques for
preparing such monoclonal antibodies may be found in, e.g., Stites,
et al. (eds.) Basic and Clinical Immunology, 4th ed., Lange Medical
Publications, Los Altos, Calif., and references cited therein;
Harlow and Lane (1988) Antibodies: A Laboratory Manual CSH Press;
Goding (1986) Monoclonal Antibodies: Principles and Practice, 2nd
ed., Academic Press, New York, N.Y.; and particularly in Kohler and
Milstein (1975) Nature 256:495-497, which discusses one method of
generating monoclonal antibodies. Summarized briefly, this method
involves injecting an animal with an analog described herein. The
animal is then sacrificed and cells taken from its spleen, which
are then fused with myeloma cells. The result is a hybrid cell or
"hybridoma" that is capable of reproducing in vitro. The population
of hybridomas is then screened to isolate individual clones, each
of which secrete a single antibody species to the analog. In this
manner, the individual antibody species obtained are the products
of immortalized and cloned single B cells from the immune animal
generated in response to a specific site recognized on the
immunogenic substance.
[0700] Other suitable techniques involve selection of libraries of
antibodies in phage or similar vectors. See, e.g., Huse, et al.
(1989) Science 246:1275-1281; and Ward, et al. (1989) Nature
341:544-546. The polypeptides and antibodies of the present
invention may be used with or without modification, including
chimeric or humanized antibodies. Frequently, the polypeptides and
antibodies will be labeled by joining, either covalently or
non-covalently, a substance which provides for a detectable signal.
A wide variety of labels and conjugation techniques are known and
are reported extensively in both the scientific and patent
literature. Suitable labels include radionuclides, enzymes,
substrates, cofactors, inhibitors, fluorescent moieties,
chemiluminescent moieties, magnetic particles, and the like.
Patents teaching the use of such labels include U.S. Pat. Nos.
3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149;
and 4,366,241. Also, recombinant immunoglobulins may be produced,
see, Cabilly, U.S. Pat. No. 4,816,567; and Queen, et al. (1989)
Proc. Nat'l Acad. Sci. USA 86:10029-10033; or made in transgenic
mice, see Mendez, et al. (1997) Nature Genetics 15:146-156; also
see Abgenix and Medarex technologies.
[0701] The instant invention is related to pharmaceutical
compositions of the instant invention or the pharmaceutical
acceptable salts derived therefrom that comprise analogs that
comprise isotopes. In some embodiments, the compositions of the
claimed invention may contain any isotope described in Cyr and
Pearson (Stabilization of radiopharmaceutical compositions using
hydrophilic thioethers and hydrophilic 6-hydroxy chromans Cyr, John
E.; Pearson, Daniel A. (Diatide, Inc., USA). PCT Int. Appl. (2002),
WO 200260491 A2 20020808), which is herein incorporated by
reference. In some embodiments the compositions of the invention
comprise analog that comprise one or more of the following
isotopes: .sup.125I, .sup.131I, .sup.211At, .sup.47Sc, .sup.67Cu,
.sup.72Ga, .sup.90Y, .sup.153Sm, .sup.159Gd, .sup.165Dy,
.sup.166Ho, .sup.175Yb, .sup.177Lu, .sup.212Bi, .sup.213Bi,
.sup.68Ga, .sup.99Tc, .sup.111In, .sup.123I, and .sup.3H.
[0702] The pharmaceutical compositions of the instant invention or
the pharmaceutical acceptable salts derived therefrom may be in a
liquid or solid dosage form. Such compositions may include any type
of dosage form such as tablets, capsules, powders, liquid
formulations, delayed or sustained release, patches, snuffs, nasal
sprays and the like. The formulations may additionally include
other ingredients such as dyes, preservatives, buffers and
anti-oxidants, for example The physical form and content of the
pharmaceutical formulations contemplated are conventional
preparations that can be formulated by those skilled in the
pharmaceutical formulation field and are based on well established
principles and compositions described in, for example, Remington:
The Science and Practice of Pharmacy, 19th Edition, 1995; British
Pharmacopoeia 2000, each of which is incorporated herein by
reference. The compositions of the present invention may also
include other active agents useful in the treatment of
cardiovascular conditions. Solid forms can be prepared according to
any means suitable in the art. For example, capsules are prepared
by mixing the analog composition with a suitable diluent and
filling the proper amount of the mixture in capsules. Tablets are
prepared by direct compression, by wet granulation, or by dry
granulation. Their formulations usually incorporate diluents,
binders, lubricants and disintegrators as well as the compound.
Diluents, but are not limited to, include various types of starch,
cellulose, crystalline cellulose, microcrystalline cellulose,
lactose, fructose, sucrose, mannitol or other sugar alcohols,
kaolin, calcium phosphate or sulfate, inorganic salts such as
sodium chloride and powdered sugar. Powdered cellulose derivatives
are also useful. Non-limiting examples of tablet binders include,
but are not limited to, starches, gelatin and sugars such as
lactose, fructose, glucose and the like. Natural and synthetic gums
are also convenient, including, but are not limited to, acacia,
alginates, methylcellulose, polyvinylpyrrolidone and the like.
Polyethylene glycol, ethylcellulose and waxes can also serve as
binders.
[0703] A lubricant can be used in a tablet formulation to prevent
the tablet and punches from sticking in the die. The lubricant
include, but are not limited to, such slippery solids as talc,
magnesium and calcium stearate, stearic acid and hydrogenated
vegetable oils.
[0704] Tablets can be coated with sugar as a flavor and sealant, or
with film-forming protecting agents to modify the dissolution
properties of the tablet. The compounds may also be formulated as
chewable tablets, by using large amounts of pleasant-tasting
substances such as mannitol in the formulation, as is now
well-established in the art.
[0705] Also contemplated are liquid formulations and solid form
preparations which are intended to be converted, shortly before
use, to liquid form preparations. Such liquid forms include, but
are not limited to, solutions, suspensions, syrups, slurries, and
emulsions. Liquid preparations may be prepared by conventional
means with pharmaceutically acceptable additives such as suspending
agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated
edible fats or oils); emulsifying agents (e.g., lecithin or
acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or
fractionated vegetable oils); and preservatives (e.g., methyl or
propyl-p-hydroxybenzoates or sorbic acid). These preparations may
contain, in addition to the active agent, colorants, flavors,
stabilizers, buffers, artificial and natural sweeteners,
dispersants, thickeners, solubilizing agents, and the like. The
compositions may be in powder form for constitution with a suitable
vehicle such as sterile water, saline solution, or alcohol, before
use. Preparations may also contain mucosal enhancers.
[0706] In some embodiments, the oral transmucosal solid dosage
further comprises a permeation enhancer. In some embodiments, the
permeation enhancer is chosen from: a bile salt, sodium dodecyl
sulfate, dimethyl sulfoxide, sodium lauryl sulfate, a derivative of
a saturated or a unsaturated fatty acid, a surfactant, a bile salt
analog, and a derivative of a bile salt. In some embodiments the
oral transmucosal dosage form is chosen from: a chewing gum, a
patch, a lozenge, a lozenge-on-a-handle, a tablet, a troche, a
pastille, a sachet, a sublingual tablet, and a rapid disintegrating
tablet. In some embodiments, the oral transmucosal solid dosage
form of wherein the composition further comprises at least one
flavoring agent, artificial coloring, sweetener, lubricating agent,
disintegration agent, lubricating agent, diluent, base, or
buffering agent. In some embodiments, the oral transmucosal solid
dosage form further comprises a sustained release agent. The
invention is directed to an oral transmucosal solid dosage form
comprising from wherein the concentration of analog is from about
0.01% to about 90% of the dry matter weight of the composition.
[0707] Solid dosage forms such as lozenges and tablets may also be
used for oral transmucosal delivery of pharmaceuticals. For
example, nitroglycerin sublingual tablets have been on the market
for many years. The sublingual tablets are designed to deliver
small amounts of the potent nitroglycerin, which is almost
immediately dissolved and absorbed. On the other hand, most
lozenges or tablets are typically designed to dissolve in the mouth
over a period of at least several minutes which allows extended
dissolution of the lozenge and absorption of the drug.
[0708] Administration of lozenges or sublingual tablets generally
utilize an "open" delivery system, in which the drug delivery
conditions are influenced by the conditions of the surrounding
environment, such as rate of saliva secretion, pH of the saliva, or
other conditions beyond the control of the formulation.
[0709] A lozenge-on-a-handle (similar to a lollipop) is another
dosage form suitable for transmucosal drug delivery. In addition to
being non-invasive and providing a particularly easy method of
delivery, the lozenge-on-a-handle (or lozenge with an integrated
oral transmucosal applicator) dosage form allows a patient or
caregiver to move the dosage form in and out of the mouth to
titrate the dose. This practice is called dose-to-effect, in which
a patient or caregiver controls the administration of the dose
until the expected therapeutic effect is achieved. This is
particularly important for certain symptoms, such as pain, nausea,
motion sickness, and premedication prior to anesthesia because each
patient needs a different amount of medication to treat these
symptoms. For these types of treatments, the patient is the only
one who knows how much medication is enough. Once the appropriate
amount of drug is delivered, the patient or caregiver can remove
the lozenge-on-a-handle, thus, stopping delivery of the drug. This
feature is especially important for particularly potent drugs,
which may present a significant advantage of terminating drug
administration once the desired effect is achieved.
[0710] As used herein, the term "oral transmucosal delivery" (OTD)
refers to the delivery of a pharmaceutical agent across a mucous
membrane in the oral cavity, pharyngeal cavity, or esophagus, and
may be contrasted, for example, with traditional oral delivery, in
which absorption of the drug occurs in the intestines. Accordingly,
routes of administration in which the pharmaceutical agent is
absorbed through the buccal, sublingual, gingival, pharyngeal,
and/or esophageal mucosa are all encompassed within "oral
transmucosal delivery," as that term is used herein. Oral
transmucosal delivery involves the administration of an oral
transmucosal solid dosage form to the oral cavity of a patient,
which is held in the oral cavity and dissolved, thereby releasing
the pharmaceutical agent for oral transmucosal delivery. Of course,
as the solid dosage form dissolves in the oral cavity, some of the
saliva containing the pharmaceutical agent may be swallowed, and a
portion of the drug may ultimately be absorbed from the
intestines.
[0711] The compositions of the invention can be administered in a
sustained release composition, such as those described in, for
example, U.S. Pat. Nos. 5,672,659 and 5,595,760, and herein
incorporate by reference. The use of immediate or sustained release
compositions depends on the type of condition being treated.
[0712] The pharmaceutical compositions of the instant invention or
the pharmaceutical acceptable salts derived therefrom may be in a
dosage amount in an effective amount for inducing or increasing the
naturally occurring biological activity of the wild-type
polypeptide upon which the analog is derived. The pharmaceutical
compositions of the instant invention or the pharmaceutical
acceptable salts derived therefrom may be in a dosage amount in an
effective amount for inducing or increasing the naturally occurring
biological activity of the wild-type secretin polypeptide upon
which the analog is derived. The pharmaceutical compositions of the
instant invention or the pharmaceutical acceptable salts derived
therefrom may be in a dosage amount in an effective amount for
increasing the half-life of the composition when administered to a
human being or other subject. In some embodiments the secretin
analog is VIP.
[0713] The present invention also encompasses methods of using the
compositions comprising a VIP analog. Any of these methods may
involve the administration of a pharmaceutical composition
comprising a VIP analog wherein the VIP analog is in a
therapeutically effective dose. Any of these methods may involve
the administration of a pharmaceutical composition comprising a VIP
analog wherein the VIP analog is selective for VPAC1, VPAC2, PAC1,
VIPR1, or VIPR2. The composition comprising an analog of the
invention produces a broad range of activities, depending on the
dosage administered. The present invention encompasses methods of
treating or preventing pulmonary hypertension, primary arterial
hypertension, pulmonary hypertension associated to post-ventricular
septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary
arterial hypertension, CREST syndrome--Calcinosis; Raynaud's
disease; loss of muscle control of the Esophagus; Sclerodactyly;
Telangiectasia, Acute respiratory distress, congestive heart
failure, chronic obstructed pulmonary disorder, asthma, chronic
obstructive pulmonary disease, sarcoidosis, small lung cell cancer,
autoimmune disease, inflammatory disease, sepsis, Hirschsprung's
Disease, sexual dysfunction, erectile dysfunction, Parkinson's
disease, Alzheimer's disease, circadian rhythm dysfunction, pain,
colorectal cancer, hepatocellular cancer, elevated blood pressure
levels, elevated blood glucose levels, hyperglycemia, diabetes,
insulin resistance, metabolic acidosis, obesity, Type I diabetes,
Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's
syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual
dysfunction comprising administering to at least one patient in
need thereof, mammal in need thereof or human in need thereof a
composition or pharmaceutical composition comprising a secretin
family analog in a therapeutically effective amount. The
compositions of the invention may also be used at lower doses in
order to prevent pulmonary hypertension, primary arterial
hypertension, pulmonary hypertension associated to post-ventricular
septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary
arterial hypertension, CREST syndrome--Calcinosis; Raynaud's
disease; loss of muscle control of the Esophagus; Sclerodactyly;
Telangiectasia, Acute respiratory distress, congestive heart
failure, chronic obstructed pulmonary disorder, asthma, chronic
obstructive pulmonary disease, sarcoidosis, small lung cell cancer,
autoimmune disease, inflammatory disease, sepsis, Hirschsprung's
Disease, sexual dysfunction, erectile dysfunction, Parkinson's
disease, Alzheimer's disease, circadian rhythm dysfunction, pain,
colorectal cancer, hepatocellular cancer, elevated blood pressure
levels, elevated blood glucose levels, hyperglycemia, diabetes,
insulin resistance, metabolic acidosis, obesity, Type I diabetes,
Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's
syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual
dysfunction in a subject in need thereof. The compositions of the
invention may also be used to prevent pulmonary hypertension,
primary arterial hypertension, pulmonary hypertension associated to
post-ventricular septal defect, idiopathic pulmonary fibrosis,
idiopathic pulmonary arterial hypertension, CREST
syndrome--Calcinosis; Raynaud's disease; loss of muscle control of
the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory
distress, congestive heart failure, chronic obstructed pulmonary
disorder, asthma, chronic obstructive pulmonary disease,
sarcoidosis, small lung cell cancer, autoimmune disease,
inflammatory disease, sepsis, Hirschsprung's Disease, sexual
dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's
disease, circadian rhythm dysfunction, pain, colorectal cancer,
hepatocellular cancer, elevated blood pressure levels, elevated
blood glucose levels, hyperglycemia, diabetes, insulin resistance,
metabolic acidosis, obesity, Type I diabetes, Type II diabetes
Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis,
uveoretinitis, osteoporosis, female sexual dysfunction in a subject
susceptible to those indications. In some embodiments, the method
of prevention comprising administering the composition or
pharmaceutical compositions of the invention after the subject is
tested for susceptibility or genetic propensity for developing the
disease, indication or disorder.
[0714] The pharmaceutical composition comprising a pharmaceutically
acceptable carrier/diluent and an analog comprising an
.alpha.-amino acid and at least one .beta.-amino acid may be
formulated by one having ordinary skill in the art with
compositions selected depending upon the chosen mode of
administration. Suitable pharmaceutical carriers are described in
the most recent edition of Remington's Pharmaceutical Sciences, A.
Osol, a standard reference text in this field, which is
incorporated herein in its entirety.
[0715] For parenteral administration, analog can be, for example,
formulated as a solution, suspension, emulsion or lyophilized
powder in association with a pharmaceutically acceptable parenteral
vehicle. Examples of such vehicles are water, saline, Ringer's
solution, dextrose solution, and 5% human serum albumin Liposomes
and nonaqueous vehicles such as fixed oils may also be used. The
vehicle or lyophilized powder may contain additives that maintain
isotonicity (e.g., sodium chloride, mannitol) and chemical
stability (e.g., buffers and preservatives). The formulation is
sterilized by commonly used techniques. For example, a parenteral
composition suitable for administration by injection is prepared by
dissolving 1.5% by weight of analog in 0.9% sodium chloride
solution.
[0716] The present invention relates to routes of administration
include intramuscular, sublingual, intravenous, intraperitoneal,
intrathecal, intravaginal, intraurethral, intradermal, intrabuccal,
via inhalation, via nebulizer and via subcutaneous injection.
Alternatively, the pharmaceutical composition may be introduced by
various means into cells that are removed from the individual. Such
means include, for example, microprojectile bombardment and
liposome or other nanoparticle device.
[0717] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In solid dosage forms, the
analogs are generally admixed with at least one inert
pharmaceutically acceptable carrier such as sucrose, lactose,
starch, or other generally regarded as safe (GRAS) additives. Such
dosage forms can also comprise, as is normal practice, an
additional substance other than an inert diluent, e.g., lubricating
agent such as magnesium state. With capsules, tablets, and pills,
the dosage forms may also comprise a buffering agent. Tablets and
pills can additionally be prepared with enteric coatings, or in a
controlled release form, using techniques know in the art.
[0718] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions and
syrups, with the elixirs containing an inert diluent commonly used
in the art, such as water. These compositions can also include one
or more adjuvants, such as wetting agent, an emulsifying agent, a
suspending agent, a sweetening agent, a flavoring agent or a
perfuming agent.
[0719] In another embodiment of the invention the composition of
the invention is used to treat a patient suffering from, or
susceptible to, pulmonary hypertension, primary arterial
hypertension, pulmonary hypertension associated to post-ventricular
septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary
arterial hypertension, CREST syndrome--Calcinosis; Raynaud's
disease; loss of muscle control of the Esophagus; Sclerodactyly;
Telangiectasia, Acute respiratory distress, congestive heart
failure, chronic obstructed pulmonary disorder, asthma, chronic
obstructive pulmonary disease, sarcoidosis, small lung cell cancer,
autoimmune disease, inflammatory disease, sepsis, Hirschsprung's
Disease, sexual dysfunction, erectile dysfunction, Parkinson's
disease, Alzheimer's disease, circadian rhythm dysfunction, pain,
colorectal cancer, hepatocellular cancer, elevated blood pressure
levels, elevated blood glucose levels, hyperglycemia, diabetes,
insulin resistance, metabolic acidosis, obesity, Type I diabetes,
Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's
syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual
dysfunction due to administration of a medication that causes onset
of or exacerbates symptoms of pulmonary hypertension, primary
arterial hypertension, pulmonary hypertension associated to
post-ventricular septal defect, idiopathic pulmonary fibrosis,
idiopathic pulmonary arterial hypertension, CREST
syndrome--Calcinosis; Raynaud's disease; loss of muscle control of
the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory
distress, congestive heart failure, chronic obstructed pulmonary
disorder, asthma, chronic obstructive pulmonary disease,
sarcoidosis, small lung cell cancer, autoimmune disease,
inflammatory disease, sepsis, Hirschsprung's Disease, sexual
dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's
disease, circadian rhythm dysfunction, pain, colorectal cancer,
hepatocellular cancer, elevated blood pressure levels, elevated
blood glucose levels, hyperglycemia, diabetes, insulin resistance,
metabolic acidosis, obesity, Type I diabetes, Type II diabetes
Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis,
uveoretinitis, osteoporosis, female sexual dysfunction in a
subject. In some embodiments, the invention relates to compositions
comprising a secretin family analog for treatment or prevention of
pulmonary hypertension, primary arterial hypertension, pulmonary
hypertension associated to post-ventricular septal defect,
idiopathic pulmonary fibrosis, idiopathic pulmonary arterial
hypertension, CREST syndrome--Calcinosis; Raynaud's disease; loss
of muscle control of the Esophagus; Sclerodactyly; Telangiectasia,
Acute respiratory distress, congestive heart failure, chronic
obstructed pulmonary disorder, asthma, chronic obstructive
pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune
disease, inflammatory disease, sepsis, Hirschsprung's Disease,
sexual dysfunction, erectile dysfunction, Parkinson's disease,
Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal
cancer, hepatocellular cancer, elevated blood pressure levels,
elevated blood glucose levels, hyperglycemia, diabetes, insulin
resistance, metabolic acidosis, obesity, Type I diabetes, Type II
diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome,
pancreatitis, uveoretinitis, osteoporosis, female sexual
dysfunction in a subject in need thereof, wherein said analog
comprises an .alpha.-amino acid and at least one .beta.-amino acid.
In some embodiments, the secretin family analog of the invention
comprises an analog of VIP.
[0720] One of skill in the art will recognize that the appropriate
dosage of the compositions and pharmaceutical compositions may vary
depending on the individual being treated and the purpose. For
example, the age, body weight, and medical history of the
individual patient may affect the therapeutic efficacy of the
therapy. Further, a lower dosage of the composition may be needed
to produce a transient cessation of symptoms, while a larger dose
may be needed to produce a complete cessation of symptoms
associated with the disease, disorder, or indication. A competent
physician can consider these factors and adjust the dosing regimen
to ensure the dose is achieving the desired therapeutic outcome
without undue experimentation. It is also noted that the clinician
and/or treating physician will know how and when to interrupt,
adjust, and/or terminate therapy in conjunction with individual
patient response. Dosages may also depend on the strength of the
particular analog chosen for the pharmaceutical composition.
[0721] The dose of the composition or pharmaceutical compositions
may vary. The dose of the composition may be once per day. In some
embodiments, multiple doses may be administered to the subject per
day. In some embodiments, the total dosage is administered in at
least two application periods. In some embodiments, the period can
be an hour, a day, a month, a year, a week, or a two-week period.
In an additional embodiment of the invention, the total dosage is
administered in two or more separate application periods, or
separate doses.
[0722] In some embodiments, subjects can be administered the
composition in which the composition is provided in a daily dose
range of about 0.0001 mg/kg to about 5000 mg/kg of the weight of
the subject. The dose administered to the subject can also be
measured in terms of total amount of analog administered per day.
In some embodiments, a subject is administered from about 0.001 to
about 3000 milligrams of analog per day. In some embodiments, a
subject is administered up to about 2000 milligrams of analog per
day. In some embodiments, a subject is administered up to about
1800 milligrams of analog per day. In some embodiments, a subject
is administered up to about 1600 milligrams of analog per day. In
some embodiments, a subject is administered up to about 1400
milligrams of analog per day. In some embodiments, a subject is
administered up to about 1200 milligrams of analog per day. In some
embodiments, a subject is administered up to about 1000 milligrams
of analog per day. In some embodiments, a subject is administered
up to about 800 milligrams of analog per day. In some embodiments,
a subject is administered from about 0.001 milligrams to about 700
milligrams of analog per dose. In some embodiments, a subject is
administered up to about 700 milligrams of analog per dose. In some
embodiments, a subject is administered up to about 600 milligrams
of analog per dose. In some embodiments, a subject is administered
up to about 500 milligrams of analog per dose. In some embodiments,
a subject is administered up to about 400 milligrams of analog per
dose. In some embodiments, a subject is administered up to about
300 milligrams of secretin analog per dose. In some embodiments, a
subject is administered up to about 200 milligrams of analog per
dose. In some embodiments, a subject is administered up to about
100 milligrams of analog per dose. In some embodiments, a subject
is administered up to about 50 milligrams of analog per dose.
[0723] In some embodiments, subjects can be administered the
composition in which the composition comprising a VIP analog or
pharmaceutically acceptable salt thereof is administered in a daily
dose range of about 0.0001 mg/kg to about 5000 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 450 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 400 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 350 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 300 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 250 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 200 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 150 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 100 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 50 mg/kg of the weight
of the subject. In some embodiments, the composition comprising a
VIP analog or pharmaceutically acceptable salt thereof is
administered in a daily dosage of up about 25 mg/kg of the weight
of the subject.
[0724] In some embodiments, the composition comprising a VIP analog
or pharmaceutically acceptable salt thereof is administered in a
daily dosage of up about 10 mg/kg of the weight of the subject. In
some embodiments, the composition comprising a VIP analog or
pharmaceutically acceptable salt thereof is administered in a daily
dosage of up about 5 mg/kg of the weight of the subject. In some
embodiments, the composition comprising a VIP analog or
pharmaceutically acceptable salt thereof is administered in a daily
dosage of up about 1 mg/kg of the weight of the subject. In some
embodiments, the composition comprising a VIP analog or
pharmaceutically acceptable salt thereof is administered in a daily
dosage of up about 0.1 mg/kg of the weight of the subject. In some
embodiments, the composition comprising a VIP analog or
pharmaceutically acceptable salt thereof is administered in a daily
dosage of up about 0.01 mg/kg of the weight of the subject. In some
embodiments, the composition comprising a VIP analog or
pharmaceutically acceptable salt thereof is administered in a daily
dosage of up about 0.001 mg/kg of the weight of the subject. The
dose administered to the subject can also be measured in terms of
total amount of VIP analog administered per day.
[0725] In some embodiments, a subject in need thereof is
administered from about 1 ng to about 500 .mu.g of analog or
pharmaceutically salt thereof per day. In some embodiments, a
subject in need thereof is administered from about 1 ng to about 10
ng of analog or pharmaceutically salt thereof per day. In some
embodiments, a subject in need thereof is administered from about
10 ng to about 20 ng of analog or pharmaceutically salt thereof per
day. In some embodiments, a subject in need thereof is administered
from about 10 ng to about 100 ng of analog or pharmaceutically salt
thereof per day. In some embodiments, a subject in need thereof is
administered from about 100 ng to about 200 ng of analog or
pharmaceutically salt thereof per day. In some embodiments, a
subject in need thereof is administered from about 200 ng to about
300 ng of analog or pharmaceutically salt thereof per day. In some
embodiments, a subject in need thereof is administered from about
300 ng to about 400 ng of analog or pharmaceutically salt thereof
per day. In some embodiments, a subject in need thereof is
administered from about 400 ng to about 500 ng of analog or
pharmaceutically salt thereof per day. In some embodiments, a
subject in need thereof is administered from about 500 ng to about
600 ng of analog or pharmaceutically salt thereof per day. In some
embodiments, a subject in need thereof is administered from about
600 ng to about 700 ng of analog or pharmaceutically salt thereof
per day. In some embodiments, a subject in need thereof is
administered from about 800 ng to about 900 ng of analog or
pharmaceutically salt thereof per day. In some embodiments, a
subject in need thereof is administered from about 900 ng to about
1 .mu.g of analog or pharmaceutically salt thereof per day. In some
embodiments, a subject in need thereof is administered from about 1
.mu.g to about 100 .mu.g of analog or pharmaceutically salt thereof
per day. In some embodiments, a subject in need thereof is
administered from about 100 .mu.g to about 200 .mu.g of analog or
pharmaceutically salt thereof per day. In some embodiments, a
subject in need thereof is administered from about 200 .mu.g to
about 300 .mu.g of analog or pharmaceutically salt thereof per day.
In some embodiments, a subject in need thereof is administered from
about 300 .mu.g to about 400 .mu.g of analog or pharmaceutically
salt thereof per day. In some embodiments, a subject in need
thereof is administered from about 400 .mu.g to about 500 .mu.g of
analog or pharmaceutically salt thereof per day. In some
embodiments, a subject in need thereof is administered from about
500 .mu.g to about 600 .mu.g of analog or pharmaceutically salt
thereof per day. In some embodiments, a subject in need thereof is
administered from about 600 .mu.g to about 700 .mu.g of analog or
pharmaceutically salt thereof per day. In some embodiments, a
subject in need thereof is administered from about 800 .mu.g to
about 900 .mu.g of analog or pharmaceutically salt thereof per day.
In some embodiments, a subject in need thereof is administered from
about 900 .mu.g to about 1 mg of analog or pharmaceutically salt
thereof per day.
[0726] In some embodiments, a subject in need thereof is
administered from about 0.0001 to about 3000 milligrams of VIP
analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 2000 milligrams
of VIP analog or pharmaceutically salt thereof day. In some
embodiments, a subject is administered up to about 1800 milligrams
of VIP analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 1600 milligrams
of VIP analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 1400 milligrams
of VIP analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 1200 milligrams
of VIP analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 1000 milligrams
of VIP analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 800 milligrams
of VIP analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered from about 0.0001 milligrams
to about 700 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 700 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 600 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 500 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 400 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 300 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 200 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 100 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 50 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 25 milligrams of VIP analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 15 milligrams of VIP analog or pharmaceutically salt
thereof per dose.
[0727] In some embodiments, a subject is administered up to about
10 milligrams of VIP analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about 5
milligrams of VIP analog or pharmaceutically salt thereof per dose.
In some embodiments, a subject is administered up to about 1
milligram of VIP analog or pharmaceutically salt thereof per dose.
In some embodiments, a subject is administered up to about 0.1
milligrams of VIP analog or pharmaceutically salt thereof per dose.
In some embodiments, a subject is administered up to about 0.001
milligrams of VIP analog or pharmaceutically salt thereof per
dose.
[0728] The dose administered to the subject can also be measured in
terms of total amount of VIP analog or pharmaceutically salt
thereof administered per ounce of liquid prepared. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 2.5 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 2.25 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 2.25 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 2.0 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.9 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.8 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.7 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.6 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.5 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.4 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.3 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.2 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.1 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 1.0 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.9 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.8 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.7 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.6 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.5 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.4 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.3 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.2 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.1 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.01 grams per ounce of solution. In some
embodiments, the VIP analog or pharmaceutically salt thereof is at
a concentration of about 0.001 grams per ounce of solution
prepared. In some embodiments, the VIP analog or pharmaceutically
salt thereof is at a concentration of about 0.0001 grams per ounce
of solution prepared. In some embodiments, the VIP analog or
pharmaceutically salt thereof is at a concentration of about
0.00001 grams per ounce of solution prepared. In some embodiments,
the VIP analog or pharmaceutically salt thereof is at a
concentration of about 0.000001 grams per ounce of solution
prepared.
[0729] Dosage may be measured in terms of mass amount of analog per
liter of liquid formulation prepared. One skilled in the art can
increase or decrease the concentration of the analog in the dose
depending upon the strength of biological activity desired to treat
or prevent any above-mentioned disorders associated with the
treatment of subjects in need thereof. For instance, one embodiment
of the invention can include up to 0.00001 grams of analog per 5 mL
of liquid formulation and up to about 10 grams of analog per 5 mL
of liquid formulation.
[0730] In some embodiments the pharmaceutical compositions of the
claimed invention comprise at least one other active agent. in some
embodiments, the active agent is a vasoactive agent. In some
embodiments the vasoactive agent is chosen from the naturally
occurring prostaglandins prostaglandin E0 (PGE0, also referred to
13,14-dihydro-PGE1; hereinafter, the abbreviation "PG" is used for
"prostaglandin"), PGE1, 19-hydroxy-PGE1, PGE2, 19-hydroxy-PGE2,
PGA1, 19-hydroxy-PGA1, PGA2, 19-hydroxy-PGA2, PGB1,
19-hydroxy-PGB1, PGB2, 19-hydroxy-PGB2, PGB3, PGD2, PGF1.alpha.,
PGF2.alpha. (dinoprost), PGE3, PGF3.alpha., PGI2 (prostacyclin),
and combinations thereof. PGE0, PGE1, PGE2, and the hydrolyzable
lower alkyl esters thereof (e.g., the methyl, ethyl and isopropyl
esters) are, however, particularly suitable. Other suitable
prostaglandins are exemplified, without limitation, by arboprostil,
carbaprostacyclin, carboprost tromethamine, dinoprost tromethamine,
dinoprostone, enprostil, iloprost, lipoprost, gemeprost,
metenoprost, sulprostone, tiaprost, viprostil (CL 115,347),
viprostil methyl ester, 16,16-dimethyl-.DELTA.2-PGE1 methyl ester,
15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester (misoprostol),
16,16-dimethyl-PGE1, 11-deoxy-15-methyl-PGE1,
16-methyl-18,18,19,19-tetrahydrocarbacyclin,
16(RS)-15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester,
(+)-4,5-didehydro-16-phenoxy-.alpha.-tetranor-PGE2 methyl ester,
11-deoxy-11.alpha.,16,16-trimethyl-PGE2,
(+)-11.alpha.,16.alpha.,16.beta.-dihydroxy-1-(hydroxymethyl)-16-methyl-tr-
ans-prostene, 9-chloro-16,16-dimethyl-PGE2, 16,16-dimethyl-PGE2,
15(S)-15-methyl-PGE2, 9-deoxy-9-methylene-16,16-dimethyl-PGE2,
potassium salt, 19(R)-hydroxy-PGE2, and
11-deoxy-16,16-dimethyl-PGE2. Additional vasoactive agents useful
as secondary active agents herein include endothelin-derived
relaxation factors ("EDRFs") such as nitric oxide releasing agents,
e.g., sodium nitroprusside and diazenium diolates, or "NONOates."
NONOates include, but are not limited to,
(Z)-1-{N-methyl-N-{6-(N-methyl-ammoniohexyl)amino}}diazen-1-ium-1,2-diola-
te ("MAHMA/NO"),
(Z)-1-{N-(3-ammoniopropyl)-N-(n-propyl)amino}-diazen-1-ium-1,2-diolate
("PAPA/NO"),
(Z)-1-{N-{3-aminopropyl}-N-{4-(3-aminopropylammonio)butyl}amino}diazen-1--
ium-1,2-diolate (spermine NONOate or "SPER/NO") and sodium
(Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (diethylamine
NONOate or "DEA/NO") and derivatives thereof). Still other
vasoactive agents include vasoactive intestinal polypeptide analogs
and derivatives thereof (particularly derivatives in the form of
hydrolyzable lower alkyl esters), smooth muscle relaxants,
leukotriene inhibitors, calcium channel blockers, P2-adrenergic
agonists, angiotensin-converting enzyme ("ACE") inhibitors,
angiotensin II receptor antagonists, and phosphodiesterase
inhibitors. Still other suitable vasoactive agents include, but are
not limited to: nitrates and like compounds such as nitroglycerin,
isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate,
molsidomine, linsidomine chlorhydrate ("SIN-1"),
S-nitroso-N-acetyl-d,l-penicillamine ("SNAP") and
S-nitroso-N-glutathione ("SNO-GLU"); long and short acting
.alpha.-blockers such as phenoxybenzamine, dibenamine, doxazosin,
terazosin, phentolamine, tolazoline, prazosin, trimazosin,
alfuzosin, tamsulosin and indoramin; ergot alkaloids such as
ergotamine and ergotamine analogs, e.g., acetergamine,
brazergoline, bromerguride, cianergoline, delorgotrile,
disulergine, ergonovine maleate, ergotamine tartrate, etisulergine,
lergotrile, lysergide, mesulergine, metergoline, metergotamine,
nicergoline, pergolide, propisergide, proterguride and terguride;
antihypertensive agents such as diazoxide, hydralazine and
minoxidil; nimodepine; pinacidil; cyclandelate; dipyridamole;
isoxsuprine; chlorpromazine; haloperidol; yohimbine; and
trazodone.
[0731] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is an inhibitor of rho
kinase, an enzyme belonging to the rhoA/rho associated kinase
pathway, which regulates the state of phosphorylation of myosin
phosphatase, in turn leading to the control of smooth muscle
contraction. One example of a suitable rho kinase inhibitor has the
following structural formula and is identified as Y-27632. Other
suitable rho kinase inhibitors are disclosed, for example, in U.S.
Pat. No. 6,218,410, which is herein incorporated by reference.
[0732] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that are peptide analogs of
.alpha.-melanocyte-stimulating hormone (.alpha.-MSH), also referred
to as "melanocortin peptides." Such peptides include the sequence
His-Phe-Arg-Trp, His-D-Phe-Arg-Trp, or are homologs thereof, and
can be cyclic. A suitable melanocortin peptide is
Ac-Nle-cyclo-(-Asp-His-D-Phe-Arg-Trp-Lys)-OH. See U.S. Pat. No.
6,051,555 to Hadley and International Patent Publication No. WO
01/00224 to Blood et al., assigned to Palatin Technologies, Inc.
The aforementioned amino acid residues have their conventional
meaning as given in Chapter 2422 of the Manual of Patent Examining
Procedure (2000). Thus, "Arg" is arginine, "Nle" is norleucine,
"His" is histamine, "Phe" is phenylalanine, "D-Phe" is
D-phenylalanine, "Trp" is tryptophan, and "Ac" refers to an acetyl
moiety, i.e., an acetyl moiety present in a peptide or amino acid
sequence that is acetylated.
[0733] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is an endothelin
antagonists, including antagonists of any or all of the three
isoforms of endothelin, i.e., ET-1, ET-2, and ET-3, and are
exemplified by: phenoxyphenylacetic acids and derivatives thereof,
such as
N-(4-isopropylbenzene-sulfonyl)-.alpha.-(4-carboxy-2-n-propylphenoxy)-3,4-
-methylenedioxyphenyl acetamide dipotassium salt,
2-{(2,6-dipropyl-4-hydroxymethyl)-phenoxy}-2-(4-phenoxyphenyl)-acetic
acid,
2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(4-phenylphenyl)acetic
acid,
2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3-carboxyphenyl)-aceti-
c acid,
2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3,4-ethylenedioxyphen-
yl)acetic acid,
2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3,4,5-trimethoxyphenyl)aceti-
c acid,
2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3,4-methylenedioxyphe-
nyl)acetic acid,
N-(4-dimethylaminobenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)--
2-(3,4-methylenedioxyphenyl)acetamide,
N-(2-methylbenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4--
methylenedioxyphenyl)acetamide,
N-(2-methoxycarbonyl-benzenesulfonyl)-2-(4-methoxy-carbonyl-2-propylpheno-
xy)-2-(3,4-methylenedioxy-phenyl)acetamide,
N-(2-chlorobenzene-sulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-
-methylenedioxyphenyl)acetamide, and others, as described in U.S.
Pat. No. 5,565,485; and certain isooxazoles, oxazoles, thiazoles,
isothiazoles and imidazoles, as described, for example, in U.S.
Pat. No. 6,136,828.
[0734] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is a peptidyl drug
including the peptidyl hormones activin, amylin, angiotensin,
atrial natriuretic peptide (ANP), calcitonin, calcitonin
gene-related peptide, calcitonin N-terminal flanking peptide,
ciliary neurotrophic factor (CNTF), corticotropin
(adrenocorticotropin hormone, ACTH), corticotropin-releasing factor
(CRF or CRH), epidermal growth factor (EGF), follicle-stimulating
hormone (FSH), gastrin, gastrin inhibitory peptide (GIP),
gastrin-releasing peptide, gonadotropin-releasing factor (GnRF or
GNRH), growth hormone releasing factor (GRF, GRH), human chorionic
gonadotropin (hCH), inhibin A, inhibin B, insulin, luteinizing
hormone (LH), luteinizing hormone-releasing hormone (LHRH),
.alpha.-melanocyte-stimulating hormone,
.beta.-melanocyte-stimulating hormone,
.gamma.-melanocyte-stimulating hormone, melatonin, motilin,
oxytocin (pitocin), pancreatic polypeptide, parathyroid hormone
(PTH), placental lactogen, prolactin (PRL), prolactin-release
inhibiting factor (PIF), prolactin-releasing factor (PRF),
secretin, somatotropin (growth hormone, GH), somatostatin (SIF,
growth hormone-release inhibiting factor, GIF), thyrotropin
(thyroid-stimulating hormone, TSH), thyrotropin-releasing factor
(TRH or TRF), thyroxine, and vasopressin. Other peptidyl drugs are
the cytokines, e.g., colony stimulating factor 4, heparin binding
neurotrophic factor (HBNF), interferon-a, interferon .alpha.-2a,
interferon .alpha.-2b, interferon .alpha.-n3, interferon-.beta.,
etc., interleukin-1, interleukin-2, interleukin-3, interleukin-4,
interleukin-5, interleukin-6, etc., tumor necrosis factor, tumor
necrosis factor-.alpha., granulocyte colony-stimulating factor
(G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF),
macrophage colony-stimulating factor, midkine (MD), and
thymopoietin.
[0735] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is a selective androgen
receptor modulators (SARMs) include LGD2226 and/or LGD1331, both
available from Ligand Pharmaceuticals (San Diego, Calif.). See
Negro-Villar et al. J. Clin. Endocrinol. & Metabol.
84(10):3459-62 (1999).
[0736] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is a suitable neuropeptide
including bradykinin, kallidin, des-Arg9-bradykinin,
des-Arg10-kallidin, des-Arg9-{Leu8}-bradykinin,
{D-Phe7}-bradykinin, HOE 140, neuropeptide Y, calcitonin
gene-related peptide (cGRP), enkaphalins and related opioid
peptides such as Met5enkaphalin, Leu5enkephalin, .alpha.-, .beta.-
and .gamma.-endorphin, .alpha.- and .beta.-neo-endorphin, and
dynorphin, as well as the neurotransmitters GABA
(.gamma.-aminobutyric acid), glycine, glutamate, acetylcholine,
dopamine, epinephrine, 5-hydroxytryptamine, substance P, serotonin,
and catecholamines.
[0737] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is a suitable serotonin
agonists include, but are not limited to 2-methyl serotonin,
buspirone, ipsaperone, tiaspirone, gepirone, ergot alkaloids,
8-hydroxy-(2-N,N-dipropyl-amino)-tetraline,
1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride,
sumatriptan, m-chlorophenylpiperazine, trazodone, zacopride,
mezacopride, and combinations thereof. Suitable serotonin
antagonists include, for example, ondansetron, granisetron,
metoclopramide, tropisetron, dolasetron, palonosetron,
trimethobenzamide, methysergide, risperidone, ketanserin,
ritanserin, clozapine, amitriptyline, MDL 100,907
(R(+)-.alpha.-(2,3-dimethoxyphenyl)-1-{2-(4-fluorophenyl)ethyl}-4-piperid-
ine-methanol) (Marion Merrell Dow), azatadine, cyproheptadine,
fenclonine, chlorpromazine, mianserin and combinations thereof.
[0738] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is an ergot alkaloids
include ergotamine and ergotamine analogs, e.g., acetergamine,
brazergoline, bromerguride, cianergoline, delorgotrile,
dihydroergotamine, disulergine, ergonovine, ergonovine maleate,
ergotamine tartrate, etisulergine, lergotrile, lysergide,
mesulergine, metergoline, metergotamine, nicergoline, pergolide,
propisergide, proterguride and terguride.
[0739] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is a calcium channel
blockers that are suitable for use according to the present
invention include, without limitation, amlodipine, felodipine,
isradipine, nicardipine, nifedipine, nimodipine, nisoldipine,
nitrendipine, bepridil, diltiazem, verapamil, and combinations
thereof. In some embodiments, the pharmaceutical compositions of
the invention comprise an active agent that is a potassium channel
openers include, but are not limited to, pinacidil, diazoxide,
cromakalim, nicorandil, minoxidil,
(N-cyano-N'-(1,1-dimethylpropyl)-N''-3-pyridyl-guanidine (P-1075),
and N-cyano-N'-(2-nitroxyethyl)-3-pridinecarboximidamide
monomethanesulfonate (KRN 2391).
[0740] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is a potassium channel
blockers include tedisamil, agitoxin-2, apamin, BDS-I, BDS-II,
charybdotoxin, .alpha.-dendrotoxin, .beta.-dendrotoxin,
.gamma.-dendrotoxin, .delta.-dendrotoxin, dendrotoxin-I,
dendrotoxin-K, E-4031, iberiotoxin, kaliotoxin, MCD-peptide,
margatoxin, noxiustoxin, paxilline, penitrem A, stichodactyla,
tertiapin, tityustoxin K alpha, verruculogen, and combinations
thereof. Although all of the active agents are available
commercially, most of the listed potassium channel blockers are
available from Alomone Labs (Jerusalem, Israel).
[0741] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is a dopamine agonist
including, for example, levodopa, bromocriptine, pergolide,
apomorphine, piribedil, pramipexole, ropinirole, and combinations
thereof. Dopamine antagonists include, without limitation,
spiroperidol, benperidol, trifluperidol, pimozide, fluphenazine,
droperidol, haloperidol, thiothixene, trifluperazine, moperone,
prochlorperazine, molindone, thioridazine, clozapine,
chlorpromazine, promazine, sulpiride, clebopride, chlorpromazine,
spiperone, flupenthixol, and combinations thereof.
[0742] In some embodiments, the pharmaceutical compositions of the
invention comprise an active agent that is a non-androgenic steroid
including progestins and estrogens. Suitable estrogens include
synthetic and natural estrogens such as: estradiol (i.e.,
1,3,5-estratriene-3,17.beta.-diol, or "17.beta.-estradiol") and its
esters, including estradiol benzoate, valerate, cypionate,
heptanoate, decanoate, acetate and diacetate; 17.alpha.-estradiol;
ethinylestradiol (i.e., 17.alpha.-ethinylestradiol) and esters and
ethers thereof, including ethinylestradiol 3-acetate and
ethinylestradiol 3-benzoate; estriol and estriol succinate;
polyestrol phosphate; estrone and its esters and derivatives,
including estrone acetate, estrone sulfate, and piperazine estrone
sulfate; quinestrol; mestranol; and conjugated equine estrogens.
Suitable progestins include acetoxypregnenolone, allylestrenol,
anagestone acetate, chlormadinone acetate, cyproterone, cyproterone
acetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone
(17.alpha.-ethinyltestosterone), ethynodiol diacetate, flurogestone
acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone
acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone,
hydroxymethylprogesterone acetate, 3-ketodesogestrel,
levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone
acetate, megestrol, megestrol acetate, melengestrol acetate,
norethindrone, norethindrone acetate, norethisterone,
norethisterone acetate, norethynodrel, norgestimate, norgestrel,
norgestrienone, normethisterone, and progesterone. It is generally
desirable to co-administer a progestin along with an estrogen so
that the estrogen is not "unopposed." As is well known in the art,
estrogen-based therapies are known to increase the risk of
endometrial hyperplasia and cancer, as well as the risk of breast
cancer, in treated individuals. Co-administration of estrogenic
agents with a progestin has been found to decrease the
aforementioned risks.
[0743] The pharmaceutical compositions of the present invention may
also include one or more chemotherapeutic agents. Suitable
chemotherapeutic agents include, but are not limited to, platinum
coordination compounds, topoisomerase inhibitors, antibiotics,
antimitotic alkaloids and difluoronucleosides.
[0744] In one embodiment of the present invention, the
chemotherapeutic agent is a platinum coordination compound. The
term "platinum coordination compound" refers to any tumor cell
growth inhibiting platinum coordination compound that provides the
platinum in the form of an ion. Suitable platinum coordination
compounds include, but are not limited to,
cis-diamminediaquoplatinum (II)-ion; chloro
(diethylenetriamine)-platinum (II) chloride; dichloro
(ethylenediamine)-platinum (II); diammine
(1,1-cyclobutanedicarboxylato) platinum (II) (carboplatin);
spiroplatin; iproplatin; diammine (2-ethylmalonato)-platinum (II);
ethylenediaminemalonatoplatinum (II); aqua
(1,2-diaminodyclohexane)-sulfatoplatinum (II);
(1,2-diaminocyclohexane) malonatoplatinum (II); (4-caroxyphthalato)
(1,2-diaminocyclohexane) platinum (II);
(1,2-diaminocyclohexane)-(isocitrato) platinum (II);
(1,2-diaminocyclohexane) cis (pyruvato) platinum (II);
(1,2-diaminocyclohexane) oxalatoplatinum (II); ormaplatin; and
tetraplatin
[0745] In some embodiments, the secretin analog and the additional
active agent or agents may be incorporated into a single
formulation, or they may be administered separately, either
simultaneously or sequentially. In one embodiment, an androgenic
agent is administered prior to administration of VIP or a VIP
agonist, i.e., the androgenic agent is administered as a
pretreatment. In some embodiments, such a method involves
administration of an androgenic agent, e.g., via oral or topical
(vulvar and/or vaginal) administration, followed by topical (again,
vulvar and/or vaginal) administration of VIP or a VIP agonist.
[0746] In some embodiments, the formulations herein are
administered by topical application to the vulvar region and/or by
vaginal drug administration. These pharmaceutical formulations may
typically contain one or more pharmaceutically acceptable carriers
suited to the particular type of formulation, i.e., gel, ointment,
suppository, or the like. The vehicles are comprised of materials
of naturally occurring or synthetic origin that do not adversely
affect the active agent or other components of the formulation.
Suitable carriers for use herein include water, silicone, waxes,
petroleum jelly, polyethylene glycol, propylene glycol, liposomes,
sugars such as mannitol and lactose, and a variety of other
materials, again depending, on the specific type of formulation
used. As described in Section IV, infra, dosage forms used for
administration to the vulvar region and/or vagina may be used to
deliver drug on an as-needed, on-demand basis, and/or throughout an
extended, sustained release profile.
[0747] The pharmaceutical compositions may also include a chemical
compound to enhance permeation of the active agent through the
mucosal tissue, i.e., a "permeation enhancer." Suitable permeation
enhancers include those generally useful in conjunction with
topical, transdermal or transmucosal drug delivery. Examples of
suitable permeation enhancers include the following: sulfoxides
such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C10MSO);
ethers such as diethylene glycol monoethyl ether (available
commercially as TRANSCUTOL.RTM. (Gattefosse S. A., Saint-Priest,
France) and diethylene glycol monomethyl ether; surfactants such as
sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium
bromide, benzalkonium chloride, Poloxamer (231, 182, 184),
TWEEN.RTM. (20, 40, 60, 80) (ICI Chemicals, Bridgewater, N.J.), and
lecithin (U.S. Pat. No. 4,783,450); the 1-substituted
azacycloheptan-2-ones, particularly
1-n-dodecylcyclaz.alpha.-cycloheptan-2-one (available under the
trademark AZONE.RTM. (Durham Pharmaceuticals, LLC, Durham, N.C.);
see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934);
alcohols such as ethanol, propanol, octanol, decanol, benzyl
alcohol, and the like; fatty acids such as lauric acid, oleic acid
and valeric acid; fatty acid esters such as isopropyl myristate,
isopropyl palmitate, methylpropionate, and ethyl oleate; polyols
and esters thereof such as propylene glycol, ethylene glycol,
glycerol, butanediol, polyethylene glycol, and polyethylene glycol
monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and
other nitrogenous compounds such as urea, dimethylacetamide (DMA),
dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone,
ethanolamine, diethanolamine and triethanolamine; terpenes;
alkanones; and organic acids, particularly salicylic acid and
salicylates, citric acid and succinic acid. Mixtures of two or more
enhancers may also be used.
[0748] In some embodiments, the pharmaceutical compositions may
include an enzyme inhibitor, i.e., a compound effective to inhibit
enzymes present in the vagina or vulvar area that could degrade or
metabolize the active agent. That is, inhibitors of enzymes that
decrease or eliminate the activity of the active agent may be
included in the formulation so as to effectively inhibit the action
of those enzymes. Such compounds include, for example, fatty acids,
fatty acid esters, and NAD inhibitors.
[0749] In some embodiments, the pharmaceutical composition may be
in the form of an ointment, cream, emulsion, lotion, gel, solid,
solution, suspension, foam or liposomal formulation. Alternatively,
the formulations may be contained within avaginal ring (e.g., as
disclosed in U.S. Pat. No. 5,188,835 to Lindskoget al., assigned to
Kabi Pharmacia AB), or within a tampon, suppository, sponge,
pillow, puff, or osmotic pump system; these platforms are useful
solely for vaginal delivery. Ointments are semisolid preparations
that are typically based on petrolatum or other petroleum
derivatives. The specific ointment base to be used, as will be
appreciated by those skilled in the art, is one that will provide
for optimum drug delivery. As with other carriers or vehicles, an
ointment base should be inert, stable, non irritating and
nonsensitizing. As explained in Remington: The Science and Practice
of Pharmacy, supra, at pages 1034-1038, ointment bases may be
grouped in four classes: oleaginous bases; emulsifiable bases;
emulsion bases; and water-soluble bases. Oleaginous ointment bases
include, for example, vegetable oils, fats obtained from animals,
and semisolid hydrocarbons obtained from petroleum. Emulsifiable
ointment bases, also known as absorbent ointment bases, contain
little or no water and include, for example, hydroxystearin
sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion
ointment bases are either water-in-oil (W/O) emulsions or
oil-in-water (0/W) emulsions, and include, for example, cetyl
alcohol, glyceryl monostearate, lanolin and stearic acid. Suitable
water-soluble ointment bases are prepared from polyethylene glycols
of varying molecular weight; again, reference may be had to
Remington: The Science and Practice of Pharmacy for further
information.
[0750] In one aspect of the invention, a method is provided for
treating sexual dysfunction in a female individual comprising
administering to the vagina and/or vulvar area a pharmaceutical
formulation comprising a secretin family analog. In some
embodiments, the secretin family analog is a vasodilator, with
vasodilators selected from the group consisting of VIP and
vasoactive intestinal polypeptide analogs and combinations of any
of the foregoing. Any number of drug delivery platforms may be
used, e.g., suppositories, ointments, creams, gels, solutions and
the like. Also, one or more additional types of drugs, i.e.,
pharmacologically active agents may be incorporated into the
pharmaceutical formulations. In other aspects of the invention,
vaginal administration of a vasoactive agent as just described is
used to improve vaginal muscle tone and tissue health, to enhance
vaginal lubrication, or to minimize collagen misdeposition
resulting from hypoxia as well as the associated lack of elasticity
resulting from the collagen misdeposition.
[0751] In another embodiment of the invention, a method is provided
for improving memory by administering a secretin family analog.
[0752] In another aspect of the invention, pharmaceutical
compositions and dosage forms are provided for carrying out the
aforementioned methods. The compositions and dosage forms contain a
vasoactive agent as described above, a pharmaceutically acceptable
vehicle, and, optionally, one or more additional pharmacologically
active agents. The formulations contain a therapeutically effective
amount of the active agent, or a therapeutically effective
concentration of the active agent, i.e., a concentration that
provides a therapeutically effective amount of active agent upon
administration of a selected volume of composition.
[0753] The subject can be any animal, including but not necessarily
limited to mammals such as a human, mouse, rat, hamster, guinea
pig, rabbit, cat, dog, monkey, cow, horse, pig, and the like. In
some embodiments, the subject is a human
[0754] According to some embodiments of the invention, the
formulation may be supplied as part of a kit. The kit comprise
comprising an analog, wherein the analog comprises an .alpha.-amino
acid and at least one .beta.-amino acid. In another embodiment, the
kit comprises a pharmaceutically acceptable salt of an analog with
a rehydration mixture. In another embodiment, the pharmaceutically
acceptable salt of an analog are in one container while the
rehydration mixture is in a second container. The rehydration
mixture may be supplied in dry form, to which water or other liquid
solvent may be added to form a suspension or solution prior to
administration. Rehydration mixtures are mixtures designed to
solubilize a lyophilized, insoluble salt of the invention prior to
administration of the composition to a subject takes at least one
dose of a purgative. In another embodiment, the kit comprises a
pharmaceutically acceptable salt in orally available pill form.
[0755] The kit may contain two or more containers, packs, or
dispensers together with instructions for preparation and
administration. In some embodiments, the kit comprises at least one
container comprising the pharmaceutical composition or compositions
described herein and a second container comprising a means for
delivery of the compositions such as a syringe. In some
embodiments, the kit comprises a composition comprising an analog
in solution or lyophilized or dried and accompanied by a
rehydration mixture. In some embodiments, the analog and
rehydration mixture may be in one or more additional
containers.
[0756] The compositions included in the kit may be supplied in
containers of any sort such that the shelf-life of the different
components are preserved, and are not adsorbed or altered by the
materials of the container. For example, suitable containers
include simple bottles that may be fabricated from glass, organic
polymers, such as polycarbonate, polystyrene, polypropylene,
polyethylene, ceramic, metal or any other material typically
employed to hold reagents or food; envelopes, that may consist of
foil-lined interiors, such as aluminum or an alloy. Other
containers include test tubes, vials, flasks, and syringes. The
containers may have two compartments that are separated by a
readily removable membrane that upon removal permits the components
of the compositions to mix. Removable membranes may be glass,
plastic, rubber, or other inert material.
[0757] Kits may also be supplied with instructional materials.
Instructions may be printed on paper or other substrates, and/or
may be supplied as an electronic-readable medium, such as a floppy
disc, CD-ROM, DVD-ROM, zip disc, videotape, audio tape, or other
readable memory storage device. Detailed instructions may not be
physically associated with the kit; instead, a user may be directed
to an internet web site specified by the manufacturer or
distributor of the kit, or supplied as electronic mail.
[0758] In another embodiment, a packaged kit is provided that
contains the pharmaceutical formulation to be administered, i.e., a
pharmaceutical formulation containing VIP analog or a for enhancing
female sexual desire and responsiveness, a container (e.g., a vial,
a bottle, a pouch, an envelope, a can, a tube, an atomizer, an
aerosol can, etc.), optionally sealed, for housing the formulation
during storage and prior to use, and instructions for carrying out
drug administration in a manner effective to enhance sexual desire
and responsiveness. The instructions will typically be written
instructions on a package insert, a label, and/or on other
components of the kit.
[0759] Depending on the type of formulation and the intended mode
of administration, the kit may also include a device for
administering the formulation (e.g., a transdermal delivery
device). The administration device may be a dropper, a swab, a
stick, or the nozzle or outlet of an atomizer or aerosol can. The
formulation may be any suitable formulation as described herein.
For example, the formulation may be an oral dosage form containing
a unit dosage of the active agent, or a gel or ointment contained
within a tube. The kit may contain multiple formulations of
different dosages of the same agent. The kit may also contain
multiple formulations of different active agents.
[0760] The present kits will also typically include means for
packaging the individual kit components, i.e., the pharmaceutical
dosage forms, the administration device (if included), and the
written instructions for use. Such packaging means may take the
form of a cardboard or paper box, a plastic or foil pouch, etc.
[0761] The invention relates to the use of an analog in the
preparation of a medicament for treating or preventing chronic
obstructive pulmonary disease, pulmonary hypertension, primary
arterial hypertension, pulmonary hypertension associated to
post-ventricular septal defect, idiopathic pulmonary fibrosis,
idiopathic pulmonary arterial hypertension, CREST
syndrome--Calcinosis; Raynaud's disease; loss of muscle control of
the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory
distress, congestive heart failure, chronic obstructed pulmonary
disorder, asthma, chronic obstructive pulmonary disease,
sarcoidosis, small cell lung carcinoma, autoimmune disease,
inflammatory disease, sepsis, Hirschsprung's Disease, sexual
dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's
disease, circadian rhythm dysfunction, pain, colorectal cancer,
hepatocellular cancer, elevated blood pressure levels, elevated
blood glucose levels, hyperglycemia, diabetes, insulin resistance,
metabolic acidosis, obesity, Type I diabetes, Type II diabetes
Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis,
uveoretinitis, osteoporosis, female sexual dysfunction due to
administration of a medication that causes onset of or exacerbates
symptoms of pulmonary hypertension, primary arterial hypertension,
pulmonary hypertension associated to post-ventricular septal
defect, idiopathic pulmonary fibrosis, idiopathic pulmonary
arterial hypertension, CREST syndrome--Calcinosis; Raynaud's
disease; loss of muscle control of the Esophagus; Sclerodactyly;
Telangiectasia, Acute respiratory distress, congestive heart
failure, chronic obstructed pulmonary disorder, asthma, chronic
obstructive pulmonary disease, sarcoidosis, small cell lung
carcinoma, autoimmune disease, inflammatory disease, sepsis,
Hirschsprung's Disease, sexual dysfunction, erectile dysfunction,
Parkinson's disease, Alzheimer's disease, circadian rhythm
dysfunction, pain, colorectal cancer, hepatocellular cancer,
elevated blood pressure levels, elevated blood glucose levels,
hyperglycemia, diabetes, insulin resistance, metabolic acidosis,
obesity, Type I diabetes, Type II diabetes Multiple Sclerosis,
osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis,
osteoporosis, female sexual dysfunction in a subject in need
thereof. In some embodiments, the invention relates to compositions
comprising a secretin family analog for treatment or prevention of
chronic obstructive pulmonary disease, pulmonary hypertension,
primary arterial hypertension, pulmonary hypertension associated to
post-ventricular septal defect, idiopathic pulmonary fibrosis,
idiopathic pulmonary arterial hypertension, CREST
syndrome--Calcinosis; Raynaud's disease; loss of muscle control of
the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory
distress, congestive heart failure, chronic obstructed pulmonary
disorder, asthma, chronic obstructive pulmonary disease,
sarcoidosis, small cell lung carcinoma, autoimmune disease,
inflammatory disease, sepsis, Hirschsprung's Disease, sexual
dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's
disease, circadian rhythm dysfunction, pain, colorectal cancer,
hepatocellular cancer, elevated blood pressure levels, elevated
blood glucose levels, hyperglycemia, diabetes, insulin resistance,
metabolic acidosis, obesity, Type I diabetes, Type II diabetes
Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis,
uveoretinitis, osteoporosis, female sexual dysfunction in a subject
in need thereof.
[0762] The present invention relates to inhibiting secretion of
TNF-.alpha. in a subject comprising administering a composition
comprising an analog to a subject, wherein said analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid. In some
embodiments the analog is a secretin family analog. In some
embodiments the analog is a VIP analog. The present invention
relates to inhibiting binding of VIP to a VIP receptor in a subject
comprising administering a composition comprising an analog to a
subject, wherein said analog comprises an .alpha.-amino acid and at
least one .beta.-amino acid. In some embodiments the analog is a
secretin family analog. In some embodiments the analog is a VIP
analog. The present invention relates to inhibiting biological
effect of GHRH in a subject comprising administering a composition
comprising an analog to a subject, wherein said analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid. In some
embodiments the analog is a secretin family analog. In some
embodiments the analog is a VIP analog. The present invention
relates to inhibiting chemotaxis of T cells in a subject comprising
administering a composition comprising an analog to a subject,
wherein said analog comprises an .alpha.-amino acid and at least
one .beta.-amino acid. In some embodiments the analog is a secretin
family analog. In some embodiments the analog is a VIP analog. The
present invention relates to inhibiting expression of LPS in a
subject comprising administering a composition comprising an analog
to a subject, wherein said analog comprises an .alpha.-amino acid
and at least one .beta.-amino acid. In some embodiments the analog
is a secretin family analog. In some embodiments the analog is a
VIP analog. The present invention relates to modulating the amount
of cyclic cAMP in a subject comprising administering a composition
comprising an analog to a subject, wherein said analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid. In some
embodiments the analog is a secretin family analog. In some
embodiments the analog is a VIP analog. The present invention
relates to increasing the activity or expression of adenylate
cyclase in a subject comprising administering a composition
comprising an analog to a subject, wherein said analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid. In some
embodiments the analog is a secretin family analog. In some
embodiments the analog is a secretin family analog and a VPAC1
antagonist. In some embodiments the analog is a secretin family
analog. and a VPAC2 agonist. In some embodiments the analog is a
VIP analog. In some embodiments, the composition or pharmaceutical
composition of the claimed invention comprises a VIP analog,
wherein the VIP analog is a VIPR1 agonist, and has substantially
reduced selectivity or no selectivity for VIPR2 or PAC1 receptors.
In some embodiments, the composition or pharmaceutical composition
of the claimed invention comprises a VIP analog, wherein the VIP
analog is a PAC1 agonist, and has substantially reduced selectivity
or no selectivity for VIPR2 or VIPR1 receptors. In some
embodiments, the composition or pharmaceutical composition of the
claimed invention comprises a VIP analog, wherein the VIP analog is
a VIPR2 agonist, and has substantially reduced selectivity or no
selectivity for VIPR1 or PAC1 receptors. In some embodiments, the
composition or pharmaceutical composition of the claimed invention
comprises a VIP analog, wherein the VIP analog is a VIPR2
antagonist, but does not antagonize VIPR1 or PAC1 receptors. In
some embodiments, the composition or pharmaceutical composition of
the claimed invention comprises a VIP analog, wherein the VIP
analog is a VIPR1 antagonist, but does not antagonize VIPR2 or PAC1
receptors. In some embodiments, the composition or pharmaceutical
composition of the claimed invention comprises a VIP analog,
wherein the VIP analog is a PAC1 antagonist, but does not
antagonize VIPR2 or VIPR1 receptors. Any of the above-mentioned
selective agonist or antagonists may be used in any of the method
claims provided herein.
[0763] The present invention relates to modulating the amount of
PLD in the nervous system of a subject comprising administering a
composition comprising an analog to a subject, wherein said analog
comprises an .alpha.-amino acid and at least one .beta.-amino acid.
In some embodiments the analog is a secretin family analog. In some
embodiments the analog is a VIP analog.
[0764] The present invention relates to modulating the amount of
antibody production of a B cell in a subject comprising
administering a composition comprising an analog to a subject,
wherein said analog comprises an .alpha.-amino acid and at least
one .beta.-amino acid. In some embodiments the analog is a secretin
family analog. In some embodiments the analog is a VIP analog.
[0765] The present invention relates to modulating the amount of
antibody production of a B cell or a B cell hybridoma cell in vitro
comprising treating a culture containing B cells or a hybridomas
with a composition comprising an analog to a subject, wherein said
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid. In some embodiments the analog is a secretin
family analog. In some embodiments the analog is a VIP analog.
[0766] The present invention relates to modulating the immune
response of a subject comprising administering a subject with a
composition comprising an analog to a subject, wherein said analog
comprises an .alpha.-amino acid and at least one .beta.-amino acid.
In some embodiments the analog is a secretin family analog. In some
embodiments the analog is a VIP analog.
[0767] The present invention relates to modulating the activation
of cystic fibrosis transmembrane conductance regulator (CFTR) in a
subject comprising administering a subject with a composition
comprising an analog to a subject, wherein said analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid. In some
embodiments the analog is a secretin family analog. In some
embodiments the analog is a VIP analog.
[0768] The present invention also relates measuring the modulation
of activity of a secretin receptor molecule by measuring receptor
activity comprising:
[0769] a) contacting a human secretin family receptor with a
secretin family analog, wherein the analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid;
[0770] b) measuring the association of the secretin family analog
to the secretin receptor in the presence and absence of an unknown
compound; and
[0771] c) comparing the rate of association of the secretin family
analog to the human secretin receptor in the presence of an unknown
compound to the rate of association of the secretin analog to the
human secretin receptor in the absence of an unknown compound.
[0772] The present invention also relates identifying a modulator
of activity of a secretin receptor molecule by measuring receptor
activity comprising:
[0773] a) contacting a human secretin family receptor with a
secretin family analog, wherein said analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid;
[0774] b) measuring the association of the secretin family analog
to the secretin receptor in the presence and absence of an unknown
compound; and
[0775] c) comparing the rate of association of the secretin family
analog to the human secretin receptor in the presence of an unknown
compound to the rate of association of the secretin analog to the
human secretin receptor in the absence of an unknown compound.
[0776] The present invention also relates to a method of measuring
the modulation of activity of a human VIP receptor molecule by
measuring receptor activity comprising:
[0777] a) contacting a human VIP family receptor with a VIP analog,
wherein the analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid;
[0778] b) measuring the association of the VIP analog to the VIP
receptor in the presence and absence of an unknown compound;
and
[0779] c) comparing the rate of association of the VIP analog to
the human VIP receptor in the presence of an unknown compound to
the rate of association of the VIP analog to the human VIP receptor
in the absence of an unknown compound.
[0780] The present invention also relates identifying a modulator
of activity of a VIP family receptor molecule by measuring receptor
activity comprising:
[0781] a) contacting a human VIP family receptor with a VIP analog,
wherein said analog comprises an .alpha.-amino acid and at least
one .beta.-amino acid;
[0782] b) measuring the association of the VIP analog to the VIP
receptor in the presence and absence of an unknown compound;
and
[0783] c) comparing the rate of association of the VIP analog to
the human VIP receptor in the presence of an unknown compound to
the rate of association of the VIP analog to the human VIP receptor
in the absence of an unknown compound. In some embodiments, the VIP
family receptor is chosen from VIPR1, VIPR2, VPAC1, VPAC.sub.2 or
PAC1.
[0784] The present invention also relates identifying a modulator
of activity of a VIP family receptor molecule by measuring receptor
activity comprising:
[0785] a) contacting a VIP family receptor with a VIP analog in a
known concentration, wherein said analog comprises an .alpha.-amino
acid and at least one .beta.-amino acid;
[0786] b) measuring the binding affinity of the VIP analog to the
VIP family receptor in the presence and absence of a compound that
binds to the VIP family receptor; and
[0787] c) comparing the binding affinity of the VIP analog to the
VIP receptor in the presence of a compound that binds to the VIP
family receptor to the binding affinity of the VIP analog to the
VIP receptor in the absence of a compound that binds to the VIP
family receptor. In some embodiments, the VIP family receptor is
chosen from VIPR1, VIPR2, VPAC1, VPAC2 or PAC1.
[0788] The invention also relates to the use of an analog with
selectivity for VPAC1, PAC1, or VPAC2 in the preparation of a
medicament for treating or preventing chronic obstructive pulmonary
disease, pulmonary hypertension, primary arterial hypertension,
pulmonary hypertension associated to post-ventricular septal
defect, idiopathic pulmonary fibrosis, idiopathic pulmonary
arterial hypertension, CREST syndrome--Calcinosis; Raynaud's
disease; loss of muscle control of the Esophagus; Sclerodactyly;
Telangiectasia, Acute respiratory distress, congestive heart
failure, chronic obstructed pulmonary disorder, asthma, chronic
obstructive pulmonary disease, sarcoidosis, small cell lung
carcinoma, autoimmune disease, inflammatory disease, sepsis,
Hirschsprung's Disease, sexual dysfunction, erectile dysfunction,
Parkinson's disease, Alzheimer's disease, circadian rhythm
dysfunction, pain, colorectal cancer, hepatocellular cancer,
elevated blood glucose levels, elevated blood pressure,
hyperglycemia, diabetes, insulin resistance, metabolic acidosis,
obesity, Type I diabetes, Type II diabetes Multiple Sclerosis,
osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis,
osteoporosis, female sexual dysfunction due to administration of a
medication that causes onset of or exacerbates symptoms of
pulmonary hypertension, primary arterial hypertension, pulmonary
hypertension associated to post-ventricular septal defect,
idiopathic pulmonary fibrosis, idiopathic pulmonary arterial
hypertension, CREST syndrome--Calcinosis; Raynaud's disease; loss
of muscle control of the Esophagus; Sclerodactyly; Telangiectasia,
Acute respiratory distress, congestive heart failure, chronic
obstructed pulmonary disorder, asthma, chronic obstructive
pulmonary disease, sarcoidosis, small cell lung carcinoma,
autoimmune disease, inflammatory disease, sepsis, Hirschsprung's
Disease, sexual dysfunction, erectile dysfunction, Parkinson's
disease, Alzheimer's disease, circadian rhythm dysfunction, pain,
colorectal cancer, hepatocellular cancer, elevated blood pressure
levels, elevated blood glucose levels, hyperglycemia, diabetes,
insulin resistance, metabolic acidosis, obesity, Type I diabetes,
Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's
syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual
dysfunction in a subject in need thereof. In some embodiments, the
invention relates to compositions comprising a secretin family
analog with selectivity for VPAC1, PAC1, or VPAC2 for treatment or
prevention of chronic obstructive pulmonary disease, pulmonary
hypertension, primary arterial hypertension, pulmonary hypertension
associated to post-ventricular septal defect, idiopathic pulmonary
fibrosis, idiopathic pulmonary arterial hypertension, CREST
syndrome--Calcinosis; Raynaud's disease; loss of muscle control of
the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory
distress, congestive heart failure, chronic obstructed pulmonary
disorder, asthma, chronic obstructive pulmonary disease,
sarcoidosis, small cell lung carcinoma, autoimmune disease,
inflammatory disease, sepsis, Hirschsprung's Disease, sexual
dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's
disease, circadian rhythm dysfunction, pain, colorectal cancer,
hepatocellular cancer, elevated blood pressure levels,
hyperglycemia, diabetes, insulin resistance, metabolic acidosis,
obesity, Type I diabetes, Type II diabetes Multiple Sclerosis,
osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis,
osteoporosis, female sexual dysfunction in a subject in need
thereof.
[0789] The present invention also relates to a method of treating
or preventing cancer in a subject in need thereof comprising
administering a VIP analog to the subject, wherein said analog
comprises an .alpha.-amino acid and at least one .beta.-amino acid
and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor
antagonist or agonist with increased selectivity for the VPAC1,
VPAC2, or PAC1 receptor as compared to the other receptors. In some
embodiments, the cancer is chosen from the following: non-small
cell lung carcinoma, small cell lung carcinoma, colorectal
carcinoma, breast carcinoma, gastric carcinoma, prostate carcinoma,
liver carcinoma, ductal pancreatic carcinoma, bladder carcinoma,
Non-Hodgkin's lymphoma, maningioma, leiomyoma, endometrial
carcinoma, pheochromocytoma, paraganglioma. The present invention
also relates to a method of treating or preventing inflammatory
disease comprising administering a VIP analog to a subject in need
thereof, wherein said analog comprises an .alpha.-amino acid and at
least one .beta.-amino acid and wherein said analog is a VPAC1,
VPAC2, or PAC1 receptor antagonist or agonist with increased
selectivity for the VPAC1, VPAC2, or PAC1 receptor as compared to
the other receptors. In some embodiments the inflammatory disease
is rheumatoid arthritis. In some embodiments, the VIP analog is
administered at a therapeutically effective dose.
[0790] The present invention also relates to a method of treating
or preventing cancer in a subject in need thereof comprising
administering a VIP analog to the subject, wherein said analog
comprises an .alpha.-amino acid and at least one .beta.-amino acid
and wherein said analog is a VPAC1 receptor antagonist with
increased selectivity for the VPAC1 receptor. The present invention
also relates to a method of treating or preventing inflammatory
disease comprising administering a VIP analog to a subject in need
thereof, wherein said analog comprises an .alpha.-amino acid and at
least one .beta.-amino acid and wherein said analog is a VPAC1
receptor antagonist with increased selectivity for the VPAC1
receptor. In some embodiments the inflammatory disease is
rheumatoid arthritis. In some embodiments, the VIP analog is
administered at a therapeutically effective dose.
[0791] The present invention also relates to a method of treating
or preventing small cell lung carcinoma comprising administering a
VIP analog to a subject in need thereof, wherein said analog
comprises an .alpha.-amino acid and at least one .beta.-amino acid
and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor
antagonist or agonist with increased selectivity for at least one
VPAC1, VPAC2, or PAC1 receptor. The present invention also relates
to a method of treating or preventing inflammatory disease
comprising administering a VIP analog to a subject in need thereof,
wherein said analog comprises an .alpha.-amino acid and at least
one .beta.-amino acid and wherein said analog is a VPAC1, VPAC2, or
PAC1 receptor antagonist or agonist with increased selectivity for
at least one of the following: VPAC1, VPAC2, or PAC1 receptors. In
some embodiments, the VIP analog is administered at a
therapeutically effective dose.
[0792] The present invention also relates to a method of treating
or preventing primary arterial hypertension (PAH) comprising
administering a VIP analog to a subject in need thereof, wherein
said analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid and wherein said analog is a VPAC1, VPAC2, or
PAC1 receptor antagonist or agonist with increased selectivity for
at least one VPAC1, VPAC2, or PAC1 receptor. The present invention
relates to a method of treating or preventing inflammatory disease
comprising administering a VIP analog to a subject in need thereof,
wherein said analog comprises an .alpha.-amino acid and at least
one .beta.-amino acid and wherein said analog is a VPAC1, VPAC2, or
PAC1 receptor antagonist or agonist with increased selectivity for
at least one of the following: VPAC1, VPAC2, or PAC1 receptors as
compared to its selectivity for the other receptors. In some
embodiments, the VIP analog is administered at a therapeutically
effective dose.
[0793] The present invention also relates to a method of treating
or preventing inflammatory disease comprising administering a VIP
analog to a subject in need thereof, wherein said analog comprises
an .alpha.-amino acid and at least one .beta.-amino acid and
wherein said analog is a VPAC1 receptor agonist with increased
selectivity for the VPAC1 receptor. The present invention relates
to a method of treating or preventing inflammatory disease
comprising administering a VIP analog to a subject in need thereof,
wherein said analog comprises an .alpha.-amino acid and at least
one .beta.-amino acid and wherein said analog is a VPAC1 receptor
agonist with increased selectivity for the VPAC1 receptor. In some
embodiments the inflammatory disease is rheumatoid arthritis. In
some embodiments, the VIP analog is administered at a
therapeutically effective dose.
[0794] The present invention also relates to a method of treating
or preventing inflammatory disease comprising administering a VIP
analog to a subject in need thereof, wherein said analog comprises
an .alpha.-amino acid and at least one .beta.-amino acid and
wherein said analog is a VPAC2 receptor agonist with increased
selectivity for the VPAC2 receptor. The present invention relates
to a method of treating or preventing inflammatory disease
comprising administering a VIP analog to a subject in need thereof,
wherein said analog comprises an .alpha.-amino acid and at least
one .beta.-amino acid and wherein said analog is a VPAC2 receptor
agonist with increased selectivity for the VPAC2 receptor. In some
embodiments the inflammatory disease is rheumatoid arthritis. In
some embodiments, the VIP analog is administered at a
therapeutically effective dose.
[0795] The present invention also relates to a method of treating
or preventing chronic obstructive pulmonary disease, pulmonary
hypertension, primary arterial hypertension, pulmonary hypertension
associated to post-ventricular septal defect, idiopathic pulmonary
fibrosis, idiopathic pulmonary arterial hypertension comprising
administering a VIP analog with selectivity for VPAC2 to a subject
in need thereof, wherein said analog comprises an .alpha.-amino
acid and at least one .beta.-amino acid and wherein said analog is
a VPAC2 receptor agonist with increased selectivity to VPAC2
receptor. In all methods of treatment or prevention, analogs of the
present invention may be administered in therapeutically effective
doses.
[0796] The present invention relates to a method of treating or
preventing chronic obstructive pulmonary disease (COPD) comprising
administering a VIP analog to a subject in need thereof, wherein
said analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid and wherein said analog is a VPAC1 receptor
antagonist or agonist with increased selectivity for the VPAC1
receptor. The present invention relates to a method of treating or
preventing COPD comprising administering a VIP analog to a subject
in need thereof, wherein said analog comprises an .alpha.-amino
acid and at least one .beta.-amino acid and wherein said analog is
a VPAC1 receptor antagonist or agonist with increased selectivity
for the VPAC1 receptor. In some embodiments, the VIP analog is
administered at a therapeutically effective dose via nebulizer or
inhaler.
[0797] The invention also relates to a method of preventing or
inhibiting activation of alveolar macrophages comprising
administering a VIP analog to a subject, wherein said analog
comprises an .alpha.-amino acid and at least one .beta.-amino acid
and wherein said analog is a VPAC1 receptor antagonist or agonist
with increased selectivity for the VPAC1 receptor. In some
embodiments, the VIP analog is administered at a therapeutically
effective dose via nebulizer or inhaler.
[0798] The present invention relates to a method of treating or
preventing chronic obstructive pulmonary disease (COPD) comprising
administering a VIP analog to a subject in need thereof, wherein
said analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid and wherein said analog is a VPAC2 receptor
agonist with increased selectivity for the VPAC2 receptor. The
present invention relates to a method of treating or preventing
COPD comprising administering a VIP analog to a subject in need
thereof, wherein said analog comprises an .alpha.-amino acid and at
least one .beta.-amino acid and wherein said analog is a VPAC2
receptor agonist with increased selectivity for the VPAC2 receptor.
In some embodiments, the VIP analog is administered at a
therapeutically effective dose via nebulizer or inhaler. The
invention relates to a method of preventing or inhibiting
activation of alveolar macrophages comprising administering a VIP
analog to a subject, wherein said analog comprises an .alpha.-amino
acid and at least one .beta.-amino acid and wherein said analog is
a VPAC2 receptor agonist with increased selectivity for the VPAC2
receptor. In some embodiments, the VIP analog is administered at a
therapeutically effective dose via nebulizer or inhaler.
[0799] The present invention also relates to methods of identifying
a selective modulator of activity of a VIP family receptor molecule
by measuring receptor activity comprising:
[0800] a) contacting a human VIP family receptor with a VIP analog,
wherein said analog comprises an .alpha.-amino acid and at least
one .beta.-amino acid;
[0801] b) measuring the association of the VIP analog to the VIP
receptor in the presence and absence of an unknown compound;
and
[0802] c) comparing the rate of association of the VIP analog to
the human VIP receptor in the presence of an unknown compound to
the rate of association of the VIP analog to the human VIP receptor
in the absence of an unknown compound.
[0803] The present invention also relates to methods of identifying
a selective modulator of activity of a VIP family receptor molecule
by measuring receptor activity comprising:
[0804] a) contacting a first and a second VIP family receptor with
a VIP analog in a known concentration, wherein said analog
comprises an .alpha.-amino acid and at least one .beta.-amino
acid;
[0805] b) measuring the rate association of the VIP analog to the
first and second VIP receptors in the presence and absence of an
unknown compound; and
[0806] c) comparing the rate of association of the VIP analog to
the first VIP receptor in the presence of an unknown compound to
the rate of association of the VIP analog to the the second VIP
receptor in the absence of an unknown compound.
[0807] The present invention also relates to methods of identifying
a selective modulator of activity of a VIP family receptor molecule
by measuring receptor activity comprising:
[0808] a) contacting a first and a second VIP family receptor with
a VIP analog in a known concentration, wherein said analog
comprises an .alpha.-amino acid and at least one .beta.-amino
acid;
[0809] b) measuring the binding affinity of the VIP analog to the
first and second VIP receptors in the presence and absence of an
unknown compound; and
[0810] c) comparing the binding affinity of the VIP analog to the
first VIP receptor in the presence of an unknown compound to the
binding affinity of the VIP analog to the the second VIP receptor
in the absence of an unknown compound. In some embodiments, the VIP
family receptor is chosen from VIPR1, VIPR2, VPAC.sub.1, VPAC.sub.2
or PAC.sub.1.
[0811] The present invention also relates to methods of inhibiting
the immune response against a transplanted organ in a subject,
wherein the subject is an organ donor recipient. in some
embodiments, the subject is a mammal. In some embodiments, the
subject is a human. In some embodiments, the subject is a human
experiencing organ rejection after transplantation.
[0812] In another embodiment, the present invention also relates to
a method for inhibiting the growth of a tumor cell, the method
comprising: contacting the tumor cell with an effective amount of a
secretin family analog, wherein the secretin family analog or
functional fragment thereof comprises at least one .beta.-amino
acid. In some embodiments, the method comprises contacting the
tumor cell with an effective amount of a combination of a
chemotherapeutic agent and a secretin family analog. In some
embodiments, the secretin analog is a VIP analog. Suitable
chemotherapeutic agents include, but are not limited to, platinum
coordination compounds, topoisomerase inhibitors, antibiotics,
antimitotic alkaloids and difluoronucleosides. In some embodiments,
the secretin analog is a VPAC1 antagonist with selectivity for
VPAC1. In some embodiments, the tumor cell is a tumor cell derived
from a breast cancer, a lung cancer, a colon cancer, a prostate
cancer, or a pancreatic cancer.
[0813] In another embodiment, the present invention also relates to
a method of inhibiting the growth of a tumor cell in a mammalian
subject in need thereof, the method comprising: administering to
the subject an effective amount of a secretin family analog or
functional fragment thereof, wherein the secretin family analog or
functional fragment thereof comprises at least one .beta.-amino
acid. In some embodiments, the method comprises administering to
the subject an effective amount of a combination of a
chemotherapeutic agent and a secretin family analog. In some
embodiments, the secretin analog is a VIP analog. In some
embodiments, the tumor cell is a tumor cell derived from a breast
cancer, a lung cancer, a colon cancer, a prostate cancer, hepatic
cancer (HCC) or a pancreatic cancer. Suitable chemotherapeutic
agents include, but are not limited to, platinum coordination
compounds, topoisomerase inhibitors, antibiotics, antimitotic
alkaloids and difluoronucleosides.
[0814] The present invention also relates to a method of treating
or preventing cancer cell growth in a subject in need thereof
comprising the steps of: administering a VIP analog or functional
fragment thereof the subject, wherein the VIP analog or functional
fragment comprises at least one .beta.-amino acid, wherein the VIP
analog or functional fragment thereof is selective or has increased
selectivity to VPAC.sub.1; wherein the VIP analog is a VPAC.sub.1
antagonist; and wherein the cancer cell is a bladder, breast,
colon, liver, lung, prostate, stomach, thyroid or uterine cancer
cell. The present invention relates to a method of treating or
preventing cancer in a subject in need thereof comprising the steps
of: administering a VIP analog or functional fragment thereof the
subject, wherein the VIP analog or functional fragment comprises at
least one .beta.-amino acid, wherein the VIP analog or functional
fragment thereof is selective or has increased selectivity to
VPAC.sub.1; wherein the VIP analog is a VPAC.sub.1 antagonist; and
wherein the cancer is a bladder, breast, colon, liver, lung,
prostate, stomach, thyroid, hepatocellular, or uterine cancer. In
some embodiments, the cancer has been diagnosed as being malignant.
In some embodiments, the subject may have an increased risk or
increased susceptibility to contracting a malignant cancer.
[0815] The present invention also relates to a method of treating
or preventing cancer cell growth in a subject in need thereof
comprising the steps of: administering a VIP analog or functional
fragment thereof the subject, wherein the VIP analog or functional
fragment comprises at least one .beta.-amino acid, wherein the VIP
analog or functional fragment thereof is selective or has increased
selectivity to VPAC.sub.2; wherein the VIP analog is a VPAC.sub.2
antagonist; and wherein the cancer cell is a lung, breast, stomach
cancer cell. In some embodiments the cancer cell is derived from a
stomach leiomyoma.
[0816] The present invention also relates to a method of treating
or preventing cancer in a subject in need thereof comprising the
steps of: administering a VIP analog or functional fragment thereof
the subject, wherein the VIP analog or functional fragment
comprises at least one .beta.-amino acid, wherein the VIP analog or
functional fragment thereof is selective or has increased
selectivity to VPAC.sub.2; wherein the VIP analog is a VPAC.sub.2
antagonist; and wherein the cancer a lung, breast, stomach, or
heptocellular cancer. In some embodiments, the cancer has been
diagnosed as being malignant. In some embodiments, the subject may
have an increased risk or increased susceptibility to contracting a
malignant cancer.
[0817] The present invention also relates to a method of treating
or preventing airway constriction comprising administering a VIP
analog or functional fragment thereof to a subject in need thereof,
wherein said analog comprises an .alpha.-amino acid and at least
one .beta.-amino acid and wherein said analog is a VPAC2 receptor
agonist. In some embodiments, the VIP analog or functional fragment
thereof has increased selectivity to VPAC2 receptor. In all methods
of treatment or prevention, analogs of the present invention may be
administered in therapeutically effective doses.
[0818] The present invention also relates to a method of treating
or preventing asthma, comprising administering a VIP analog or
functional fragment thereof to a subject in need thereof, wherein
said analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid and wherein said analog is a VPAC2 receptor
agonist. In some embodiments, the VIP analog or functional fragment
thereof has increased selectivity to VPAC2 receptor. In all methods
of treatment or prevention, analogs of the present invention may be
administered in therapeutically effective doses. In some
embodiments, the VIP analog or functional fragment thereof may be
administered via an inhaler or nebulizer.
[0819] The present invention also relates to a method of treating
or preventing cancer cell growth in a subject in need thereof
comprising the steps of: administering a VIP analog or functional
fragment thereof the subject, wherein the VIP analog or functional
fragment comprises at least one .beta.-amino acid, wherein the VIP
analog or functional fragment thereof is selective or has increased
selectivity to PAC.sub.1; wherein the VIP analog is a PAC.sub.1
antagonist; and wherein the cancer cell is a nerve cell, adrenal
cell, pituitary cell, or breast cell. The present invention also
relates to a method of treating or preventing cancer in a subject
in need thereof comprising the steps of: administering a VIP analog
or functional fragment thereof the subject, wherein the VIP analog
or functional fragment comprises at least one .beta.-amino acid,
wherein the VIP analog or functional fragment thereof is selective
or has increased selectivity to PAC.sub.1; wherein the VIP analog
is a PAC.sub.1 antagonist; and wherein the cancer is a
glioblastoma, neuroblastoma, adrenal, pituitary,
catecholamine-secreting tumors, pheochromocytomas, paragangliomas,
endometrial cancers, or breast cancer. In some embodiments, the
cancer has been diagnosed as being malignant. In some embodiments,
the subject may have an increased risk or increased susceptibility
to contracting a malignant cancer.
[0820] The invention also relates to methods of treating or
preventing the aforementioned diseases using the analogs of the
present invention. Any analog described in the present invention
may or may not have preferred selectivity of one of its receptors
versus another. The invention relates to analogs based upon the
polypeptide sequences identified in Tables 1, 2, 3, and 4. All
modified and unmodified variants of the sequences listed in Table 4
are contemplated as being part of the invention. For instance, the
sequence of Biotin-Bombesin is listed in Table 4 as
Biotin--EQRLGNQWAVGHLM--NH2 (SEQ ID NO:67). Not only do analogs of
the claimed invention include biotinylated sequence above with an
amidated methionine, but the analogs of the present invention also
relate to the unmodified or modified polypeptide backbone
EQRLGNQWAVGHLM as well as functional fragments thereof. In some
embodiments the polypeptide analog is derived from one of the
following amino acid sequences of Table 4:
TABLE-US-00032 TABLE 4 Targets from which the Analogs are derived
1. Galanin 2. neurokinin A 3. neurokinin B 4. RGD 5. Osteogenic
growth peptide 6. Parathyroid hormone 7. Kallidin 8. T cell
receptor peptide 9. PDGF 10. Amylin 11. Calcitonin 12. GHRH 13.
Thymopoietin 14. cecropin 15. TRH 16. EPO 17. FGF 18. Stem Cell
Factor 19. Gp120 20. Gp160 21. CD4 22. IGF 23. IGF receptor 24.
Insulin 25. GMCSF 26. GCSF 27. MCSF 28. Kentsin 29. LAP 30. Tuftsin
31. Prolactin 32. Angiotensin II 33. Angiotensin II receptor 34.
Dynorphin 35. Calcitonin 36. Cholecystokinin 37. Pepstatin 38.
Bestatin 39. Leupeptin 40. Luteinizing hormone 41. Neurotensin 42.
Motilin 43. TGF-alpha 44. TGF-beta 45. BMP-1 46. BMP-2 47. BMP-3
48. BMP-4 49. BMP-5 50. BMP-7 51. BMP-8 52. BMP-9 53. Bombesin 54.
Enterostatin 55. Glucagon 56. GLP-1 57. Beta-Endorphin 58. ACTH 59.
Alpha-MSH 60. .gamma.-MSH 61. adrenal peptide E 62. alpha casein
fragment 63. beta casomorphin 64. dermorphin 65. kyotorphin 66.
metophamide 67. neuropeptide FF (NPFF) 68. melanocyte inhibiting
factor 69. vasotocin 70. Protein kinase C 71. Amyloid 72. Amyloid
fibrin 73. Calpain 74. Charybdotoxin 75. Apamin 76. Phospholipase
A2 77. Phospholipase A2 receptor 78. ENaC-alpha 79. ENaC-beta 80.
ENaC-gamma 81. IgG subunit 82. Endotoxin 83. ADNF 84.
Adrenomedullin 85. Apelin 86. Ghrelin 87. Mastoparan (MCD peptides)
88. Melanin concentrating hormone 89. Nociceptin 90. Nocistatin 91.
Orexin 92. Receptor activity modulating protein, 93. Urotensin 94.
Glycoprotein IIb/IIIa inhibitors 95. c7E3 Fab 96. Apo-lipoprotein
A-I 97. IL-1 98. IL-2 99. IL-3 100. IL-4 101. IL-5 102. IL-6 103.
IL-7 104. IL-8 105. IL-9 106. IL-10 107. IL-12 108. IL-15 109.
IL-18 110. IL-22 111. IL-23 112. IL-24 113. IL-26 114. IL-27 115.
IL-28 116. brain-derived neurotrophic factor 117. nerve growth
factor (BDNF) 118. neurotrophin 3 119. Corticotropin releasing
factor 120. MHC I bind protei 121. P-selectin 122. LFA-1 123. LFA-3
124. EPGF 125. EPGF receptor 126. Oxytocin 127. Vasopressin 128.
Defensin, alpha 1 129. Neutrophil defensin 3 130. Neutrophil
defensin 4 131. Defensin-5 132. Defesin-6 133. Beta-defensin 1 134.
Beta-defensin-3 135. Beta defensin 103 136. Beta-defensin 107 137.
Beta-defensin 110 138. Beta-defensin 136 139. RK-1
(MPCSCKKYCDPWEVIDGSCGLFNSKYICCREK) 140. dermaseptin S4 141.
magainin 1 142. magainin 2 143. magainin A 144. magainin B 145.
magainin G 146. MSI-78 147. MSI-99 148. MSI-130 149. MSI-511 150.
Myp30 151. Pexiganan 152. Laminin 153. YIGSR 154. Gastrin 155.
Gastrin releasing peptide 156. GnRH 157. Secretin 158. Bradykinin
159. Substance P 160. RANTES 161. MCP-1 162. MIP-1 alpha 163.
MIP-1beta 164. PDWHF 165. CRF 166. Endothelin 167. Integrin 168.
Neuropeptide Y 169. LHRH 170. Enkephilin 171. alpha-neo-endorphin,
porcine 172. beta-neoendorphin 173. Ac-beta-endorphin, camel,
bovine, ovine 174. Ac-beta-endorphin 1-27, camel, 175.
Ac-beta-endorphin, human bovine, ovine 176. Ac-beta-endorphin 1-26,
human 177. Ac-beta-endorphin 1-27, human 178. Ac-gamma-endorphin
(Ac-beta- 179. acetyl-alpha-endorphin lipotropin 61-77) 180.
alpha-endorphin (beta-lipotropin 61- 181. alpha-neo-endorphin
analog 76) 182. alpha-neo-endorphin 1-7 183.
{Arg.sup.8}-alpha-neoendorphin 1-8 184. beta-endorphin
(beta-lipotropin 61- 185. beta-endorphin 1-27, camel, bovine, 91),
camel, bovine, ovine ovine 186. beta-endorphin, equine 187.
beta-endorphin (beta-lipotropin 61-91), human 188. beta-endorphin
(1-5) + (16-31), human 189. beta-endorphin 1-26, human 190.
beta-endorphin 1-27, human 191. beta-endorphin 6-31, human 192.
beta-endorphin 18-31, human 193. beta-endorphin, porcine 194.
beta-endorphin, rat 195. beta-lipotropin 1-10, porcine 196.
beta-lipotropin 60-65 197. beta-lipotropin 61-64 198.
beta-lipotropin 61-69 199. beta-lipotropin 88-91 200.
biotinyl-beta-endorphin (biotinyl- 201. biocytin-beta-endorphin,
human bets-lipotropin 61-91) 202. gamma-endorphin (beta-lipotropin
203. {DAla.sup.2}-alpha-neo-endorphin 1-2, amide 61-77) 204.
{DAla.sup.2}-beta-lipotropin 61-69 205.
{DAla.sup.2}-gamma-endorphin 206. {Des-Tyr.sup.1}-beta-endorphin,
human 207. {Des-Tyr.sup.1}-gamma-endorphin (beta- lipotropin 62-77)
208. {Leu.sup.5}-beta-endorphin, camel, 209.
{Met.sup.5,Lys.sup.6}-alpha-neo-endorphin 1-6 bovine, ovine 210.
{Met.sup.5,Lys.sup.6,7}-alpha-neo-endorphin 211.
{Met.sup.5,Lys.sup.6,Arg.sup.7}-alpha-neo-endorphin 1-7 1-7 212.
endothelin-1 (ET-1) 213. endothelin-1 {Biotin-Lys.sup.9} 214.
endothelin-1 (1-15), human 215. endothelin-1 (1-15), amide, human
216. Ac-endothelin-1 (16-21), human 217.
Ac-{DTrp.sup.16}-endothelin-1 (16-21), human 218.
{Ala.sup.3,11}-endothelin-1 219. {Dpr1,Asp.sup.15}-endothelin-1
220. {Ala.sup.2}-endothelin-3, human 221.
{Ala.sup.18}-endothelin-1, human 222. {Asn.sup.18}-endothelin-1,
human 223 224. {Res-701-1}-endothelin B receptor 225.
Suc-{Glu.sup.9,Ala.sup.11,15}-endothelin-1 (8-21), antagonist
IRL-1620 226. endothelin-C-terminal hexapeptide 227.
{D-Val.sup.22}-big endothelin-1 (16-38), human 228. endothelin-2
(ET-2), human, canine 229. endothelin-3 (ET-3), human, rat,
porcine, rabbit 230. biotinyl-endothelin-3 (biotinyl-ET-3) 231.
prepro-endothelin-1 (94-109), porcine 232. BQ-518 233. BQ-610 234.
BQ-788 235. endothelium-dependent relaxation antagonist 236.
FR139317 237. IRL-1038 238. JKC-30 1 239. JKC-302 240. PD-145065
241. PD-142893 242. sarafotoxin S6a (atractaspis 243. sarafotoxin
S6b (atractaspis engaddensis) engaddensis) 244. sarafotoxin S6c
(atractaspis 245. {Lys.sup.4}-sarafotoxin S6c engaddensis) 246.
sarafotoxin S6d 247. big endothelin-1, human 248. biotinyl-big
endothelin-1, human 249. big endothelin-1 (1-39), porcine 250. big
endothelin-3 (22-41), amide, 251. big endothelin-1 (22-39), rat
human 252. big endothelin-1 (1-39), bovine 253. big endothelin-1
(22-39), bovine 254. big endothelin-1 (19-38), human 255. big
endothelin-1 (22-38), human 256. big endothelin-2, human 257. big
endothelin-2 (22-37), human 258. big endothelin-3, human 259. big
endothelin-1, porcine 260. big endothelin-1 (22-39) (prepro- 261.
big endothelin-1, rat endothelin-1 (74-91)) 262. big endothelin-2
(1-38), human 263. big endothelin-2 (22-38), human 264. big
endothelin-3, rat 265. biotinyl-big endothelin-1, human 266.
{Tyr.sup.123}-prepro-endothelin (110- 267. {BQ-123} 130), amide,
human 268. {BE18257B} 269. {BE-18257A}/{W-7338A} 270. {BQ-485} 271.
FR139317 272. PD-151242 and TTA-386 273. {BQ-3020} {RES-701-3} and
{IRL- 1720} 274. adrenorphin 275. free acid amidorphin
(proenkephalin A (104-129)-NII2) 276. bovine BAM-12P 277. bovine
adrenal medulla enkephalin 278.
{D-Ala.sup.2,D-Leu.sup.5}-enkephalin 279.
{D-Ala.sup.2,D-Met.sup.5}-enkephalin 280.
{DAla.sup.2}-Leu-enkephalin 281. amide
{DAla.sup.2,Leu.sup.5,Arg.sup.6}-enkephalin 282.
{Des-Tyr.sup.1,DPen.sup.2,5}-enkephalin 283.
{Des-Tyr.sup.1,DPen.sup.2,Pen.sup.5}-enkephalin 284.
{Des-Tyr.sup.1}-Leu-enkephalin 285. {D-Pen.sup.2,5}-enkephalin 286.
{DPen.sup.2,Pen.sup.5}-enkephalin 287. enkephalinase substrate 288.
{D-Pen.sup.2,pCI-Phe.sup.4,D-Pen.sup.5}- 289. Leu-enkephalin
enkephalin 290. amide biotinyl-Leu-enkephalin 291.
{D-Ser.sup.2}-Leu-enkephalin-Thr (delta- receptor peptide) (DSLET)
292. {D-Thr.sup.2}-Leu-enkephalin-Thr 293.
{Lys.sup.6}-Leu-enkephalin (DTLET) 294.
{Met.sup.5,Arg.sup.6}-enkephalin 295.
{Met.sup.5,Arg.sup.6-enkephalin-Arg
{Met.sup.5,Arg.sup.6,Phe.sup.7}-enkephalin 296. amide
Met-enkephalin biotinyl-Met- 297. {D-Ala.sup.2}-Met-enkephalin
enkephalin 298. amide Met-enkephalin-Arg-Phe Met- 299. amide
{Ala.sup.2}-Met-enkephalin enkephalin 300. amide
{DMet.sup.2,Pro.sup.5}-enkephalin 301. amide
{DTrp.sup.2}-Met-enkephalin, amide, metorphinamide (adrenorphin)
peptide B 302. bovine 3200-Dalton adrenal peptide E 303. bovine
peptide F 304. bovine preproenkephalin B 186-204 305. human
spinorphin 306. bovine and thiorphan (D,L,3- 307. platelet factor-4
(58-70) mercapto-2-benzylpropanoyl-glycine) 308. human echistatin
(Echis carinatus) E 309. human echistatin (Echis carinatus) P 310.
L selectin conserved region 311. fibrinopeptide A fibronectin 312.
human {Tyr.sup.0}-fibrinopeptide A 313. human fibrinopeptide B 314.
human {Glu.sup.1}-fibrinopeptide B 315. human
{Tyr.sup.15}-fibrinopeptide B 316. human fibrinogen beta-chain 317.
fibrinolysis inhibiting factor FN-C/H-1 fragment of 24-42
fibrinogen binding (fibronectin heparin-binding fragment) inhibitor
peptide 318. FN-C/H-V (fibronectin heparin- 319. heparin-binding
peptide laminin penta binding fragment) peptide, amide
Leu-Asp-Val-NH.sub.2 (LDV--NH.sub.2), 320. human, bovine, rat, 321.
chicken necrofibrin 322. human necrofibrin, rat 323. platelet
membrane glycoprotein IIB peptide 296-306 324. human galanin 1-19
325. human preprogalanin 1-30 326. human preprogalanin 65-88 327.
human preprogalanin 89-123 328. human galanin 329. porcine galanin
1-16 330. porcine, rat galanin 331. rat biotinyl-galanin 332. rat
preprogalanin 28-67 333. rat galanin 1-13-bradykinin 2-9 334. amide
M40 335. galanin 1-13-Pro-Pro-(Ala-Leu) 2-Ala- amide C7 336.
galanin 1-13-spantide-amide GMAP 337. amide GMAP 16-41 1-41 338.
amide GMAP 25-41 339. amide galantide and entero-kassinin
340. gastrin 341. chicken gastric inhibitory peptide (GIP) 342.
human gastrin I 343. human biotinyl-gastrin I 344. human big
gastrin-1 345. human gastrin releasing peptide 346. human gastrin
releasing peptide 1-16 347. human gastric inhibitory polypeptide
(GIP) 348. porcine gastrin releasing peptide 349. porcine
biotinyl-gastrin releasing peptide 350. porcine gastrin releasing
peptide 14- 351. porcine, human little gastrin 27 352. rat
pentagastrin gastric inhibitory 353. porcine gastric inhibitory
peptide 1-30, peptide 1-30 amide 354. porcine {Tyr.sup.0-gastric
inhibitory 355. human and gastric inhibitory peptide, rat peptide
23-42 356. {Des-His'-Glu.sup.9}-glucagon 357. exendin-4 358.
glucagon 359. human biotinyl-glucagon 360. human glucagon 19-29
361. human glucagon 22-29 362. human
{Des-His.sup.1-Glu.sup.9}-glucagon 363. amide glucagon-like peptide
1 364. amide glucagon-like peptide 1 365. human glucagon-like
peptide 1 (7-36) glucagon-like peptide 2 366. rat
biotinyl-glucagon-like peptide-1 367. (biofinyl-preproglucagon
78-107, amide) (7-36) 368. glucagon-like peptide 2 369. human
intervening peptide-2 oxyntomodulin/glucagon 37 370. valosin
(peptide VQY), porcine 371. Gn-RH associated peptide 25-53 372.
human Gn-RH associated peptide 1- 373. human Gn-RH associated
peptide 1-13 24 374. human Gn-RH associated peptide 1- 375. rat
gonadotropin releasing peptide 13 376. human
{Tyr.sup.0}-GAP({Tyr.sup.0}-Gn-RH 377. proopiomelanocortin (POMC)
precursor Precursor Peptide 14-69) 27-52, porcine 378. TGF-d 379.
TGF beta 380. TF alpha 381. TGF 34-43 382. EGF, any mammalian
version 383. human acidic fibroblast growth factor basic 384.
fibroblast growth factor 385. basic fibroblast growth factor 13-18
386. basic fibroblast growth factor 120- 387. brain derived acidic
fibroblast growth 125 factor 1-11 388. brain derived basic
fibroblast growth 389. brain derived acidic fibroblast growth
factor 1-24 factor 102-111 390. {Cys(Acm.sup.20,31)}-epidermal
growth 391. epidermal growth factor receptor peptide factor 20-31
985-996 392. insulin-like growth factor (IGF)-I 393. chicken IGF-I
394. rat IGF-I 395. human Des (1-3) IGF-I 396. human R3 IGF-I 397.
human R3 IGF-I 398. human long R3 IGF-I 399. human adjuvant peptide
analog 400. anorexigenic peptide Des (1-6) 401. IGF-II 402. human
R6 IGF-II 403. human IGF-I analogue IGF 1 (24-41) 404. IGF 1
(57-70) 405. IGF I (30-41) 406. IGF II IGF II (33-40) 407.
{Tyr.sup.0}-IGF II (33-40) 408. liver cell growth factor midkine
409. midkine 60-121 410. alpha-TGF 34-43 411. human alpha-TGF 34-43
412. human alpha-TGF 34-43 413. rat nerve growth factor (NGF) 414.
mouse platelet-derived growth factor 415. platelet-derived growth
factor 416. transforming growth factor-.alpha. 417. human and rat
transforming growth factor-I 418. growth hormone (hGH) 419. human
growth hormone 1-43 420. human growth hormone 6-13 421. human
growth hormone releasing factor 422. murine growth hormone
releasing 423. bovine growth hormone releasing factor factor 424.
porcine growth hormone releasing 425. rat growth hormone
pro-releasing factor factor 1-29, amide 426. human biotinyl-growth
hormone 427. human growth hormone releasing factor releasing factor
1-29, amide 428. human {D-Ala.sup.2}-growth hormone 429. human
{N-Ac-Tyr.sup.1,D-Arg.sup.2}-GRF 1-29, releasing factor 1-29, amide
amide 430. {His.sup.1,Nle.sup.27}-growth hormone 431. growth
hormone releasing factor 1-37 releasing factor 1-32, amide 432.
human growth hormone releasing 433. human growth hormone releasing
factor factor 140 1-40, amide 434. human growth hormone releasing
435. human growth hormone releasing factor factor 30-44, amide 436.
mouse growth hormone releasing 437. ovine growth hormone releasing
factor factor 438. rat biotinyl-growth hormone releasing 439. rat
GHRP-6({His.sup.1,Lys.sup.6}-GHRP) factor 440. hexarelin (growth
hormone releasing 441. {D-Lys3}-GHRP-6 hexapeptide) 442.
{Arg.sup.8}-GTP-binding protein 443. Gs alpha GTP-binding protein
fragment fragment 445. G beta GTP-binding protein fragment 446.
GAlpha GTP-binding protein fragment 447. Go Alpha GTP-binding
protein 448. Gs Alpha and GTP-binding protein fragment fragment
449. G Alpha i2 450. guanylin 451. human guanylin 452. rat
uroguanylin 453. human uroguanylin 454. inhibin 455. bovine inhibin
456. alpha-subunit 1-32 457. human {Tyr.sup.0}-inhibin,
alpha-subunit 458. human seminal plasma inhibin-like 1-32 peptide
459. human {Tyr.sup.0}- seminal plasma 460. human inhibin
inhibin-like peptide 461. alpha-subunit 1-32 462. porcine and
{Tyr.sup.0}-inhibin, alpha-subunit 1-32, porcine 463. human insulin
464. porcine IGF-I 465. human insulin-like growth factor II 466.
pro-insulin-like growth factor 11 (68- (69-84) 102) 467. human
pro-insulin-like growth factor 468. human {Asp.sup.B28}-insulin II
(105-128) 469. human {Lys.sup.B28}-insulin 470. human
{Leu.sup.B28}-insulin 471. human {Val.sup.B28}-insulin 472. human
{Ala.sup.B28}-insulin 473. human {Asp.sup.B28,Pro.sup.B29}-insulin
474. human {Lys.sup.B28,Pro.sup.B29}-insulin 475. human
{Leu.sup.B28 Pro.sup.B29}-insulin 476. human
{Val.sup.B28,Pro.sup.B29}-insulin 477. human
{Ala.sup.B28,Pro.sup.B29}-insulin 478. human {Gly.sup.A21}-insulin
479. human {Gly.sup.A21 Gln.sup.B30}-insulin 480. human
{Ala.sup.A21}-insulin 481. human {Ala.sup.A21 Gln.sup.B30}insulin
482. human {Gln.sup.B30}-insulin 483. human {Gln.sup.B30}-insulin
484. human {Gly.sup.A21 Glu.sup.B30}-insulin 485. human
{Gly.sup.A21 Gln.sup.B3 Glu.sup.B30}-insulin 486. human {Gln.sup.B3
Glu.sup.B30}-insulin 487. human B22-B30 insulin 488. human B23-B30
insulin 489. human B25-B30 insulin 490. human B26-B30 insulin 491.
human B27-B30 insulin 492. human B29-B30 insulin 493. A chain of
human insulin 494. B chain of human insulin 495. interleukin-1 beta
165-181, rat 496. rat IL-8 497. laminin alpha1 (I)-CB3 435-438, rat
498. laminin binding inhibitor 499. leptin 93-105 500. human leptin
22-56, rat 501. Tyr-leptin 26-39, human 502. leptin 116-130, amide,
mouse 503. leucomyosuppressin (LMS) 504. leucopyrokinin (LPK) 505.
leucokinin I 506. leucokinin II 507. leucokinin III 508. leucokinin
IV 509. leucokinin VI 510. leucokinin VII 511. leucokinin VIII 512.
antide Gn-RH II 513. chicken luteinizing hormone- 514. (GnRH)
biotinyl-LH-RH releasing hormone (LH-RH) 515. cetrorelix (D-20761)
516. {D-Ala.sup.6}-LH-RH 517. {Gln.sup.8}-LH-RH (Chicken LH-RH)
518. {DLeu.sup.6,Val.sup.7}LH-RH 1-9 519. ethyl amide
{D-Lys.sup.6}-LH-RH 520. {D-Phe.sup.2,Pro.sup.3,D-Phe.sup.6}-LH-RH
521. {DPhe.sup.2,DAla.sup.6} LH-RH 522. {Des-Gly.sup.10}-LH-RH,
ethyl amide 523. {D-Ala.sup.6,Des-Gly.sup.10}-LH-RH, ethyl 524.
{DTrp.sup.6}-LH-RH, ethyl amide amide 525.
{D-Trp.sup.6,Des-Gly.sup.10}-LH-RH, ethyl 526.
{DSer(But).sub.6,Des-Gly.sup.10}-LH-RH, ethyl amide (Deslorelin)
amide ethyl amide leuprolide 527. LH-RH 4-10 528. LH-RH 7-10 LH-RH
529. free acid LH-RH 530. lanprey LH-RH 531. salmon
{Lys.sup.8}-LH-RH 532. {Trp.sup.7,Leu.sup.8} LH-RH, free acid 533.
{(t-Bu)DSer.sup.6,(Aza)Gly.sup.10}-LH-RH 534.
{(t-Bu)DSer.sup.6,(Aza)Gly.sup.10}-LH-RH free acid 535. mastoparan
536. mas7 537. mas8 538. mas17 539. mastoparan X 540. mast cell
degranulating peptide HR-1 541. mast cell degranulating peptide
HR-2 542. {Ac-Cys.sup.4,DPhe.sup.7,Cys.sup.100} alpha-MSH 4- 13
543. amide alpha-melanocyte stimulating 544. free acid beta-MSH,
porcine hormone alpha-MSH 545. biotinyl-alpha-melanocyte 546.
biotinyl-{Nle.sup.4,D-Phe.sup.7} stimulating hormone 547.
alpha-melanocyte stimulating 548. {Des-Acetyl}-alpha-MSH
{DPhe.sup.7}- hormone alpha-MSH, amide 549. gamma-1-MSH, amide 550.
{Lys.sup.0}-gamma-1-MSH, amide 551. MSH release inhibiting factor,
amide 552. {Nle.sup.4}-alpha-MSH, amide 553.
{Nle.sup.4,D-Phe.sup.7}-alpha-MSH N-Acetyl 554.
{Nle.sup.4,DPhe.sup.7} alpha-MSH 4-10, amide 555. beta-MSH, human
556. gamma-MSH 557. morphiceptin (beta-casomorphin 14 558.
{D-Pro.sup.4}-morphiceptin amide) 559.
{N-MePhe.sup.3,D-Pro.sup.4}-morphiceptin 560. motilin 561. canine
motilin 562. porcine biotinyl-motilin 563. porcine
{Leu.sup.13}-motilin 564. Ac-Asp-Glu achatina cardio-excitatory
peptide-1 (ACEP-1) (Achatina fulica) 565. adipokinetic hormone
(AKH) 566. adipokinetic hormone (Heliothis zea and (Locust) Manduca
sexta) 567. alytesin Tabanus atratus 568. adipokinetic hormone
(Taa-AKH) 569. adipokinetic hormone II (Locusta 570. adipokinetic
hormone II (Schistocera migratoria) gregaria) 571. adipokinetic
hormone III (AKH-3) 572. adipokinetic hormone G (AKH-G) (Gryllus
bimaculatus) 573. allatotropin (AT) (Manduca sexta) 574.
allatotropin 6-13 (Manduca sexta) 575. APGW amide (Lymnaea
stagnalis) 576. buccalin 577. {Des-Ser.sup.1}-cerebellin corazonin
578. crustacean cardioactive peptide (CCAP) (American Cockroach
Periplaneta americana) 579. crustacean erythrophore DF2 580.
diazepam-binding inhibitor fragment (Procambarus clarkii) 581.
human diazepam binding inhibitor 582. eledoisin related peptide
FMRF amide fragment (ODN) (molluscan cardioexcitatory neuropeptide)
583. cerebellin 584. human granuliberin R head activator
neuropeptide {His.sup.7}-corazonin 585. stick insect
hypertrehalosaemic factor 586. Tabanus atratus hypotrehalosemic II
hormone (Taa-HoTH) 587. rat NGE (prepro-MCH 110-128) 588.
methiodide piperidine-4-sulphonic acid neuropeptide joining peptide
of proopiomelanocortin 589. (POMC) 590. bovine joining peptide 591.
rat KSAYMRF amide (P. reclivivus) 592. kassinin kinetensin levitide
593. litorin LUQ 81-91 (Aplysia 594. LUQ 83-91 (Aplysia
californica) californica) 595. myoactive peptide I (Periplanetin
CC- 596. myoactive peptide II (Periplanetin CC-2) 1) 597.
myomodulin neuron specific peptide 598. neuron specific enolase
404-443 599. rat neuropeptide FF neuropeptide K 600. porcine NEI
(prepro-MCH 131-143) neuropeptide 601. rat NGE (prepro-MCH 110-128)
602. rat NFI (Procambarus clarkii)
neuropeptide 603. PBAN-1 (Bombyx mori) 604. Hez-PBAN (Heliothis
zea) 605. SCPB (cardioactive peptide from 606. secretoneurin, rat
uperolein aplysia) 607. urechistachykinin I 608. urechistachykinin
II 609. xenopsin-related peptide I 610. xenopsin-related peptide II
611. pedal peptide (Pep) 612. aplysia peptide F1 613. lobster,
phyllomedusin 614. polistes mastoparan 615. proctolin 616.
ranatensin Ro I (Lubber Grasshopper, Romalea microptera) 617. Ro II
(Lubber Grasshopper, Romalea 618. SALMF amide 1 (S1) microptera)
619. SALMF amide 2 (S2) 620. SCPA 621. {Leu.sup.31,Pro.sup.34}
neuropeptide Y, 622. B1BP3226 NPY antagonist Bis (31/31') human
neuropeptide F (Moniezia expansa)
{{Cys.sup.31,Trp.sup.32,Nva.sup.34} NPY 31-36}. neuropeptide Y,
human 623. rat neuropeptide Y 1-24 amide 624. human
biotinyl-neuropeptide Y 625. {D-Tyr.sup.27,36,D-Thr.sup.32}-NPY
27-36 626. Des 10-17 (cyclo 7-21) {Cys.sup.7,21,Pro.sup.34}- NPY
C2-NPY 627. {Leu.sup.31,Pro.sup.34} neuropeptide Y 628. human
neuropeptide Y 629. porcine prepro NPY 68-97 630. human
N-acetyl-{Leu.sup.28,Leu.sup.31} NPY 24- 36 neuropeptide Y 631.
porcine {D-Trp.sup.32}-neuropeptide Y 632. porcine {D-Trp.sup.32}
NPY 1-36 633. human {Leu.sup.17,DTrp.sup.32} neuropeptide 634.
human {Leu.sup.31,Pro.sup.34}-NPY Y 635. porcine NPY 2-36 636.
porcine NPY 3-36 637. human NPY 3-36 638. porcine NPY 13-36 639.
human NPY 13-36 640. porcine NPY 16-36 641. porcine NPY 18-36 642.
porcine NPY 20-36 643. FY 22-36 NPY 26-36 644. Pro.sup.34}-NPY 1-36
645. human {Pro.sup.34}-neuropeptide Y 646. porcine PYX-1 647.
PYX-2 648. T4- {NPY(33-36)}4 649. Tyr(OMe).sup.21}-neuropeptide Y,
human 650. glial derived neurotropic factor (GDNF) 651. brain
derived neurotropic factor 652. ciliary neurotropic factor (CNTF)
(BDNF) 653. orexin A 654. human orexin B 655. rat orexin B 656.
mouse orexin B 657. alpha-casein fragment 90-95 658. BAM-18P 659.
casomokinin L 660. casoxin D 661. crystalline DALDA 662.
dermenkephalin (deltorphin) (Phylomedusa sauvagei) 663.
{D-Ala.sup.2}-deltorphin I 664. {D-Ala.sup.2}-deltorphin II 665.
endomorphin-1 666. endomorphin-2 667. kyotorphin 668.
{DArg.sup.2}-kyotorphin 669. morphine tolerance peptide 670.
morphine modulating peptide 671. C-terminal fragment morphine 672.
nociceptin {orphanin FQ} (ORL1 modulating neuropeptide
(A-18-F--NH2) agonist) 673. TIPP 674. Tyr-MIF-1 675. Tyr-W-MIF-1
676. valorphin LW-hemorphin-6 677. human Leu-valorphin-Arg 678.
Z-Pro-D-Leu 679. {Asu.sup.6}-oxytocin 680. oxytocin 681.
biotinyl-oxytocin 682. {Thr.sup.4,Gly.sup.7}-oxytocin 683. tocinoic
acid ({Ile.sup.3}-pressinoic acid) 684. PACAP 1-27, human, ovine,
rat 685. PACAP (1-27)-Gly-Lys-Arg-NH.sub.2 686. human
{Des-Gln.sup.16}-PACAP 6-27 687. human, ovine, rat PACAP38 688.
frog PACAP27-NH.sub.2 689. human, ovine, rat biotinyl-PACAP27- 690.
human, ovine, rat PACAP 6-27 NH2 691. human, ovine, rat PACAP38
692. human, ovine, rat biotinyl-PACAP38 693. human, ovine, rat
PACAP 6-38 694. human, ovine, rat PACAP27-NH.sub.2 695. human,
ovine, rat biotinyl-PACAP27- 696. human, ovine, rat PACAP 6-27
NH.sub.2 697. human, ovine, rat PACAP38 698. human, ovine, rat
biotinyl-PACAP38 699. human, ovine, rat PACAP 6-38 700. human,
ovine, rat PACAP38 16-38 701. human, ovine, rat PACAP38 31-38 702.
human, ovine, rat PACAP38 31-38 703. human, ovine, rat
PACAP-related 704. human peptide (PRP) 705. PACAP-related peptide
(PRP), rat 706. chromostatin 707. bovine pancreastatin (hPST-52)
708. pancreastatin 24-52 (hPST-29) (chromogranin A 250-301, amide)
709. human chromogranin A 286-301, 710. human pancreastatin amide
711. porcine biotinyl-pancreastatin 712. porcine
{Nle.sup.8}-pancreastatin 713. porcine
{Tyr.sup.0,Nle.sup.8}-pancreastatin 714. porcine
{Tyr.sup.0}-pancreastatin 715. porcine parastatin 1-19 716. porcine
pancreastatin (chromogranin A 347-365) 717. chromogranin A
264-314-amide 718. rat biotinyl-pancreastatin 719.
biotinyl-chromogranin A 264-314- 720. {Tyr.sup.0}-pancreastatin
amide 721. rat pancreastatin 26-51 722. pancreastatin 33-49,
porcine 723. pancreatic polypeptide 724. avian pancreatic
polypeptide 725. human C-fragment pancreatic 726. human C-fragment
pancreatic polypeptide acid polypeptide amide 727. human pancreatic
polypeptide (Rana 728. ancreatic polypeptide temporaria) 729.
salmon pancreatic polypeptide 730. {Asp.sup.76-parathyroid hormone
39-84 731. human {Asp.sup.76}-parathyroid hormone 732. human
{Asn.sup.76}-parathyroid hormone 1- 53-84 84 733. hormone
{Asn.sup.76}-parathyroid 734. human {Asn.sup.8,
Leu.sup.18}-parathyroid hormone 64-84 hormone 1-34 735. human
{Cys.sup.5,28}-parathyroid 736. human hypercalcemia malignancy
factor hormone 1-34 1-40 737. {Leu.sup.18}-parathyroid hormone 1-34
738. human {Lys(biotinyl) .sup.13 739.
{Nle.sup.8,18,Tyr.sup.34}-parathyroid hormone 740.
{Nle.sup.8,18,Tyr.sup.34}-parathyroid hormone 3- 1-34 amide 34
amide 741. bovine {Nle.sup.8,18,Tyr.sup.34}-parathyroid 742. human
{Nle.sup.8,18,Tyr.sup.34}-parathyroid hormone 1-34 hormone 1-34
amide 743. human {Nle.sup.8,18,Tyr.sup.34}-parathyroid 744. human
{Nle.sup.8,18,Tyr.sup.34}-parathyroid hormone 3-34 amide hormone
7-34 amide 745. bovine {Nle.sup.8,21,Tyr.sup.34}-parathyroid 746.
rat parathyroid hormone 44-68 hormone 1-34 amide 747. human
parathyroid hormone 1-34 748. bovine parathyroid hormone 3-34 749.
bovine parathyroid hormone 1-31 750. human parathyroid hormone 1-34
amide 751. human parathyroid hormone 13-34 752. human parathyroid
hormone 1-34 753. rat parathyroid hormone 1-38 754. human
parathyroid hormone 1-44 755. human parathyroid hormone 28-48 756.
human parathyroid hormone 39-68 757. human parathyroid hormone
39-84 758. human parathyroid hormone 53-84 759. human parathyroid
hormone 69-84 760. human parathyroid hormone 70-84 761. human
{Pro.sup.34}-peptide YY (PYY) 762. human {Tyr.sup.0}-hypercalcemia
malignancy factor 1-40 763. {Tyr.sup.0}-parathyroid hormone 1-44
764. human {Tyr.sup.0}-parathyroid hormone 1-34 765. human
{Tyr.sup.1}-parathyroid hormone 766. human {Tyr.sup.27}-parathyroid
hormone 27- 1-34 48 767. human {Tyr.sup.34}-parathyroid hormone
768. bovine {Tyr.sup.43}-parathyroid hormone 43- 7-34 amide 68 769.
human {Tyr.sup.52,Asn.sup.76}-parathyroid 770.
{Tyr.sup.63}-parathyroid hormone 63-84, hormone 52-84 human 771.
PTHrP ({Tyr.sup.36}-PTHrP 1-36 amide) 772. chicken hHCF-(1-34)-NH2
(humoral hypercalcemic factor) 773. human PTH-related protein 1-34
774. human biotinyl-PTH-related protein 1-34 775. human
{Tyr.sup.0}-PTH-related protein 1- 776. human
{Tyr.sup.34}-PTH-related protein 1-34 34 amide 777. human
PTH-related protein 1-37 778. human PTH-related protein 7-34 amide
779. human PTH-related protein 38-64 780. human PTH-related protein
67-86 amide amide 781. human PTH-related protein 107-111 782.
human, rat, mouse PTH-related protein 107-111 free acid 783.
PTH-related protein 107-138 784. human and PTH-related protein
109-111 785. peptide T {D-Ala.sup.1}-peptide T 786.
{D-Ala.sup.1}-peptide T amide 787. prolactin-releasing peptide 31
788. human prolactin-releasing peptide 20 789. human
prolactin-releasing peptide 31 790. rat prolactin-releasing peptide
20 791. rat prolactin-releasing peptide 31 792. bovine
prolactin-releasing peptide 20 793. human PYY 3-36 794. human
biotinyl-PYY 795. human PYY 796. human {Leu.sup.31,Pro.sup.34}-PYY
797. porcine PYY 798. rat PYY 799. acetyl 800. angiotensinogen 1-14
801. human angiotensinogen 1-14 802. porcine renin substrate
tetradecapeptide 803. rat {Cys.sup.8}-renin substrate 804. rat
{Leu.sup.8}-renin substrate tetradecapeptide tetradecapeptide 805.
rat {Val.sup.8}-renin substrate 806. canine secretin
tetradecapeptide, rat. 807. chicken secretin 808. human
biotinyl-secretin 809. human secretin 810. porcine secretin 811.
rat secretin 812. BIM-23027 813. biotinyl-somatostatin biotinylated
814. human cortistatin 14 cortistatin 17 815. rat cortistatin 17
816. human {Tyr.sup.0}-cortistatin 17 817. human cortistatin 29
818. rat {D-Trp.sup.8}-somatostatin 819.
{DTrp.sup.8,DCys.sup.14}-somatostatin 820.
{DTrp.sup.8,Tyr.sup.11}-somatostatin 821.
{D-Trp.sup.11}-somatostatin NTB 822. {Nle.sup.8}-somatostatin 1-28
(Naltriben) 823. octreotide (SMS 201-995) 824. prosomatostatin 1-32
825. porcine {Tyr.sup.0}-somatostatin 826. {Tyr.sup.0}-somatostatin
827. {Tyr.sup.1}-somatostatin 28 (1-14) 828.
{Tyr.sup.11}-somatostatin {Tyr.sup.0} 829.
{D-Trp.sup.8}-somatostatin 830. somatostatin 831. somatostatin
antagonist 832. somatostatin-25 833. somatostatin-28 834.
somatostatin 28 (1-12) 835. biotinyl-somatostatin-28 836.
{Tyr.sup.0}-somatostatin-28 837.
{Leu.sup.8,D-Trp.sup.22,Tyr.sup.25}-somatostatin- 838.
biotinyl-{Leu.sup.8,D-Trp.sup.22,Tyr.sup.25}- 28 somatostatin-28
839. somatostatin-28 (1-14) 840. RC-160 841. G protein antagonist-2
Ac-{Arg.sup.6, 842. Ac-Trp-3,5-bis(trifluoromethyl)benzyl
Sar.sup.9, Met(02).sup.11}-substance P 6-11 {Arg.sup.3}- ester
Ac-{Arg.sup.6,Sar.sup.9,Met(O2).sup.11}-substance P substance P
843. 6-11 {D-Ala.sup.4}-substance P 844. 4-11
{Tyr.sup.6,D-Phe.sup.7,D-His.sup.9}-substance P 845. 6-11 (sendide)
biotinyl-substance P 846. {Tyr.sup.8}-substance P
biotinyl-NTE{Arg.sup.3}-substance P 847.
{Sar.sup.9,Met(O2).sup.11}-substance P 848.
{D-Pro.sup.2,DTrP.sup.7,9}-substance P 849.
{D-Pro.sup.4,O-TrP.sup.7,9}-substance P 850. 4-11 substance P 851.
4-11 {DTrp.sup.2,7,9}-substance P 852.
{(Dehydro)Pro.sup.2,4,Pro.sup.9}-substance P 853.
{Dehydro-Pro.sup.4}-substance P 854. 4-11
{Glp.sup.5,(Me)Phe.sup.8,Sar.sup.9}-substance P 855. 5-11
{Glp.sup.5,Sar.sup.9}-substance P 856. 5-11 {Glp.sup.5}-substance P
857. 5-11 hepta-substance P (substance P 858.
{MePhe.sup.8,Sar.sup.9}-substance P 5-11) hexa-substance
P(substance P6-11) 859. {Nle.sup.11}-substance P 860.
Octa-substance P(substance P4-11) 861. {pGlu.sup.1}-hexa-substance
P 862. ({pGlu.sup.6}-substance P6-11) 863.
{pGlu.sup.6,D-Pro.sup.9}-substance P 6-11 864.
{(pNO.sub.2)Phe.sup.7Nle.sup.11}-substance P 865. penta-substance P
(substance P7-11) 866. {Pro.sup.9}-substance P GR73632 867.
substance P7-11 868. {Sar.sup.4}-substance P4-11 869.
{Sar.sup.9}-substance P septide 870.
({pGlu.sup.6,Pro.sup.9}-substance P 6-11) 871. spantide I 872.
spantide II 873. cod substance P 874. trout substance P 875.
antagonist substance P-Gly-Lys-Arg 876. substance P 1-4 877.
substance P 1-6 878. substance P 1-7 879. substance P 1-9 880.
deca-substance P (substance P 2-11) 881. nona-substance P
(substance P 3-11) 882. substance P tetrapeptide (substance P 8-
11)
883. substance P tripeptide (substance P 9- 884. substance P, free
acid 11) 885. substance P methyl ester 886. {Tyr.sup.8,Nle.sup.11}
substance P 887. {Ala.sup.5,beta-Ala.sup.8} neurokinin A 888. 4-10
eledoisin 889. locustatachykinin I (Lom-TK-I) 890.
locustatachykinin II (Lom-TK-II) (Locusta migratoria) (Locusta
migratoria) 891. neurokinin A 4-10 892. neurokinin A (neuromedin L,
substance K) 893. cod neurokinin A 894. biotinyl-neurokinin A
(biotinyl- neuromedin L, biotinyl-substance K) 895.
{Tyr.sup.0}-neurokinin A 896. {Tyr.sup.6}-substance K 897. FR64349
898. {Lys.sup.3,Gly.sup.8-(R)-gamma-lactam-Leu.sup.9}- neurokinin A
3-10 899. GR83074 900. GR87389 901. GR94800 902.
{Beta-Ala.sup.8}-neurokinin A 4-10 903. {Nle.sup.10}-neurokinin A
4-10 904. {Trp.sup.7,beta-Ala.sup.8}-neurokinin A 4-10 905.
neurokinin B (neuromedin K) 906. biotinyl-neurokinin B (biotinyl-
neuromedin K) 907. {MePhe.sup.7}-neurokinin B 908.
{Pro.sup.7}-neurokinin B 909. {Tyr.sup.0}-neurokinin B 910.
neuromedin B 911. porcine biotinyl-neuromedin B 912. porcine
neuromedin B-30 913. porcine neuromedin B-32 914. porcine
neuromedin B 915. receptor antagonist neuromedin C 916. porcine
neuromedin N 917. porcine neuromedin (U-8) 918. porcine neuromedin
(U-25) 919. porcine neuromedin U 920. rat neuropeptide-gamma
(gamma- preprotachykinin 72-92) 921. PG-KII phyllolitorin 922.
{Leu.sup.8}-phyllolitorin (Phyllomedusa sauvagei) 923. physalaemin
924. physalaemin 1-11 925. scyliorhinin II, amide 926. dogfish
senktide 927. selective neurokinin B receptor 928.
{Ser.sup.2}-neuromeclin C peptide 929. beta-preprotachykinin 69-91
930. human beta-preprotachykinin 111-129 931. human tachyplesin I
932. xenopsin 933. human xenopsin 25 (xenin 25) 934.
biotinyl-thyrotropin-releasing hormone 935. {Glu.sup.1}-TRH 936.
His-Pro-diketopiperazine 937. {3-Me-His.sup.2}-TRH 938.
pGlu-Gln-Pro-amide pGlu-His {Phe.sup.2}- TRH 939. prepro TRH 53-74
940. prepro TRH 83-106 941. prepro-TRH 160-169 942. Ps4,
TRH-potentiating peptide 943. prepro-TRH 178-199 944.
thyrotropin-releasing hormone (TRH) 945. TRH, free acid 946. TRH-SH
Pro 947. TRH precursor peptide 948. omega-agatoxin TK agelenin,
(spider, Agelena opulenta) 949. apamin (honeybee, Apis mellifera)
950. calcicudine (CaC) (green mamba, Dedroaspis angusticeps) 951.
calciseptine (black mamba, 952. charybdotoxin (ChTX) (scorpion,
Leiurus Dendroaspis polylepis polylepis) quinquestriatus var.
hebraeus) 953. chlorotoxin conotoxin GI (marine 954. conotoxin GS
(marine snail, Conus snail, Conus geographus) geographus) 955.
conotoxin MI (Marine Conus magus) 956. alpha-conotoxin EI, Conus
ermineus 957. alpha-conotoxin SIA 958. alpha-conotoxin ImI
alpha-conotoxin SI (cone snail, Conus striatus) 959.
micro-conotoxin GIIIB (marine snail, 960. omega-conotoxin GVIA
(marine snail, Conus geographus) Conus geographus) 961.
omega-conotoxin MVIIA (Conus 962. omega-conotoxin MVIIC (Conus
magus) magus) 963. omega-conotoxin SVIB, (cone snail, 964.
endotoxin inhibitor geographutoxin I Conus striatus) (GTX-I)
(.mu.-Conotoxin GIIIA) 965. iberiotoxin (IbTX) (scorpion, Buthus
967. kaliotoxin 1-37 kaliotoxin (scorpion, tamulus) Androctonus
mauretanicus mauretanicus) 968. mast cell-degranulating peptide
969. margatoxin (MgTX) (scorpion, (MCD-peptide, peptide 401)
Centruriodes Margaritatus) 970. neurotoxin NSTX-3 (Papua New 971.
PLTX-II (spider, Plectreurys tristes) Guinean spider, Nephilia
maculata) 972. scyllatoxin (leiurotoxin I) 973. stichodactyla sheep
VIP toxin (ShK) 974. stichodactyla porcine VIP toxin 975.
stichodactyla rat VIP toxin (ShK) (ShK) 976.
VIP-Gly-Lys-Arg-NH.sub.2 biotinyl-PHI 977. porcine {Glp.sup.16} VIP
16-28 (biotinyl-PHI-27) 978. porcine PHI (PHI-27) 979. porcine PHI
(PHI-27) 980. rat PHM-27 (PHI) 981. human prepro VIP 81-122 982.
human preproVIP/PHM 111-122 983. prepro VIP/PHM 156-170 984.
biotinyl-PHM-27 (biotinyl-PHI) 985. human vasoactive intestinal
contractor (endothelin-beta) 986. vasoactive intestinal
octacosa-peptide 987. chicken vasoactive intestinal peptide 988.
guinea pig biotinyl-VIP 989. human VIP peptide 1-12 990. porcine
VIP peptide 1-12 991. rat VIP peptide 1-12 992. sheep VIP peptide
1-12 993. human VIP peptide 10-28 994. porcine VIP peptide 10-28
995. rat VIP peptide 10-28 996. sheep VIP peptide 10-28 997. human
VIP peptide 11-28 998. porcine VIP peptide 11-28 999. rat VIP
peptide 11-28 1000. sheep VIP peptide 11-28 1001. human VIP peptide
6-28 1002. porcine VIP peptide 6-28 1003. rat VIP peptide 6-28
1004. sheep VIP peptide 6-28 1005. vasoactive intestinal peptide
antagonist 1006. vasoactive intestinal peptide 1007. vasoactive
intestinal peptide receptor antagonist
({Ac-Tyr.sup.1,D-Phe.sup.2}-GHRF 1-29 antagonist
(4-Cl-D-Phe.sup.6,Leu.sup.17}-VIP) amide) 1008. vasoactive
intestinal peptide 1009. Ala{.sup.11,22,28}VIP receptor binding
inhibitor, L-8-K 1010. Ala{.sup.2,8,9,11,19,22,24,25,27,28} VIP
1011. {K.sup.15,R.sup.16,L.sup.27}-VIP(1-7)/GRF(8-27) 1012.
Ro25-1553 1013. Ro25-1392 1014. BAY55-9837 1015. R3P65 1016.
Maxadilan 1017. PG97-269 1018. PG99-465 1019. Max.d.4. 1020. M65
(Dickson & Finlayson, 1021. {Asu.sup.1,6,Arg.sup.8}-vasopressin
Pharmacology & Therapeutics, Volume 121, Issue 3, March 2009,
Pages 294-316). 1022. vasotocin 1023.
{Asu.sup.1,6,Arg.sup.8}-vasotocin 1024. {Lys.sup.8}-vasopressin
1025. {Arg.sup.8}-desamino vasopressin 1026. desglycinamide 1027.
{Arg.sup.8}-vasopressin (AVP) 1028. {Arg.sup.8}-vasopressin
desglycinamide 1029. biotinyl-{Arg.sup.8}-vasopressin (biotinyl-
AVP) 1030. {D-Arg.sup.8}-vasopressin 1031.
desamino-Arg.sup.8-vasopressin 1032.
desamino-{D-Arg.sup.8}-vasopressin 1033.
{deamino-{D-3-(3'-pyridyl-Ala)}- (DDAVP) {Arg.sup.8}-vasopressin
1034. {1-(beta-Mercapto-beta,beta- 1035. vasopressin metabolite
neuropeptide cyclopentamethylene propionic acid), 2-(O-
methyl)tyrosine}-{Arg.sup.8}-vasopressin 1036.
{pGlu.sup.4,Cys.sup.6} vasopressin 1037. {pGlu.sup.4,Cys.sup.6}
{Lys.sup.8}-deamino metabolite neuropeptide vasopressin
desglycinamide 1038. {Lys.sup.8}-vasopressin 1039.
{Mpr.sup.1,Val.sup.4,DArg.sup.8}-vasopressin 1040.
{Phe.sup.2,Ile.sup.3,Orn.sup.8}-vasopressin 1041.
({Phe.sup.2,Orn.sup.8}-vasotocin) 1042. {Arg.sup.8}-vasotocin 1043.
{d(CH.sub.2).sub.5,Tyr(Me).sub.2,Orn.sup.8}-vasotocin 1044. human
CMV protease substrate 1045. HCV core protein 59-68 1046. HCV NS4A
1047. protein 1840 (JT strain) 1048. HCV NS4A protein 21-34 (JT
1049. hepatitis B virus receptor binding strain) fragment 1050.
hepatitis B virus pre-S region 120- 1051. {Ala.sup.127}-hepatitis B
virus pre-S region 145 120-131 1052. herpes virus inhibitor 2 1053.
HIV envelope protein fragment 254-274 1054. HIV gag fragment
129-135 1055. HIV substrate P 18 peptide 1056. peptide T 1057. {3,5
diiodo-Tyr.sup.7} peptide T 1058. R15K 1059. HIV-1 inhibitory
peptide T20 1060. T21 1061. V3 1062. decapeptide P 18-110 1063.
virus replication inhibiting peptide 1064. buforin I 1065. buforin
II 1066. cecropin A 1067. cecropin B 1068. cecropin P1 1069.
porcine gaegurin 2 (Rana rugosa) 1070. gaegurin 5 (Rana rugosa)
1071. indolicidin 1072. protegrin-(PG)-I 1073. magainin 1 1074.
magainin 2 1075. T-22 1076. {Tyr.sup.5,12,Lys.sup.7}-poly-phemusin
II 1077. Alzheimer's disease beta-protein (SP28) peptide 1078.
calpain inhibitor peptide 1079. capsase-1 inhibitor V 1080.
capsase-3 1081. substrate IV caspase-1 inhibitor I 1082.
cell-permeable caspase-1 inhibitor 1083. caspase-3 substrate III VI
1084. caspase-1 substrate V 1085. fluorogenic caspase-3 inhibitor I
1086. cell-permeable caspase-6 1087. ICE inhibitor III 1088.
{Des-Ac,biotin}-ICE inhibitor III 1089. IL-1B converting enzyme
(ICE) inhibitor II 1090. IL-1 B converting enzyme (ICE) 1091. MDL
28170 substrate IV 1092. MG-132 1093. alpha-ANP (alpha-chANP) 1094.
chicken anantin ANP 1-11 1095. rat ANP 8-30 1096. frog ANP 11-30
1097. frog ANP-21 (fANP-21) 1098. frog ANP-24 (fANP-24) 1099. frog
ANP-30 1100. frog ANP fragment 5-28 1101. human ANP 7-23 1102.
canine ANP 7-23 1103. human ANP fragment 7-28 1104. human
alpha-atrial natriuretic 1105. canine alpha-atrial natriuretic
polypeptide 1-28 polypeptide 1-28 1106. human A71915 1107. canine
A71915 1108. rat atrial natriuretic factor 8-33 1109. rat atrial
natriuretic polypeptide 3-28 1110. human atrial natriuretic
polypeptide 1111. human atrial natriuretic polypeptide 5- 4-28 27
1112. canine atrial natriuretic polypeptide 1113. human atrial
natriuretic aeptide (ANP) 5-27 1114. eel atriopeptin I 1115. rat
atriopeptin II 1116. rabbit atriopeptin II 1117. mouse atriopeptin
II 1118. rat atriopeptin III 1119. rabbit atriopeptin III 1120.
mouse atriopeptin III 1121. rat atrial natriuretic factor (rANF),
1122. rabbit atrial natriuretic factor 1123. mouse atrial
natriuretic factor (rANF), (rANF), 1124. rat, auriculin A (rat ANF
126-149) 1125. auriculin B (rat ANF 126-150) 1126. beta-ANP (1-28,
dimer, antiparallel) 1127. biotinyl-alpha-ANP 1-28 beta-rANF 17-48
1128. human biotinyl-atrial natriuretic 1129. canine
biotinyl-atrial natriuretic factor factor (biotinyl-rANF)
(biotinyl-rANF) 1130. rat cardiodilatin 1-16 1131. human C-ANF 4-23
1132. rat Des-{Cys.sup.105,Cys.sup.121}-atrial 1133. rat
{Met(O).sup.12} ANP 1-28 natriuretic factor 104-126 1134. human
{Mpr.sup.7,DAla.sup.9}ANP 7-28, 1135. rat prepro-ANF 104-116 amide
1136. human prepro-ANF 26-55 (proANF 1137. human prepro-ANF 56-92
(proANF 31- 1-30) 67) 1138. human prepro-ANF 104-123 1139. human
{Tyr.sup.0}-atriopeptin I 1140. rat {Tyr.sup.0}-atriopeptin II
1141. rabbit {Tyr.sup.0}-atriopeptin II 1142. mouse
{Tyr.sup.0}-atriopeptin II 1143. rat {Tyr.sup.0-prepro ANF 104-123}
1144. rabbit {Tyr.sup.0-prepro ANF 104-123} 1145. mouse
{Tyr.sup.0-prepro ANF 104-123} 1146. human urodilatin (CDD/ANP 95-
1147. ventricular natriuretic peptide (VNP), 126) eel 1148.
ventricular natriuretic peptide 1149. alpha bag cell peptide (VNP),
rainbow trout 1150. alpha-bag cell peptide 1-9 1151. alpha-bag cell
peptide 1-8 1152. alpba-bag cell peptide 1-7 1153. beta-bag cell
factor 1154. gamma-bag cell factor 1155. alpha-s1 1156. casein
101-123 (bovine milk) 1157. biotinyl-bombesin 1158. bombesin 8-14
1159. {Leu.sup.13-psi (CH.sub.2NH)Leu.sup.14}-bombesin 1160.
{D-Phe.sup.6,Des-Met.sup.14}-bombesin 1161. 6-14 ethylamide
{DPhe.sup.12} bombesin 1162. {DPhe.sup.12,Leu.sup.14}-bombesin
1163. {Tyr.sup.4}-bombesin 1164. {Tyr.sup.4,DPhe.sup.12}-bombesin
1165. bone GLA protein 1166. bone GLA protein 45-49 1167.
{Glu.sup.17,Gla.sup.21,24}-osteocalcin 1-49 1168. human
myclopeptide-2 (MP-2) 1169. osteocalcin 1-49 1170. human
osteocalcin 37-49 1171. {Tyr.sup.38,Phe.sup.42,46} bone GLA protein
38- 49 1172. {Ala.sup.2,6,des-Pro.sup.3}-bradykinin 1173.
bradykinin bradykinin (Bowfin. Gar)
1174. bradykinin potentiating peptide 1175. bradykinin 1-3 1176.
bradykinin 1-5 1177. bradykinin 1-6 1178. bradykinin 1-7 1179.
bradykinin 2-7 1180. bradykinin 2-9 1181. {DPhe.sup.7} bradykinin
1182. {Des-Arg.sup.9}-bradykinin 1183.
{Des-Arg.sup.10}-Lys-bradykinin 1184. ({Des-Arg.sup.10}-kallidin)
1185. {D-N--Me-Phe.sup.7}-bradykinin 1186.
{Des-Arg.sup.9,Leu.sup.8}-bradykinin 1187. Lys-bradykinin
(kallidin) 1188. Lys-(Des-Arg.sup.9,Leu.sup.8}-bradykinin 1189.
({Des-Arg.sup.10,Leu.sup.9}-kallidin) 1190.
{Lys.sup.0-Hyp.sup.3}-bradykinin 1191. ovokinin 1192.
{Lys.sup.0,Ala.sup.3}-bradykinin 1193. Met-Lys-bradykinin 1194.
peptide K12 1195. bradykinin potentiating peptide 1196.
{(pCl)Phe.sup.5,8}-bradykinin 1197. T-kinin (Ile-Ser-bradykinin)
1198. {Thi..sup.5,8,D-Phe.sup.7}-bradykinin 1199.
{Tyr.sup.0}-bradykinin {Tyr.sup.5}-bradykinin 1200.
{Tyr.sup.8}-bradykinin 1201. kallikrein 1202. BNP 32 1203. canine
BNP-like Peptide 1204. eel BNP-32 1205. human BNP-45 1206. mouse
BNP-26 1207. porcine BNP-32 1208. porcine biotinyl-BNP-32 1209.
porcine BNP-32 1210. rat biotinyl-BNP-32 1211. rat BNP45 (BNP
51-95, 5K cardiac natriuretic peptide) 1212. human {Tyr.sup.0}-BNP
1-32 1213. C-peptide 1214. human {Tyr.sup.0}-C-peptide 1215. C-type
natriuretic peptide 1216. chicken C-type natriuretic peptide- 1217.
porcine C-type natriuretic peptide-53 22 (CNP-22) (CNP-53) 1218.
rat C-type natriuretic peptide-53 1219. human C-type natriuretic
peptide-53 (CNP-53) (CNP-53) 1220. porcine C-type natriuretic
peptide- 1221. rat C-type natriuretic peptide-53 53 1222. (porcine)
1-29 (CNP-531-29) 1223. (rat) 1-29 (CNP-531-29) 1224. prepro-CNP
1-27 1225. rat prepro-CNP 30-50 1226. porcine vasonatrin peptide
(VNP) 1227. rat vasonatrin peptide (VNP) 1228. {Tyr.sup.0}-C-type
natriuretic peptide-22 1229. biotinyl-calcitonin
({Tyr.sup.0}-CNP-22) 1230. human biotinyl-calcitonin 1231. rat
biotinyl-calcitonin 1232. salmon calcitonin 1233. chicken
calcitonin 1234. eel calcitonin 1235. human calcitonin 1236.
porcine calcitonin 1237. rat calcitonin 1238. salmon calcitonin 1-7
1239. human calcitonin 8-32 1240. salmon katacalcin (PDN-21) (C-
1241. human N-proCT (amino-terminal procalcitonin) procalcitonin
cleavage peptide) 1242. acetyl-alpha-CGRP 19-37 1243. human
alpha-CGRP 19-37 1244. human alpha-CGRP 23-37 1245. human
biotinyl-CGRP 1246. human biotinyl-CGRP II 1247. human
biotinyl-CGRP 1248. rat beta-CGRP 1249. rat biotinyl-beta-CGRP
1250. rat CGRP 1251. human calcitonin C-terminal adjacent peptide
CGRP 1-19 1252. human CGRP 20-37 1253. human CGRP 8-37 1254. human
CGRP II 1255. human CGRP 1256. rat CGRP 8-37 1257. rat CGRP 29-37
1258. rat CGRP 30-37 1259. rat CGRP 31-37 1260. rat CGRP 32-37
1261. rat CGRP 33-37 1262. rat CGRP 31-37 1263. rat
({Cys(Acm).sup.2,7}-CGRP elcatonin 1264. {Tyr.sup.0}-CGRP,human
{Tyr.sup.0}- 1265. human {Tyr.sup.0}-CGRP 28-37 CGRP II 1266. rat
{Tyr.sup.0}-CGRP 1267. {Tyr.sup.22}-CGRP 22-37, rat 1268. human
CART 55-102 1269. human CART 1270. rat CART 55-102 1271.
beta-casomorphin 1272. human beta-casomorphin 1-3 1273.
beta-casomorphin 1-3, amide 1274. beta-casomorphin, bovine 1275.
beta-casomorphin 1-4 1276. bovine beta-casomorphin 1-5 1277. bovine
beta-casomorphin 1-5, amide 1278. bovine beta-casomorphin 1-6 1279.
bovine {DAla.sup.2}-beta-casomorphin 1-3, amide 1280. bovine
{DAla.sup.2,Hyp.sup.4,Tyr.sup.5}-beta- 1281.
{DAla.sup.2,DPro.sup.4,Tyr.sup.5}-beta-casomorphin casomorphin 1-5
amide 1-5, amide 1282. {DAla.sup.2,Tyr.sup.5}-beta-casomorphin 1-
1283. bovine {DAla.sup.2,4,Tyr.sup.5}-beta- 5, amide casomorphin
1-5, amide 1284. bovine {DAla.sup.2,(pCl)Phe.sup.3}-beta- 1285.
bovine {DAla.sup.2}-beta-casomorphin 1-4, casomorphin, amide amide
1286. bovine {DAla.sup.2}-beta-casomorphin 1287. bovine
{DAla.sup.2}-beta-casomorphin 1-5, 1-5 amide 1288. bovine
{DAla.sup.2,Met.sup.5}-beta- 1289. bovine
{DPro.sup.2}-beta-casomorphin 1-5, casomorphin 1-5 amide 1290.
bovine {DAla.sup.2}-beta-casomorphin 1291. bovine
{DPro.sup.2}-beta-casomorphin 1-4, 1-6 amide 1292.
{Des-Tyr.sup.1}-beta-casomorphin 1293. bovine
{DAla.sup.2,4,Tyr.sup.5}-beta- casomorphin 1-5, amide 1294. bovine
{DAla.sup.2,(pCl)Phe.sup.3}-beta- 1295. bovine
{DAla.sup.2}-beta-casomorphin 1-4, casomorphin, amide amide 1296.
bovine {DAla.sup.2}-beta-casomorphin 1297. bovine
{DAla.sup.2}-beta-casomorphin 1-5, 1-5 amide 1298. bovine
{DAla.sup.2,Met.sup.5}-beta- 1299. bovine
{DPro.sup.2}-beta-casomorphin 1-5, casomorphin 1-5 amide 1300.
bovine {DAla.sup.2}-beta-casomorphin 1301. bovine
{DPro.sup.2}-beta-casomorphin 14, 1-6 amide 1302.
{Des-Tyr.sup.1}-beta-casomorphin 1303. bovine
{Val.sup.3}-beta-casomorphin 1-4, amide 1304. defensin 1 (human)
1305. HNP-1 (human neutrophil peptide-1) 1306. N-formyl-Met-Leu-Phe
1307. caerulein 1308. cholecystokinin 1309.
cholecystokinin-pancreozymin CCK-33 1310. human cholecystokinin
octapeptide 1311. cholecystokinin octapeptide (CCK 26- 14
(non-sulfated) (CCK 26-29, unsulfated) 33) 1312. cholecystokinin
octapeptide (non- 1313. cholecystokinin heptapeptide (CCK 27-
sulfated) (CCK 26-33, unsulfated) 33) 1314. cholecystokinin
tetrapeptide (CCK 1315. porcine CR 1409 30-33) CCK-33 1316.
cholecystokinin antagonist CCK 1317. N-acetyl cholecystokinin, CCK
26-30 flanking peptide (unsulfated) 1318. sulfated N-acetyl
cholecystokinin, 1319. sulfated N-acetyl cholecystokinin, CCK CCK
26-31 26-31 1320. non-sulfated prepro CCK fragment 1321. proglumide
V-9-M 1322. colony-stimulating factor (CSF) 1323. GMCSF 1324. MCSF
1325. G-CSF 1326. astressin alpha-helical CRF 12-41 1327.
biotinyl-CRF 1328. ovine biotinyl-CRF 1329. porcine CRF 1330. human
CRF 1331. rat CRF 1332. bovine CRF 1333. ovine CRF 1334. porcine
{Cys.sup.21}-CRF 1335. CRF antagonist human (alpha-helical CRF
9-41) 1336. CRF antagonist rat (alpha-helical 1337. CRF 6-33 CRF
9-41) 1338. human {DPro.sup.5}-CRF 1339. rat {DPro.sup.5}-CRF 1340.
human {D-Phe.sup.12,Nle.sup.21,38}-CRF 12- 1341. rat
{D-Phe.sup.12,Nle.sup.21,38}-CRF 12-41 41 1342. human
eosinophilotactic peptide 1343. rat eosinophilotactic peptide
{Met(0).sup.21}- {Met(0).sup.21}-CRF CRF 1344. ovine
{Nle.sup.21,Tyr.sup.32}-CRF 1345. ovine prepro CRF 125-151 1346.
human sauvagine 1347. frog {Tyr.sup.0}-CRF 1348. human
{Tyr.sup.0}-CRF 1349. rat {Tyr.sup.0}-CRF 1350. ovine
{Tyr.sup.0}-CRF 34-41 1351. ovine {Tyr.sup.0}-urocortin urocortin
amide 1352. human urocortin 1353. rat urotensin I (Catostomus
commersoni) 1354. urotensin II 1355. urotensin II (Rana ridibunda
1356. cortistatin 29 1357. cortistatin 29 (1-13) 1358.
{Tyr.sup.0}-cortistatin 29 1359. pro-cortistatin 28-47 1360.
pro-cortistatin 51-81 1361. tumor necrosis factor 1362. TNF-r3
1363. dermorphin 1364. dermorphin analog 1-4 1365. big dynorphin
(prodynorphin 209-240) 1366. porcine biotinyl-dynorphin A 1367.
{DAla.sup.2,DArg.sup.6}dynorphin A 1-13 (biotinyl-prodynorphin
209-225) 1368. porcine {D-Ala.sup.2}-dynorphin A 1369. porcine
{D-Ala.sup.2}-dynorphin A amide 1370. porcine
{D-Ala.sup.2}-dynorphin A 1-13, 1371. porcine
{D-Ala.sup.2}-dynorphin A 1-9 amide 1372. porcine
{DArg.sup.6}-dynorphin A 1-13 1373. porcine {DArg.sup.8}-dynorphin
A 1-13 1374. porcine {Des-Tyr.sup.1}-dynorphin A 1- 1375.
{D-Pro.sup.10}-dynorphin A 1-11 8 1376. porcine dynorphin A amide
1377. porcine dynorphin A 1-6 1378. porcine dynorphin A 1-7 1379.
porcine dynorphin A 1-8 1380. porcine dynorphin A 1-9 1381. porcine
dynorphin A 1-10 1382. porcine dynorphin A 1-10 amide 1383. porcine
dynorphin A 1-11 1384. porcine dynorphin A 1-12 1385. porcine
dynorphin A 1-13 1386. porcine dynorphin A 1-13 amide 1387. porcine
DAKLI (dynorphin A-analogue kappa ligand) 1388. DAKLI-biotin 1389.
({Arg.sup.11,13}-dynorphin A (1-13)-Gly-
NH(CH.sub.2).sub.5NH-biotin) dynorphin A 2-17 1390. porcine
dynorphin 2-17, amide 1391. porcine dynorphin A 2-12 1392. porcine
dynorphin A 3-17, amide 1393. porcine dynorphin A 3-8 1394. porcine
dynorphin A 3-13 1395. porcine dynorphin A 3-17 1396. porcine
dynorphin A 7-17 1397. porcine dynorphin A 8-17 1398. porcine
dynorphin A 6-17 1399. porcine dynorphin A 13-17 1400. porcine
dynorphin A (prodynorphin 1401. porcine dynorphin B 1-9 209-225)
1402. {MeTyr.sup.1,MeArg.sup.7,D-Leu.sup.8}- 1404. porcine
{Phe.sup.7}-dynorphin A 1-7 dynorphin 1-8 ethyl amide
{(nMe)Tyr.sup.1} dynorphin A 1-13, 1403.amide 1405. porcine
{Phe.sup.7}-dynorphin A 1-7, 1406. prodynorphin 228-256 (dynorphin
B 29) amide (leumorphin) 1407. human ACTH 1-10 1408. ACTH 1-13
1409. human ACTH 1-16 1410. human ACTH 1-17 1411. ACTH 1-24 1412.
human ACTH 4-10 1413. ACTH 4-11 1414. ACTH 6-24 1415. ACTH 7-38
1416. human ACTH 18-39 1417. human ACTH 1418. rat ACTH 12-39 1419.
rat beta-cell tropin (ACTH 22-39) 1420. biotinyl-ACTH 1-24 1421.
human biotinyl-ACTH 7-38 1422. human corticostatin 1423. rabbit
{Met(02).sup.4,DLys.sup.8,Phe.sup.9} 1424. human
{Met(0).sup.4,DLys.sup.8,Phe.sup.9}ACTH 4- ACTH 4-9 9 1425. human
N-acetyl, ACTH 1-17 1426. ebiratide 1427. adrenomedullin 1428.
adrenomedullin 1-52 1429. human adrenomedullin 1-12 1430. human
adrenomedullin 13-52 1431. human adrenomedullin 22-52 1432. human
pro-adrenomedullin 45-92 1433. human pro-adrenomedullin 153-185
1434. human adrenomedullin 1-52 1435. porcine pro-adrenomedullin
(N-20) 1436. porcine adrenomedullin 1-50 1437. rat adrenomedullin
11-50 1438. rat proAM-N20 (proadrenomedullin N- terminal 20 peptide
1439. allatostatin I 1440. allatostatin II 1441. allatostatin III
1442. allatostatin IV 1443. acetyl-amylin 8-37 1444. human
acetylated amylin 8-37 1445. rat AC187 amylin antagonist AC253
1446. amylin antagonist AC625 1447. amylin antagonist amylin 8-37
1448. human amylin (IAPP) 1449. cat amylin (insulinoma or islet
1450. human amylin 1-13 (diabetes-associated amyloid
polypeptide(IAPP)) amylin amide peptide 1-13) 1451. human amylin
20-29 (IAPP 20-29) 1452. human AC625 amylin antagonist 1453. amylin
8-37 1454. human amylin (IAPP) 1455. cat amylin 1456. rat amylin
8-37 1457. rat biotinyl-amylin 1458. rat biotinyl-amylin amide
1459. human biotinyl-amylin amide 1460. Alzheimer's disease
beta-protein 12-28 (SP17) 1461. amyloid beta-protein 25-35 1462.
amyloid beta/A4-protein precursor 328- 332 1463. amyloid beta/A4
protein precursor 1464. amyloid beta-protein 1-43 amyloid beta-
(APP) 319-335 protein 1-42 1465. amyloid beta-protein 1-40 1466.
amyloid beta-protein 10-20 1467. amyloid beta-protein 22-35 1468.
Alzheimer's disease beta-protein (SP28) 1469. beta-amyloid peptide
1-42 1470. rat beta-amyloid peptide 1-40 1471. rat beta-amyloid
1-11 1472. beta-amyloid 31-35 1473. beta-amyloid 32-35 1474.
beta-amyloid 35-25 1475. beta-amyloid/A4 protein precursor 1476.
beta-amyloid precursor protein 657-676 96-110 1477. beta-amyloid
1-38 1478. {Gln.sup.11}-Alzheimer's disease beta- protein
1479. {Gln.sup.11}-beta-amyloid 1-40 1480.
{Gln.sup.22}-beta-amyloid 6-40 1481. non-A beta component of 1482.
Alzheimer's disease amyloid .beta.-peptide Alzheimer's disease
amyloid (NAC) P3, (A beta 17-40) 1483. SAP (serum amyloid P
component) 1484. A-779 Ala-Pro-Gly-angiotensin II 194-204 1485.
{Ile.sup.3,Val.sup.5}-angiotensin II 1486. angiotensin III 1487.
antipeptide angiogenin fragment 1488. angiogenin fragment 108-123
108-122 1489. angiotensin I converting enzyme 1490. human
angiotensin I converting enzyme inhibitor angiotensin I substrate
angiotensin I 1-7 1491. human angiopeptin angiotensin II 1492.
human angiotensin II antipeptide angiotensin II 1-4 1493. human
angiotensin II 3-8 1494. human angiotensin II 4-8 1495. human
angiotensin II 5-8 1496. human angiotensin III ({Des-Asp.sup.1}-
angiotensin II) 1497. human angiotensin III inhibitor 1498.
angiotensin-converting enzyme inhibitor ({Ile.sup.7}-angiotensin
III) (Neothunnus macropterus) 1499.
{Asn.sup.1,Val.sup.5}-angiotensin I 1500. goosefish
{Asn.sup.1,Val.sup.5,Asn.sup.9}- angiotensin I 1501. salmon
{Asn.sup.1,Val.sup.5, Gly.sup.9}- 1502. eel
{Asn.sup.1,Val.sup.5}-angiotensin 11-7 angiotensin I 1503. eel
{Asn.sup.1,Val.sup.5}-angiotensin II 1504. goosefish
{Asn.sup.1,Val.sup.5}-angiotensin II 1505. salmon
{Asn.sup.1,Val.sup.5}-angiotensin II 1506. biotinyl-angiotensin I
1507. human biotinyl-angiotensin II 1508. human
biotinyl-Ala-Ala-Ala-angiotensin II 1509.
{Des-Asp.sup.1}-angiotensin I 1510. human
{p-aminophenylalanine.sup.6}- angiotensin II 1511. renin substrate
(angiotensinogen 1- 1512. human preangiotensinogen 1-14 (renin 13)
substrate tetradecapeptide) 1513. human renin substrate 1514.
porcine {Sar.sup.1}-angiotensin II tetradecapeptide
(angiotensinogen 1-14) 1515. {Sar.sup.1}-angiotensin II 1-7 amide
1516. {Sar.sup.1,Ala.sup.8}-angiotensin II 1517.
{Sar.sup.1,Ile.sup.8}-angiotensin II {Sar.sup.1, 1518.
{Sar.sup.1,Tyr(Me).sup.4}-angiotensin II Thr.sup.8}-angiotensin II
(Sarmesin) 1519. {Sar.sup.1,Val.sup.5,Ala.sup.8}-angiotensin II
1520. {Sar.sup.1,Ile.sup.7}-angiotensin III 1521. synthetic
tetradecapeptide renin 1522. {Val.sup.4}-angiotensin III substrate
(No. 2) 1523. {Val.sup.5}-angiotensin II 1524.
{Val.sup.5}-angiotensin I 1525. human {Val.sup.5}-angiotensin I
1526. bullfrog {Val.sup.5,Asn.sup.9}-angiotensin I 1527. fowl
{Val.sup.5,Ser.sup.9}-angiotensin I 1528. Ac-SQNY 1529. bovine
bactenecin 1530. CAP 37 (20-44) 1531. carbormethoxycarbonyl-DPro-
1532. CD36 peptide P 139-155 DPhe-OBzl 1533. CD36 peptide P93-110
1534. cecropin A-melittin hybrid peptide 1535.
{CA(1-7)M(2-9)NH.sub.2} cecropin B, 1536. CYS(Bzl)84 CD fragment
81-92 free acid 1537. defensin (human) 1538. HNP-2 1539.
dermaseptin immunostimulating 1540. human lactoferricin peptide
1541. bovine lactoferricin 1542. Hepatocyte Growth Factor (HGF)
1543. HGFR
TABLE-US-00033 (SEQ ID NO:42) .alpha.-Bag Cell Peptide (1-9)
APRLREYSL (SEQ ID NO:43) .gamma.-Bag Cell Peptide RLRFD (SEQ ID
NO:44) .beta.-Bag Cell Peptide RLRFH (SEQ ID NO:45) BAM 3200
Peptide E YGGFMRRVGPEWWMDYQKRYGGFL (SEQ ID NO:46) BAM-18P
YGGFMRRVGRPEWWMDYQ (SEQ ID NO:47) BAM-12P, Bovine Adrenal Medulla
Docosapeptide YGGFMRRVGRPE (SEQ ID NO:48) BAM-12P (7-12) RVGRPE
(SEQ ID NO:49) bFGF (119-126), Basic Fibroblast Growth Factor,
human, bovine KRTGQYKL (SEQ ID NO:50) bFGF Inhibitory Peptide
APSGHYKG (SEQ ID NO:51) bFGF Inhibitory Peptide II MWYRPDLDERKQQKRE
(SEQ ID NO:52) (Glu63) Bax BH3, mutant STKKLSECEKRIGDELDSNM (SEQ ID
NO:53) BAD (103-126), human NLWAAQRYGRELRRMSDEFVDSFK (SEQ ID NO:54)
BAD (103-127), human NLWAAQRYGRELRRMSDEFVDSFKK (SEQ ID NO:55)
BAD(NT-1) PEFEPSEQEDSSSAERC-NE12 (SEQ ID NO:56) Bak-BH3,
TAMRA-labeled GQVGRQLAIIGDDINR-K(TAMRA)-NH2 (SEQ ID NO:57) Bax BH3
peptide (55-74), wild type STKKLSECLKRIGDELDSNM (SEQ ID NO:58) Bcl
9-2 GSEGLSKEQLEHRERSLQTLRDIERLLLRSGETEPFLKGPPGGAG-NH2 (SEQ ID
NO:59) BMf-BH3 LQHRAEVQIARKLQCIADQFHRLHT (SEQ ID NO:60) Noxa BH3,
Peptide I PAELEVECATQLRRFGDKLNFRQKLL (SEQ ID NO:61) {D-Phe12,
Leu14}-Bombesin Pyr-QRLGNQWAVGfLL-NH2 (SEQ ID NO:62)
{D-Phe12}-Bombesin Pyr-QRLGNQWAVGfLM-NH2 (SEQ ID NO:63) {D-Tyr6,
.beta.-Ala11, Phe13, Nle14}-Bombesin (6-14)
yQWAV-(.beta.-A)-HF-Nle- NH2 (SEQ ID NO:64) {D-Tyr6, .beta.-Ala11,
.beta.-Phe13, Nle14}-Bombesin (1-14)
Pyr-QRLGyQWAV-(.beta.-A)-H-(.beta.-F)-Nle-NH2 (SEQ ID NO:65)
{Lys3}-Bombesin Pyr-QKLGNQWAVGHLM-NH2 (SEQ ID NO:66) {Tyr4,
D-Phe12}-Bombesin Pyr-QRYGNQWAVGfLM-NH2 (SEQ ID NO:66)
{Tyr4}-Bombesin Pyr-QRYGNQWAVGHLM-NH2 (SEQ ID NO:68)
Biotin-Bombesin Biotin-EQRLGNQWAVGHLM-NH2 (SEQ ID NO:68)
Biotin-LC-LC-Bombesin Biotin-LC-LC-EQRLGNQWAVGHLM-NH2 (SEQ ID
NO:65) Bombesin Pyr-QRLGNQWAVGHLM-NH2 (SEQ ID NO:68) Bombesin,
FAM-labeled FAM-EQRLGNQWAVGHLM-NH2 (SEQ ID NO:69)
{D-Phe7}-Bradykinin RPPGFSfFR (SEQ ID NO:70) {Des-Arg1}-Bradykinin
PPGFSPFR {Des-Arg10}-HOE I40 rRP-Hyp-G-Thi-S-(D-Tic)-Oic (SEQ ID
NO:71) {Ile-Ser}-Bradykinin (T-Kinin) ISRPPGFSPFR (SEQ ID NO:73)
{Leu8, Des-Arg9}-Bradykinin RPPGFSPL (SEQ ID NO:73)
{Lys0}-Bradykinin (Kallidin) KRPPGFSPFR (SEQ ID NO:74) Angiotensin
Converting Enzyme Inhibitor BPP 9a Pyr-WPRPQIPP (SEQ ID NO:75)
Biotin-Bradykinin Biotin-RPPGFSPFR (SEQ ID NO:76) Bradykinin
RPPGFSPFR (SEQ ID NO:77) Bradykinin Potentiator B, Angiotensin I
Converting Enzyme Inhibitor Pyr-GLPPRPKIPP (SEQ ID NO:78)
Bradykinin Potentiator C, Angiotensin I Converting Enzyme Inhibitor
Pyr-GLPPGPPIPP (SEQ ID NO:79) Hemopressin PVNFKLLSHHOE I40
rRP-(Hyp)-G-(Thi)-S-(D-Tic)-(Oic)-R (SEQ ID NO:80) C-peptide
(57-87), human EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ (SEQ ID NO:81)
Proinsulin C-peptide (55-89), human
RREAEDLQVGQVELGGGPGAGSLQPLALEGSLQKR (SEQ ID NO:82) {Trp63,
64}-C3a(63-77) WWGKKYRASKLGLAR (SEQ ID NO:83) C3a (70-77) ASHLGLAR
(SEQ ID NO:84) C3f fragment, Human c3 (1286-1297) THRIHWESASLL (SEQ
ID NO:85) C3f, Human c3 (1282-1298) SSKITHRIHWESASLLR (SEQ ID
NO:86) Complement anaphylatoxin C5a (37-53), human
RAARISLGPRCIKAFTE (SEQ ID NO:87) .alpha.-CGRP (19-37), human
SGGVVKNNFVPTNVGSKAF-NH2 (SEQ ID NO:88) {Tyr0}-.alpha.-CGRP, human
YACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH2 (Disulfide bridge:
between amino acids 3 and 8) (SEQ ID NO:89) Biotin-Calcitonin,
human Biotin-CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP-NH2 (Disulfide
bridge: between amino acids 1-7) (SEQ ID NO:90) Calcitonin Gene
Related Peptide, CGRP (8-37), human
VTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH2 (SEQ ID NO:91) Calcitonin Gene
Related Peptide, CGRP (8-37), rat
VTHRLAGLLSRSGGVVKDNFVPTNVGSEAF-NH2 (SEQ ID NO:92) Calcitonin Gene
Related Peptide, CGRP, chicken
ACNTATCVTHRLADFLSRSGGVGKNNFVPTNVGSKAF-NH2 (Disulfide bridge: 2-7)
(SEQ ID NO:93) Calcitonin Gene Related Peptide, CGRP, human
ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH2 (Disulfide bridge: 2-7)
(SEQ ID NO:94) Calcitonin N-Terminal Flanking Peptide, human,
N-Procalcitonin
APFRSALESSPADPATLSEDEARLLLAALVQDYVQMKASELEQEQEREGSSLDSPRS (SEQ ID
NO:95) Calcitonin, chicken CASLSTCVLGKLSQELHKLQTYPRTDVGAGTP-NH2
(Disulfide bridge: 1-7) (SEQ ID NO:96) Calcitonin, eel
CSNLSTCVLGKLSQELHKLQTYPRTDVGAGTP-NH2 (Disulfide bridge: 1-7) (SEQ
ID NO:102) Calcitonin, human CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP-NH2
(Disulfide bridge: 1-7) (SEQ ID NO:97) Calcitonin, human,
FAM-labeled FAM-CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP-NH2 (Disulfide
bridge: 1-7) (SEQ ID NO:98) Calcitonin, porcine
CSNLSTCVLSAYWRNLNNFHRFSGMGFGPETP-NH2 (Disulfide bridge: 1-
(SEQ ID NO:99) Calcitonin, rat CGNLSTCMLGTYTQDLNKFHTFPQTSIGVGAP-NH2
(Disulfide bridge: 1-7) (SEQ ID NO:100) Calcitonin, salmon
CSNLSTCVLGKLSQELHKLQTYPRTNTGSGTP-NH2 (Disulfide bridge: 1-7) (SEQ
ID NO:101) Calcitonin-Lys(Biotin), human
CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAPK(Biotin (Disulfide bridge: 1-7)
Calcitonin-Lys(Biotin), human, FAM-labeled
FAM-CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAPK(Biotin) (Disulfide bridge:
1-7) (SEQ ID NO:103) {-2}pPSA, Prostate-Specific Antigen, truncated
SRIVGGWECEK (SEQ ID NO:104) {-4}pPSA ILSRIVGGWECEK (SEQ ID NO:105)
{A90,95}Bid BH3 (77-100), mouse ESQEEIIHNIARHAAQIGAEMDHN (SEQ ID
NO:106) {Ala6, Va115} MUC5AC Analog 2 GTTPSAVPTTSTTSVP (SEQ ID
NO:107) {APLILSR}pPSA APLILSRIVGGWECEK (SEQ ID NO:108) {Arg67}Bax
H2-H3 (53-86), {R67} Helix 2-3 (53-86), mutant
DASTKKLSECLKRIRDELDSNMELQRMIAAVDTD (SEQ ID NO:109) {Asn370}
tyrosinase (368-376) YMNGTMSQV (SEQ ID NO:110) {Asp370}-Tyrosinase
(368-376) YMDGTMSQV (SEQ ID NO:111) {Cys(Acm)33}-Endostatin (6-49)
FQPVLHLVALNSPLSGGMRGIRGADFQ-C(Acm)-FQQARAVGLAGTFRAF (SEQ ID NO:112)
{Gln340}-Maspin, Reactive Site Loop (RSL), (330-345)
GGDSIEVPGAQILQHK (SEQ ID NO:57) {Glu63} Bax BH3, mutant
STKKLSECEKRIGDELDSNM (SEQ ID NO:113) {Ile12, Val15} MUC5AC Analog 3
GTTPSPVPTTSITSVP (SEQ ID NO:114) {Ile161} IMAGE-A2 (157-166)
YLQLIFGIEV (SEQ ID NO:115) {p5er155}-BAD BH3 (146-159)
RYGRELRRM-pS-DEFE (SEQ ID NO:116) {pThr145}-p21 (140-147)
RKRRQ-pT-SM (SEQ ID NO:117) {Ser244} Tyrosinase (240-251)
DAEKSDICTDEY (SEQ ID NO:118) {Val165+56NY-ESO-1(157-165) SLLMWITQV
(SEQ ID NO:119) 234 CM KYICNSSCM (SEQ ID NO:120) 234 CW KYMCNSSCM
(SEQ ID NO:121) 53BP2 (490-498), p53-Binding Loop (CDB3) REDEDEIEW
(SEQ ID NO:122) Adipophilin SVASTITGV (SEQ ID NO:123) Amphoterin
(150-183) KLKEKYEKDIAAYRAKGKPDAAKKGVVKAEKSKK (SEQ ID NO:124)
Antennapedia Bak BH3 (Ant-BH3) (71-89) Fusion peptide
RQIKIVVFQNRRMKWKKMGQVGRQLAIIGDDINRRY (SEQ ID NO:1366) Anti-Flt1
Peptide GNQWFI Bad (103-127), human, all d-isomers
nlwaaqrygrelrrmsdefydsfkk (SEQ ID NO:126) BAD (CT-1)
KKGLPRPKSAGTATQMRQSSSWTC-NH2 (SEQ ID NO:127) BAD BH3 (103-123)
NLWAAQRYGRELRRMSDEFVD (SEQ ID NO:128) BAD BH3 (146-159)
RYGRELRRMSDEFE (SEQ ID NO:129) BAD Peptide, biotin-labeled
Biotin-LC-AGAGRSRHSSYPAGT (SEQ ID NO:130) BAFF-R (160-183)
SVPVPATELGSTELVTTKTAGPEQ (SEQ ID NO:131) BAGE (2-10) AARAVFLAL (SEQ
ID NO:132) Bak BH3 GQVGRQLAIIGDDINR (SEQ ID NO:133) Bak BH3 (67-87)
PSSTMGQVGRQLAIIGDDINR (SEQ ID NO:134) Bak BH3 (69-93)
STMGQVGRQLAIIGDDINRRYDSEF (SEQ ID NO:135) Bak BH3 (71-89)
MGQVGRQLAIIGDDINRRY (SEQ ID NO:136) Bak BH3(73-87) QVGRQLAIIGDDINR
Bak BH3 peptide, Mca labeled 7-methoxycoumarine-4-yl acetyl
(Mca)-GQVGRQLAIIGDDINR (SEQ ID NO:137) Bax BH3 KKLSECLKRIGDELDS
(SEQ ID NO:138) Bax BH3 (58-71) KLSECLKRIGDELD Bax BH3 peptide
(55-74), wild type STKKLSECLKRIGDELDSNM (SEQ ID NO:139) Bax BH3L63A
KKLSECAKRIGDELDS (SEQ ID NO:140) Bax H2-H3 (53-86), Helix 2-3
DASTKKLSECLKRIGDELDSNMELQRMIAAVDTD (SEQ ID NO:141) Bax H3 (71-86),
Helix 3 (71-86) DSNMELQRMIAAVDTD (SEQ ID NO:142) Bax I
PQDASTKKLSECLKRIGDELDSNMEL (SEQ ID NO:58) Bcl 9-2
GSEGLSKEQLEHRERSLQTLRDIERLLLRSGETEPFLKGPPGGAG-NH2 (SEQ ID NO:143)
Bcl-2 BH3 (85-105) ALSPVPVVHLTLRQAGDFSRR (SEQ ID NO:144) Bcl-2 BH3
Peptide II LSPVPPVVHLALRQAGDDFSRRYRG (SEQ ID NO:145) Bcl-2 Binding
Peptide, Bad BH3 Peptide LWAAQRYGRELRRMSDEFEGSFKGL (SEQ ID NO:146)
Bcl-XL BH3 (85-98) AVKQALREAGDEFE (SEQ ID NO:147) Bcl9-2, mutant
GSEGLSKEQLEHRERSFQTLRDIERLLLRSGETEPFLKGPPGGAG-NH2 (SEQ ID NO:148)
BDC25(A) GKKVAAPAWARMG (SEQ ID NO:159) BH3 BIM Peptide (52-71),
human Ac-MRPEIVVIAQELRRIGDEFNA (SEQ ID NO:150) Bid BH3 (77-100),
mouse ESQEEIIHNIARHLAQIGDEMDHN (SEQ ID NO:151) Bid BH3 (79-99)
QEDIIRNIARHLAQVGDSMDR (SEQ ID NO:152) Bid BH3 (85-98)
NIARHLAQVGDSMD (SEQ ID NO:153) Bid BH3 Peptide EDIIRNIARHLAQVGDSMDR
(SEQ ID NO:153) Bid BH3, FAM labeled 5-FAM-EDIIRNIARHLAQVGDSMDR
(SEQ ID NO:153) Bid BH3, Peptide II, TAMRA labeled
5-TAMRA-EDIIRNIARHLAQVGDSMDR Bid BH3-r8 .sub.dR .sub.dR .sub.dR vR
.sub.dR .sub.dR .sub.dR .sub.dR - GEDIIRNIARHLAQVGDSMDR (SEQ ID
NO:156)
Bid BH3-R8 RRRRRRRRGEDIIRNIARHLAQVGDSMDR (SEQ ID NO:157) Bid BH3-R9
RRRRRRRRRGEDIIRNIARHLAQVGDSMDR (SEQ ID NO:158) Bid-BH3
RNIARHLAQVGDSMDR Bik BH3 (50-70) (SEQ ID NO:159) Bik BH3 (56-69)
ALALRLACIGDEMD (SEQ ID NO:160) BIK BH3 Peptide MEGSDALALRLACIGDEMDV
(SEQ ID NO:161) Bim BH3 (87-100) WIAQELRRIGDEFN (SEQ ID NO:162) Bim
BH3 Fragment I, TAMRA labeled 5-TAMRA-DNRPEIVVIAQELRRIGDEFNAYYAR
(SEQ ID NO:163) Bim BH3, Fragment II, TAMRA labeled
5-TAMRA-MRPEIWIAQELRRIGDEFNA (SEQ ID NO:164) Bim BH3, Peptide III
DMRPEIWIAQELRRIGDEFNAYYAR (SEQ ID NO:165) Bim BH3, Peptide IV
DMRPEIWIAQELRRIGDEFNAYYARR (SEQ ID NO:166) Bim-23056 fFYwKVFnal-NH2
(SEQ ID NO:167) BMF BH3 peptide HQAEVQIARKLQLIADQFHR (SEQ ID
NO:168) BNIP3-.alpha. BH3 peptide VVEGEKEVEALKKSADWVSD (SEQ ID
NO:169) BRCAA1 (610-619) SSKKQKRSHK (SEQ ID NO:170) c-Myc peptide
epitope EQKLISEEDL (SEQ ID NO:171) CEA, CAP-1, Carcinoembryonic
Antigen YLSGANLNL (SEQ ID NO:172) CEA Related, QYSWFVNGTF
QYSWFVNGTF (SEQ ID NO:173) CEA Related, TYACFVSNL TYACFVSNL (SEQ ID
NO:174) CEA, CAP-1-6-D, {Asp6}-Carcinoembryonic Antigen YLSGADLNL
(SEQ ID NO:175) Cell Penetrating ARF Peptide (26-44) .sub.dR
.sub.dR .sub.dR .sub.dR .sub.dR .sub.dR .sub.dR .sub.dR .sub.dR
KFVRSRRPRTASCALAFVN (SEQ ID NO:176) Cell Penetrating Mutant ARF
(37-44) Peptide .sub.dR .sub.dR .sub.dR .sub.dR .sub.dR .sub.dR
.sub.dR .sub.dR .sub.dR SCALAFVN (SEQ ID NO:177) Cripto-1, CR-1
CPPSFYGRNCEHDVRKE (SEQ ID NO:178) CTT, Gelatinase Inhibitor
CTTHWGFTLC (Disulfide Bridge: 1-10) (SEQ ID NO:179) Cys-p21
(139-154) CGRKRRQTSMTDFYHSK (SEQ ID NO:180) E7 (43-62), HPV
Oncoprotein GQAEPDRAHYNIVTFCCKCD (SEQ ID NO:181) E7 (43-77), HPV
Oncoprotein GQAEPDRAHYNIVTFCCKCDSTLRLCVQSTHVDIR (SEQ ID NO:182)
EGFR (662-681) RRELVEPLTPSGEAPNQALLR (SEQ ID NO:183) Ep-CAM
(263-271) GLKAGVIAV (SEQ ID NO:184) Epidermal Mitosis Inhibiting
Pentapeptide Pyr-EDSG (SEQ ID NO:185) F42, Gastric Signet Ring Cell
Carcinoma Derived Peptide YSWMDISCWI (SEQ ID NO:186) G154, gp100
(154-162) KTWGQYWQV (SEQ ID NO:187) G209, gp100 (209-217) ITDQVPFSV
(SEQ ID NO:188) G209-2M, gp100 (209-217) IMDQVPFSV (SEQ ID NO:189)
G280-9, gp100 (280-288), Lys (biotin) YLEPGPVTA-K(Biotin) (SEQ ID
NO:190) G280-9V, 100(280-288) Lys(biotin) YLEPGPVTV-K(Biotin) (SEQ
ID NO:191) GAD65 (206-220) TYEIAPVFVLLEYVT (SEQ ID NO:192) GAD65
(78-97) KPCNCPKGDVNYAFLHATDL (SEQ ID NO:193) GnT-V (nt38-67)
VLPDVFIRCV (SEQ ID NO:194) gp100 (177-186) AMLGTHTMEV (SEQ ID
NO:195) gp100 (178-187) MLGTHTMEV (SEQ ID NO:196) gp100 (25-33),
human KVPRNQDWL (SEQ ID NO:197) gp100 (457-466) LLDGTATLRL (SEQ ID
NO:198) gp100 (476-485) VLYRYGSFSV (SEQ ID NO:199) gp100 (570-579)
SLADTNSLAV (SEQ ID NO:200) gp100 (614-622) LIYRRRLMK (SEQ ID
NO:201) gp100 (619-627) RLMKQDFSV (SEQ ID NO:202) gp100 (639-647)
RLPRIFCSC (SEQ ID NO:203) GPC3 (144-152) FVGEFFTDV (SEQ ID NO:204)
GPC3 (298-306), mouse EYILSLEEL (SEQ ID NO:205) GRP78 Binding
Chimeric Peptide Motif WIFPWIQL-GG-klaklakklaklak-NH2 (SEQ ID
NO:206) hACC1 (1258-1271), phosphorylated DSPPQ-pS-PTFPEAGH (SEQ ID
NO:207) HB-1(18-41) WKSELVEVDDVYLRHSSSLTYRL (SEQ ID NO:208)
HB-1(26-41) EDDVYLRHSSSLTYRL (SEQ ID NO:209) HER-2/Neu (654-662),
GP2 IISAVVGIL (SEQ ID NO:210) HIF-1 {alpha} (556-574)
DLDLEMLAPYIPMDDDFQL (SEQ ID NO:211) HIF-2 (66-84)
SLEAQGIKADRETVAVKPT (SEQ ID NO:212) HPV16 E7(86-93) TLGIVCPI (SEQ
ID NO:213) HRK BH Peptide SSAAQLTAARLKALGDELHQ (SEQ ID NO:214)
IL-11R- alpha Binding Peptide II CGRRAGGSC (S-S bonded) (SEQ ID
NO:215) iLRP1, iLRP, Immature Laminin Receptor Protein (58-66)
LLLAARAIV (SEQ ID NO:216) iLRP2, iLRP (60-68) LAARAIVAI (SEQ ID
NO:217) iLRP3, iLRP(146-154) ALCNTDSPL
(SEQ ID NO:218) iLRP4, iLRP(7-15) VLQMKEEDV (SEQ ID NO:219) IP3
peptide, (Lys)TAMRA labeled MPRFMDYWEGLN-K(5/6-TMR) (SEQ ID NO:220)
IP3 peptide, Acetylated and Biotinylated Ac-MPRFMDYWEGLNK-K(Biotin)
(SEQ ID NO:221) IP3 Truncated Peptide, Acetylated Ac-FMDYWEGLN (SEQ
ID NO:222) Kisspeptin-10, Metastin (45-54) YNWNSFGLRF-NH2 (SEQ ID
NO:223) KM-HN-1(107-116) VFGTRIEKDL (SEQ ID NO:224)
KM-HN-1(196-204) NYNNFYRFL (SEQ ID NO:225) KM-HN-1(335-343)
HFCRKCKKL (SEQ ID NO:226) KM-HN-1(499-508) EYSKECLKEF (SEQ ID
NO:227) KM-HN-1(65-74) SFQALRMQTL (SEQ ID NO:228) KM-HN-1(770-778)
EYLSLSDKI (SEQ ID NO:229) Laminin Peptide (CDPGYIGSR) NEW
CDPGYIGSR-NH2 (SEQ ID NO:230) Livin7, ML-IAP KWFPSCQFLL (SEQ ID
NO:231) LyP-1, Peptide 1 NEW CGNKRTRGC (S-S Bonded) (SEQ ID NO:232)
LyP-1, Peptide 2 CGNKRTRGC (SEQ ID NO:233) MAGE-1(161-169)
EADPTGHSY (SEQ ID NO:234) MAGE-1 (230-238) STAPPAHGV (SEQ ID
NO:235) MAGE-3 (112-120) KVAELVHFL (SEQ ID NO:236) MAGE-3 (114-127)
AELVHFLLLKYRAR (SEQ ID NO:237) MAGE-3 (121-134) LLKYRAREPVTKAE (SEQ
ID NO:238) MAGE-3 (161-169) EVDPIGHLY (SEQ ID NO:239) MAGE-3
(271-279) FLWGPRALV (SEQ ID NO:240) MAGE-A1(96-104) SLFRAVITK (SEQ
ID NO:241) MAGE-A1 (237-245) KLLTQDLVQ (SEQ ID NO:242) MAGE-A1
Antigen (278-286), human KVLEYVIKV (SEQ ID NO:43) MAGE-A10
(183-191) MLLVFGIDV (SEQ ID NO:244) MAGE-A10 (254-262) GLYDGMEHL
(SEQ ID NO:245) MAGE-A2 (112-120) KMVELVHFL (SEQ ID NO:246) MAGE-A2
(157-166) YLQLVFGIEV (SEQ ID NO:247) MAGE-A3 (167-176) MEVDPIGHLY
(SEQ ID NO:248) MAGE-A3 (195-203) IMPKAGLLI (SEQ ID NO:249) MAGE-A4
Antigen (230-239), human GVYDGREHTV (SEQ ID NO:251) MAGE-C2
(336-344) ALKDVEERV (SEQ ID NO:251) Malaria CSP (334-342) YLKKIKNSL
(SEQ ID NO:252) Maspin Reactive Site Loop (RSL), (330-345)
GGDSIEVPGARILQHK (SEQ ID NO:253) Melan-A/MART-1 (24-34) AEEAAGIGILT
(SEQ ID NO:254) Melanoma Antigen Family A 3 (196-204); MAGE-3
(196-204) MPKAGLLII (SEQ ID NO:255) Melanoma Antigen Family A 8
(115-123); MAGE-8 (115-123) KVAELVRFL (SEQ ID NO:256) Melanoma
Antigen Family A 9B (223-231), MAGE-9B (223-231) ALSVMGVYV (SEQ ID
NO:257) Melanosomal Antigen II DAEKCDKTDEY (SEQ ID NO:234) MUC-1
(9-17) STAPPAHGV (SEQ ID NO:258) MUC1, tandem repeat fragment
PDTRPAPGSTAPPAHGVTSA (SEQ ID NO:259) MUC5AC3 GT-T*-PSPVPTTSTTSAP
(SEQ ID NO:260) MUC5AC, Analog 1 GTTPSPVPTTSTTSAP (SEQ ID NO:261)
MUC5AC, Analog B TTSTTSAPTTS (SEQ ID NO:262) MUC5AC-13
GTTPSPVPTTST-T*-SAP (SEQ ID NO:263) MUC5AC-3/13
GT-T*-PSPVPTTST-T*-SAP (SEQ ID NO:264) MUM-1(261-69) EEKLIVVLF (SEQ
ID NO:265) MycC Peptide YEQLRNSRA (SEQ ID NO:266) MZ2-F YRPRPRRY
(SEQ ID NO:267) NES Adenoviral E1A VMLAVQEGIDL (SEQ ID NO:268) NES
Nmd3p (491-500) INIDELLDEL (SEQ ID NO:269) NES p120ctn
CSLEEELDVLVLDDEGG (SEQ ID NO:270) NES Topoisomerase II alpha
(1054-1066) FILEKIDGKIIIE (SEQ ID NO:271) Noxa A BH3 peptide
AELPPEFAAQLRKIGDKVYC (SEQ ID NO:272) Noxa A BH3 peptide, cell
permeable .sub.sR .sub.dR .sub.dR .sub.dR .sub.dR .sub.dR .sub.dR
.sub.dR GAELPPEFAAQLRKIGDKVYC (SEQ ID NO:273) NuBCP- A FSRSLHSLL
(SEQ ID NO:274) Nuclear Export Signal, NES HIV Rev LQLPPLERLTLD
(SEQ ID NO:275) Nuclear Export Signal, NES MAPKK ALQKKLEELELD (SEQ
ID NO:276) Nuclear Export Signal, NES p53 FRELNEALELKD (SEQ ID
NO:277) NY-ESO-1(53-62) ASGPGGGAPR (SEQ ID NO:278) ORF5 fragment
PASKKTDPQK (SEQ ID NO:279) p21 (140-147)
RKRRQTSM (SEQ ID NO:280) p53 (12-20) PPLSQETFS (SEQ ID NO:281) p53
(17-26) ETFSDLWKLL (SEQ ID NO:282) p53 (17-26), FITC labeled
FITC-LC-ETFSDLWKLL-NH2 (SEQ ID NO:283) p53 (65-73) RMPEAAPPV (SEQ
ID NO:284) p53 Mutant Form (361-371), Pab 421 KKGQSTSRHKK-NH2 (SEQ
ID NO:285) p53 Tumor Suppressor (361-393), human
GSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD (SEQ ID NO:286) p53 Tumor
Suppressor (361-393), LC-Biotin, human
Biotin-LC-GSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD-NH2 (SEQ ID NO:287)
p53, (12-26) PPLSQETFSDLWKLL (SEQ ID NO:288) Pirh2-Derived Peptide
(CDB62) (120-137) LKCNLCLTTNLRGKHKCI (SEQ ID NO:289) PNC-28, MDM
Binding Domain ETFSDLWKLLKKWKMRRNQFWVKVQRG (SEQ ID NO:290) PRAME
epitope (PRA300-309) Tumor-associated antigen ALYVDSLFFL (SEQ ID
NO:291) Pro-TGF-.alpha. HADLLAVVAASQ (SEQ ID NO:292)
Pro-TGF-.alpha. HADLLAVVAASQ (SEQ ID NO:293) Prostate Vasculature
Marker, biotin-labeled SMSIARL-K(epsilon-LC-Biotin) (SEQ ID NO:294)
Prostate-Specific Antigen, PSA propeptide APLILSR (SEQ ID NO:295)
PSA1(141-150) FLTPKKLQCV (SEQ ID NO:296) PSA2 (146-154) KLQCVDLHV
(SEQ ID NO:297) Rab24 (179-199) QVMTEDKGVDLSQKANPYFYS (SEQ ID
NO:298) Rad51 (175-190) (CDB55) AERYGLSGSDVLDNVA (SEQ ID NO:299)
Rad51 (179-190) GLSGSDVLDNVA (SEQ ID NO:300) RAGE derived peptide
SPSSNRIRNT (SEQ ID NO:301) Shepherdin (79-87) KHSSGCAFL (SEQ ID
NO:302) Stromal Target Antigen SIYYYRYGL (SEQ ID NO:303) STT
Gelatinase Inhibitor modification, negative control STTHWGFTLS (SEQ
ID NO:304) Survivin ELTLGEFLKL (SEQ ID NO:305) Survivin (85-93)
AFLSVKKQF (SEQ ID NO:306) Survivin 2B (80-88) AYACNTSTL (SEQ ID
NO:307) Telomerase Reverse Transcriptase p572Y (TERT572Y) RLFFYRKSV
(SEQ ID NO:308) TP53 Q9NP68, p53 Mutant Form (361-377), Lys371 (Ac)
KKGQSTSRHK-K(Ac)-LMFKTEG (SEQ ID NO:309) TRP-1, Fragment MSLQRQFL
(SEQ ID NO:310) TRP-2 (180-188) NEW SVYDFFVVVL (SEQ ID NO:311)
TRP-2 coding region fragment LLPGGRPYR (SEQ ID NO:312) Tumor
Necrosis Factor-a Converting Enzyme, TACE (807-823), human
ASFKLQRQNRVDSKETE (SEQ ID NO:313) Tyrosinase (146-156) SSDYVIPIGTY
(SEQ ID NO:314) Tyrosinase (192-200) SEIVVRDIDF (SEQ ID NO:315)
Tyrosinase (206-214), T9206 AFLPWHRLF (SEQ ID NO:316) Tyrosinase
(240-251) DAEKCDICTDEY (SEQ ID NO:317) Tyrosinase (450-462)
SYLQDSDPDSFQD (SEQ ID NO:318) Tyrosinase (56-70) QNILLSNAPLGPQFP
(SEQ ID NO:319) Tyrosinase(243-251), core nonamer sequence
KCDICTDEY (SEQ ID NO:320) VEGFR-2/KDR I, murine FSNSTNDILI (SEQ ID
NO:321) VEGFR-2/KDR II, murine VILTNPISM (SEQ ID NO:322) VEGFR2/KDR
Antagonist ATWLPPR (SEQ ID NO:323) WP9QY, TNF-alpha Antagonist
YCWSQYLCY (Disulfide bridge: 2-8) (SEQ ID NO:324) Human Cardiac
Troponin I (hcTnI) (39-58) SKISASRKLQLKTLLLQIAK (SEQ ID NO:325)
CART (55-102), human VPIYEKKYGQVPMCDAGEQCAVRKGARIGKLCDCPRGTSCNSFLL
KCL (Disulfide bridge: 74-94, 68-86, and 88-101) (SEQ ID NO:326)
.beta.- Casomorphin (1-7), human YPFVEPI Caspase Related Peptides
Ac-AEVD-pNA Ac-AEVD-pNA Biotin-Caspase 1 Inhibitor II
Biotin-YVAD-CMK Biotin-Caspase 1 Substrate V (SEQ ID NO:327)
Caspase 1 (ICE) Inhibitor I Ac-YVAD-CHO (SEQ ID NO:328) Caspase 1
(ICE) Substrate 1, chromogenic Ac-YEVD-pNA (SEQ ID NO:329) Caspase
1 (ICE) Substrate 1m, fluorogenic Ac-YEVD-AMC (SEQ ID NO:330)
Caspase 1 (ICE) Substrate 2, chromogenic Ac-YVAD-pNA Caspase 1
(ICE) Substrate 2f, fluorogenic Ac-YVAD-AFC Caspase 1 (ICE)
Substrate 2f, fluorogenic Ac-YVAD-AFC Caspase 1 (ICE) Substrate 2m,
fluorogenic Ac-YVAD-AMC Caspase 1 (ICE) Substrate 2r, fluorogenic
(Ac-YVAD)2-Rh110 (SEQ ID NO:331) Caspase 1 (ICE) Substrate 3f,
fluorogenic Ac-WEHD-AFC Caspase 1 (ICE) Substrate 3f, fluorogenic
Ac-WEHD- AFC (SEQ ID NO:332) Caspase 1 (ICE) Substrate 3m,
fluorogenic Ac-WEHD- AMC Caspase 1 (ICE) Substrate 3r, fluorogenic
(Ac-WEHD)2-Rh110 Caspase 1 (ICE) substrate for FRET assays DABCYL-
YVADAPV-EDANS Caspase 1 Inhibitor Caspase 1 Inhibitor I Caspase 1
Inhibitor II Ac-YVAD-CMK Caspase 1 Inhibitor IV, Boc-D-CMK
Boc-D(OBz1)-CMK Caspase 1 Inhibitor VIII Ac-WEHD-CHO (SEQ ID
NO:334) Caspase 1 Substrate III Ac-WEHD- pNA (SEQ ID NO:335)
Caspase 2 (ICH-1) Substrate 1, chromogenic Ac-VDVAD-pNA Caspase 2
(ICH-1) Substrate 1, chromogenic Ac-VDVAD-pNA Caspase 2 (ICH-1)
Substrate 1f, fluorogenic Ac-VDVAD-AFC Caspase 2 (ICH-1) Substrate
1m, fluorogenic Ac-VDVAD-AMC (SEQ ID NO:336) Caspase 2 (ICH-1)
Substrate 2, fluorogenic Mca-VDVADGWK(Dnp)- NH2 (SEQ ID NO:337)
Caspase 2 Inhibitor Ac-VDVAD-CHO (SEQ ID NO:338) Caspase 2
Substrate 3r (D)2-Rh110 Caspase 2 Substrate, chromogenic
Ac-VDQQD-pNA (SEQ ID NO:339) Caspase 3 (163-175) CRGTELDCGIETD (SEQ
ID NO:340) Caspase 3 (Apopain) Inhibitor 1 Ac-DEVD-CHO (SEQ ID
NO:341) Caspase 3 (Apopain) Inhibitor 1b Biotin-DEVD-CHO Caspase 3
(Apopain) Substrate 1, chromogenic Ac-DEVD-pNA Caspase 3 (Apopain)
Substrate 1f, fluorogenic Ac-DEVD- AFC Caspase 3 (Apopain)
Substrate 1m, fluorogenic Ac-DEVD- AMC Caspase 3 (Apopain)
Substrate 1m, fluorogenic Ac-DEVD- AMC Caspase 3 (Apopain)
Substrate 1r-z, fluorogenic (Z-DEVD)2-Rh110 Caspase 3 (Apopain)
Substrate 1z, chromogenic Z-DEVD-pNA (SEQ ID NO:342) Caspase 3
(Apopain) Substrate 2, chromogenic Ac-DQMD-pNA (SEQ ID NO:343)
Caspase 3 Inhibitor 1 Ac-DMQD-CHO (SEQ ID NO:344) Caspase 3
Substrate 1, chromogenic Ac-DMQD-pNA Caspase 3 Substrate 1f,
fluorogenic Ac-DMQD-AFC Caspase 3 Substrate 1m, fluorogenic
Ac-DMQD-AMC Caspase 3 Substrate 1r, fluorogenic (Ac-DMQD)2-Rh110
(SEQ ID NO:345) Caspase 3 Substrate, chromogenic Ac-VQVD-pNA (SEQ
ID NO:346) Caspase 4 (ICH-2) Substrate 1, chromogenic Ac-LEVD-pNA
Caspase 4 (ICH-2) Substrate 1f, fluorogenic Ac-LEVD-AFC Caspase 4
(ICH-2) Substrate 1m, fluorogenic Ac-LEVD- AMC Caspase 4 (ICH-2)
Substrate 1r, fluorogenic (Ac-LEVD)2-Rh110 (SEQ ID NO:347) Caspase
6 (Mch 2) Inhibitor 1 Ac-VEID-CHO (SEQ ID NO:348) Caspase 6 (Mch2)
Substrate 1, chromogenic Ac-VEID-pNA Caspase 6 (Mch2) Substrate 1f,
fluorogenic Ac-VEID-AFC Caspase 6 (Mch2) Substrate 1m, fluorogenic
Ac-VEID-AMC Caspase 6 (Mch2) Substrate 1r, fluorogenic
(Ac-VEID)2-Rh110 Caspase 6 (Mch2) Substrate 2, fluorogenic
Mca-VQVDGW-K(Dnp)-NH2 Caspase 6 Substrate V, fluorogenic Ac-VEHD-
AFC Caspase 8 Inhibitor 1 Ac-IETD-CHO Caspase 8 Substrate 1,
chromogenic Ac-IETD-pNA Caspase 8 Substrate 1f, fluorogenic
Ac-IETD-AFC Caspase 8 Substrate 1f-z, fluorogenic Z-IETD-AFC
Caspase 8 Substrate 1m, fluorogenic Ac-IETD-AMC Caspase 8 Substrate
1r-z, fluorogenic (Z-IEHD)2-Rh110 Caspase 8 Substrate 1r-z,
fluorogenic (Z-IETD)2-Rh110 Caspase 9 Substrate 1, chromogenic
Ac-LEHD-pNA Caspase 9 Substrate 1f, fluorogenic Ac-LEHD-AFC Caspase
9 Substrate 1r, fluorogenic (Ac-LEHD)2-Rh110 Caspase 9 Substrate
2m, fluorogenic Ac-LEHD-AMC Caspase Inhibitor II CHO Ac-VAD-CHO
Caspase Inhibitor II CMK Ac-VAD-CMK Caspase-1 Substrate V,
Fluorogenic Mca-YVADAP-K(Dnp) Caspase-1/Caspase-4 Substrate II,
Fluorogenic Ac-WVAD-AMC (SEQ ID NO:349) ICE Inhibitor I, cell
permeable Ac-AAVLPAVLLALLAPYVAD-CHO (SEQ ID NO:350) Smac N7 Protein
AVPIAQK Z-DEVD-AFC Z-DEVD-AMC (SEQ ID NO:351) 37,43Gap 27, Connexin
Mimetic SRPTEKTIFII (SEQ ID NO:352) 37, 40 GAP26, Connexin Mimetic
VCYDQAFPISHIR (SEQ ID NO:353) 40Gap 27, Connexin Mimetic
SRPTEKNVFIV (SEQ ID NO:354) 43Gap 26, Connexin Mimetic
VCYDKSFPISHVR (SEQ ID NO:355) 43Gap 36, Connexin Mimetic
KRDPCHQVDCFLSRPTEK (SEQ ID NO:356) Alpha B-Crystallin (73-92)
DRFSVNLDVKHFSPEELKVK (SEQ ID NO:357) Calreticulin (CRT) Binding
Peptide 1 GQPMYGQPMY Calreticulin (CRT) Binding Peptide 1,
biotin-labeled BIOTIN-GQPMYGQPMY (SEQ ID NO:358) DAM1 (221-241)
SFVLNPTNIGMSKSSQGHVTK (SEQ ID NO:359) Hyaluronan Inhibitor
GAHWQFNALTVR (SEQ ID NO:360) L1CD cell adhesion molecule
(1144-1163) KRSKGGKYSVKDKEDTQVDS (SEQ ID NO:361) L1FLCD (1173-1185)
FGEYRSLESDNEE (SEQ ID NO:362) pALA, Polyalanine Peptide AAADAAAAL
(SEQ ID NO:363) S1P1 VSTSIPEVKALRSSVSDYGNYDIIVRHYNYTGKLNIGAEKDHGIK
(SEQ ID NO:364) Pen2W2F, FAM Labeled 5-FAM-RQIKIFFQNRRMKFKK-NH2
(SEQ ID NO:365) Hel 11-7 NEW KLLKLLLKLWLKLLKLLL (SEQ ID NO:366)
HIV-1 Rev (34-0) TRQARRNRRRRWRERQR (SEQ ID NO:367)
HIV-1 Tat (48-60) GRKKRRQRRRPPQ (SEQ ID NO:368) Human T-cell
Lymphotrophic Virus (HTLV)-II Rex, (4-16) TRRQRTRRARRNR (SEQ ID
NO:369) Lipid Membrane Translocating Peptide KKAAAVLLPVLLAAP (SEQ
ID NO:370) Lipid Membrane Translocating Peptide, D-isomer
kkaaavilpyllaap (SEQ ID NO:371) Mastoparan INLKALAALAKKIL-NH2 (SEQ
ID NO:372) Mastoparan 7 INLKALAALAKALL-NH2 (SEQ ID NO:373)
Mastoparan X INVVKGIAAMAKKLL-NH2 (SEQ ID NO:374) MEK1 Derived
Peptide Inhibitor 1 MPKKKPTPIQLNP (SEQ ID NO:375)
Membrane-Permeable Sequence, MPS AAVALLPAVLLALLAK (SEQ ID NO:376)
MPG.DELTA.NLS, HIV related; GALFLGFLGAAGSTMGAWSQPKSKRKV (SEQ ID
NO:377) MPS-G.alpha.i2 AAVALLPAVLLALLAKNNLKDCGLF (SEQ ID NO:378)
MPS-G.alpha.i3 AAVALLPAVLLALLAKNNLKECGLY Myristoyl-MEK1 Derived
Peptide Inhibitor 1 Myr-MPKKKPTPIQLNP (SEQ ID NO:379) NGR Peptide 1
CNGRCGGklaklakklaklak-NH2 (Disulfide bridge: 1-5) (SEQ ID NO:380)
NGR Peptide 2 CNGRCGGLVTT (Disulfide bridge: 1-5) (SEQ ID NO:381)
NGR Peptide 3 CNGRC-NH2 (Disulfide bridge: 1-5) (SEQ ID NO:382) NGR
Peptide 4 CNGRCGGkklklllkll (Disulfide bridge: 1-5) (SEQ ID NO:383)
Nuclear Localiation Signal Peptide PKKKRKV (SEQ ID NO:384) P22 N
(14-30) NAKTRRHERRRKLAIER (SEQ ID NO:385) PenArg,FAM Labeled
5-FAM-RQIRIVVFQNRRMRWRR-NH2 (SEQ ID NO:386) Pep-1-Cysteamine
Ac-KETWWETVVWTEWSQPKKKRKV-cysteamine (SEQ ID NO:387) Pep-1: Chariot
(Non-Covalent Delivery of Peptides and Proteins)
KETWWETVVWTEWSQPKKKRKV (SEQ ID NO:388) phi 21 N Peptide (12-29)
TAKTRYKARRAELIAERR (SEQ ID NO:389) Phospho-IkBa-derived peptide,
FAM labeled 5-FAM-GRHDSGLD-pS-MK-NH2 (SEQ ID NO:390) Rabies Virus
Glycoprotein (RVG) YTIVVMPENPRPGTPCDIFTNSRGKRASNG (SEQ ID NO:391)
Rabies Virus Matrix Protein Fragment (RV-MAT)
MNLLRKIVKNRRDEDTQKSSPASAPLDDG (SEQ ID NO:392) Stearyl-MEK-1 Derived
Peptide Inhibitor 1, amide Ste-MPKKKPTPIQLNP-NH2 (SEQ ID NO:393)
SV-40 Large T-antigen Nuclear Localization Signal (NLS)
CGGGPKKKRKVED (SEQ ID NO:394) SV40 T-Ag-derived Nuclear
Localization Signal (NLS) Peptide PKKKRKVEDPYC (SEQ ID NO:395)
SynB1 RGGRLSYSRRRFSTSTGRA (SEQ ID NO:396) TAT (47-57) YGRKKRRQRRR
TAT (47-57) YGRKKRRQRRR TAT (47-57) GGG-Cys(Npys)
YGRKKRRQRRRGGG-C(Npys)-NH2 TAT (47-57), FAM-labeled FAM-YGRKKRRQRRR
TAT (47-57), TAMRA-labeled TAMRA-YGRKKRRQRRR TAT (47-57)-Lys(TAMRA)
YGRKKRRQRRR-K(TAMRA) (SEQ ID NO:397) Tat (48-57) GRKKRRQRRR (SEQ ID
NO:398) Tat-C (48-57) CGRKKRRQRRR (SEQ ID NO:399) Tat-NR2Bct
YGRKKRRQRRRKLSSIESDV (SEQ ID NO:400) TAT-N5F222 Fusion Peptide
YGRKKRRQRRR-GGG-LDKEFNSIFRRAFASRVFPPE (SEQ ID NO:401) TAT-NSF700
Fusion Peptide YGRKKRRQRRR-GGG-LLDYVPIGPRFSNLVLQALLVL (SEQ ID
NO:402) Transdermal Peptide ACSSSPSKHCG (SEQ ID NO:403) Transportan
GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO:404) Yeast PRP6 (129-144)
TRRNKRNRIQEQLNRK (SEQ ID NO:405) {Cys58}105Y, Cell Penetrating
Peptide, .alpha.1-antitrypsin (358-374) CSIPPEVKFNKPFVYLI (SEQ ID
NO:406) 105Y, .alpha.1-antitrypsin (359-374) SIPPEVKFNKPFVYLI (SEQ
ID NO:407) Aminopeptidase N Ligand (CD13), NGR peptide CNGRCG
(Disulfide bridge: 1-5) (SEQ ID NO:408) Antennapedia Leader Peptide
(CT) KKWKMRRNQFVVVKVQRG (SEQ ID NO:409) Antennapedia Peptide, acid
RQIKIVVFQNRRMKWKK (SEQ ID NO:410) Antennapedia Peptide, amide
RQIKIVVFQNRRMKWKK-NH2 (SEQ ID NO:411) Antennapedia Peptide,
FAM-labeled 5-FAM-RQIKIVVFQNRRMKWKK-NH2 (SEQ ID NO:412)
Anti-BetaGamma (MPS-Phosducin-like protein C terminus)
AAVALLPAVLLALLAVTDQLGEDFFAVDLEAFLQEFGLLPEKE (SEQ ID NO:413) Bcl-2
Binding Peptide, cell permeable
Decanoyl-KNLWAAQRYGRELRRMSDEFEGSFKGL (SEQ ID NO:414)
Alpha-A-Crystallin (70-88) KFVIFLDVKHFSPEDLTVK (SEQ ID NO:415)
Hsc70-binding Peptide II NIVRKKK (SEQ ID NO:416)
Cholecystokinin-Pancreozymin Peptides {Thr28,
Nle31}-Cholecystokinin (25-33), sulfated RD-Y(SO3H)-TGW-Nle-DF-NH2
(SEQ ID NO:417) Caerulein Pyr-QD-Y(SO3H)-TGWMDF-NH2 (SEQ ID NO:418)
Cholecystokinin (1-21) KAPSGRVSMIKNLQSLDPSHR (SEQ ID NO:419)
Cholecystokinin (10-20) IKNLQSLDPSH (SEQ ID NO:420) Cholecystokinin
(26-33), CCK Octapeptide, sulfated D-Y(SO3H)-MGWMDF-NH2 (SEQ ID
NO:421) Cholecystokinin (26-33), CCK8 DYMGWMDF-NH2 Cholecystokinin
(26-33), free acid DYMGWMDF (SEQ ID NO:422) Cholecystokinin
Flanking Peptide, non-sulfated SAEEYEYPS (SEQ ID NO:423)
Cholecystokinin, CCK (27-33), CCK7 YMGWMDF-NH2 (SEQ ID NO:424)
Prepro CCK fragment, V-9-M
VPVEAVDPM (SEQ ID NO:425) CRF {Tyr0}-Corticotropin Releasing
Factor, {Tyr0}-CRF, human, rat
YSEEPPISLDLTFHLLREVLEEMARAEQLAQQAHSNRKLMEII-NH2 (SEQ ID NO:426)
{Tyr0}-Corticotropin Releasing Factor, {Tyr0}-CRF, ovine
YSQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA-NH2 Biotin-Corticotropin
Releasing Factor, Biotin-CRF, human, rat
Biotin-SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII-NH2 (SEQ ID
NO:427) Corticotropin Releasing Factor, CRF, human, rat
SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII-NH2 (SEQ ID NO:428)
Somatostatin {Tyr0}-Somatostatin 28 YSANSNPAMAPRERKAGCKNFFVVKTFTSC
(Disulfide bridge: 18-29 (SEQ ID NO:429) {Tyr1}-Somatostatin 14
YGCKNFFWKTFTSC (Disulfide bridge: 3-14) (SEQ ID NO:430) Big
Endothelin-1 (1-38), human CSCSSLMDKECVYFCHLDIIVVVNTPEHVVPYGLGSPRS
(Disulfide bridge: 1-15 and 3-1) (SEQ ID NO:431) 1: VIP vasoactive
intestinal peptide isoform 1 preprotein
>gi|4507897|ref|NP_0033721| VIP peptides isoform 1 preproprotein
{Homo sapiens}
MDTRNKAQLLVLLTLLSVLFSQTSAWPLYRAPSALRLGDRIPFEGANEPDQVSLKEDIDMLQ
NALAENDTPYYDVSRNARHADGVFTSDFSKLLGQLSAKKYLESLMGKRVSSNISEDPVPVKR
HSDAVFTDNYTRLRKQMAVKKYLNSILNGKRSSEGESPDFPEELEK Residues 125-152
constitute the active form: HSDAVFTDNYTRLRKQMAVKKYLNSILN VPAC.sub.1
Interacting residues are likely (numbered from 1 using the active
sequence): H1, V5, F6, R14, K15, K21, Y22, L23, N24, and I26
VPAC.sub.2 Interacting residues are likely (numbered from 1 using
the active sequence): H1, V5, T11, R14, K15, K21, Y22, L23, I26 and
N28 (SEQ ID NO:432) 2: VIP vasoactive intestinal peptide isoform 2
preprotein >gi|37588853|ref|NP_9194161| VIP peptides isoform 2
preproprotein {Homo sapiens}
MDTRNKAQLLVLLTLLSVLFSQTSAWPLYRAPSALRLGDRIPFEGANEPDQVSLKEDIDMLQ
NALAENDTPYYDVSRNARHADGVFTSDFSKLLGQLSAKKYLESLMGKRVSNISEDPVPVKR
HSDAVFTDNYTRLRKQMAVKKYLNSILNGKRSSEGESPDFPEELEK Residues 124-151
constitute the active form: HSDAVFTDNYTRLRKQMAVKKYLNSILN VPAC.sub.1
Interacting residues are likely (numbered from 1 using the active
sequence): H1, V5, F6, R14, K15, K21, Y22, L23, N24, and I26
VPAC.sub.2 Interacting residues are likely (numbered from 1 using
the active sequence): H1, V5, T11, R14, K15, K21, Y22, L23, I26 and
N28 (SEQ ID NO:433) 3 VIP Synthetic sequence 1
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY(Bay55-9837) (SEQ ID NO:434) 4 VIP
Synthetic sequence 2 HADAVFTAAYARIAKQMAAKKALAAIAA (10Ala) (SEQ ID
NO:435) 5 VIP Synthetic sequence 3 HSDAVFTDNYARLRKQMAVKKALNSILA
(3Ala) (SEQ ID NO:436) 6 VIP Synthetic sequence 1
YFDAIFTNSYRKVLGQLSARKLLQDIMSR AcYF-GRF1-29 (SEQ ID NO:437) 7, VIP
Synthetic sequence 2 FTDNYTRLRKQMAVKKYLNSILN VIP 6-28 (SEQ ID
NO:438) 8 VIP Synthetic sequence 3 HSDAVFTDNYTRLRKQLAVKKYLNSILN
(F-6+32p-Cl-dF) (SEQ ID NO:439) 9 VIP Synthetic sequence
Ac-HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:440) 10 VIP Synthetic
sequence HTDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:441) 11 VIP
Synthetic sequence HSEAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:442)
12 VIP Synthetic sequence HSDAVFTDQYTRLRKQVAAKKYLQSIKQKRY (SEQ ID
NO:443) 13 VIP Synthetic sequence HTEAVFTDNYTRLRKQVAAKKYLQSIKNKRY
(SEQ ID NO:444) 14 VIP Synthetic sequence
HTEAVFTDQYTRLRKQVAAKKYLQSIKQKRY (SEQ ID NO:445) 15 VIP Synthetic
sequence Ac-HTDAVFTDQYTRLRKQVAAKKYLQSIKQKRY (SEQ ID NO:446) 16 VIP
Synthetic sequence HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYC (SEQ ID NO:447)
17 VIP Synthetic sequence HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYC-PEG22kD
(SEQ ID NO:448) 18 VIP Synthetic sequence
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYC-PEG43kD (SEQ ID NO:449) 19 VIP
Synthetic sequence HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYSWC (SEQ ID
NO:450) 20 VIP Synthetic sequence
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYSWC-PEG22kD (SEQ ID NO:451) 21 VIP
Synthetic sequence HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYSWC-PEG43kD (SEQ
ID NO:452) 22 VIP Synthetic sequence
HSDAVFTDQYTRLRKQVAAKKYLQSIKQKRYC (SEQ ID NO:453) 23 VIP Synthetic
sequence HSDAVFTDQYTRLRKQVAAKKYLQSIKQKRYC-PEG22kD (SEQ ID NO:454)
24 VIP Synthetic sequence HSDAVFTDQYTRLRKQVAAKKYLQSIKQKRYC-PEG43kD
(SEQ ID NO:455) 25 VIP Synthetic sequence
Ac-HSDAVFTENYTKLRKQN.sub.leAAKK*YLNDIKKGGT(Ro25-1553) (SEQ ID
NO:456) 26 VIP Synthetic sequence
Ac-HSDAVFTENY.sub.MTKLRKQN.sub.leAAKK*YLND*LKK (Ro 25-1392) (SEQ ID
NO:457) 27 VIP Synthetic sequence HSDAVFTDNYTRLRRQLAVRRYLNSILNGRR
(LK312532) (SEQ ID NO:458) 28 VIP Synthetic sequence
Ac-H.sub.dFDAVFTNSYRKVLKRLSARKLLQDIL (PG 97-269) (SEQ ID NO:459) 29
VIP Synthetic sequence HSDAVFTNSYRKVLKRLSARKLLQDIL(k15r16127VIP
GFR) (SEQ ID NO:460) 30 VIP Synthetic sequence
H.sub.dADAIFTA.sub.ibAYRKVLAALA.sub.ibARKALAAAG.sub.ab(GER-6) (SEQ
ID NO:461) 31 VIP Synthetic sequence HSDGITTSEYSKMRGRAQVQKFIQNLM
(R16-chicken) (SEQ ID NO:462) 32 VIP Synthetic sequence
HSDAVFTDYYTRLRKQMD.sub.ipVKKYLNSILN (y9Dip18-VIP) (SEQ ID NO:463)
33 VIP Synthetic sequence FTDYYTRLRKQMD.sub.ipVKKYLNSILN
(y9Dip18-VIP) (SEQ ID NO:464) 34 VIP Synthetic sequence
HSDAVFTDNYTK.sub.mLRKQMAVKKYLNSIKKGGT (SEQ ID NO:465) 35 VIP
Synthetic sequence Ac-HSDAVFTNSYRKVLKRLSARKLLQDIL (PG 97-268) (SEQ
ID NO:466) 36 VIP Synthetic sequence
Ac-HDAI.sub.dRTNSYRKVLKRLSAKKYLQDN.sub.ledR.sub.hR (JV-1-53?) (SEQ
ID NO:467) 37 VIP Synthetic sequence
AC-H.sub.dFDAIF.sub.4clTNRYRKVLA.sub.buQLSARKLLQDINleDR.sub.hR
(JV-1-51) (SEQ ID NO:468) 38 VIP synthetic sequence
HSDAVFTDQYTRLRKQLAAKKYLQSLKKKRY (RBAYL) (SEQ ID NO:469) 39 VIP
synthetic sequence HSDAVFTDNYTRLRKQVAAKKYLQSLKNKRY (rBAY) (SEQ ID
NO:470) 40 VIP synthetic sequence
Hexanoyl-HSDAVFTDNYTRLRKQMAVKKYLNSILN (c6VIP) (SEQ ID NO:471) 41
VIP synthetic sequence Hexanoyl-HSDAVETDNYTRLRKQMAAKKYLNSIKK
(c6a19k27k28-VIP) (SEQ ID NO:472)
HSDAVFTEQY(OMe)TRAibRAibQLAAAibOrnY(OMe)LQSIK AibOrn (SEQ ID
NO:473) HSDAVFTEK(CO(CH2)2SH)Y(OMe)TOrnLRAibQVAAAibOrn YLQSIOrnOrn
(SEQ ID NO:474) HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLOSIOrnK(W) Orn
(SEQ ID NO:475)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibK(CO(CH.sub.2).sub.2SH)YLQ SIOrnOrn
(SEQ ID NO:476) HSDAVFTEQY(OMe)TOrnLRAibQVAAK
CO(CH.sub.2).sub.2SH)OrnYLQ SIOrnOrn (SEQ ID NO:477)
HSDAVFTEQY(OMe)TOrnLRAibQVCAAibOrnYLOSIOrnOrn (SEQ ID NO:478)
HSDAVFTEQY(OMe)TOrnLRCQVAAAibOrnYLOSIOrnOrn (SEQ ID NO:479)
HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYLQSIOrnOrn (SEQ ID NO:480)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYAibQSIOrnOrn (SEQ ID NO:481)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLQAibIOrnOrn
(SEQ ID NO:482) HSDAVFTEQY(OMe)TOrnLRAibQVAAbuAibOrnYLQAibIOrnOrn
(SEQ ID NO:483) HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYLQAibIOrnOrn
(SEQ ID NO:484) HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYAibQAibIOrnOrn
(SEQ ID NO:485) HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYAibQSIOrnOrn
(SEQ ID NO:486) HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSIOrnOrn
(SEQ ID NO:487) HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYAibQAibIOrn
Orn (SEQ ID NO:488) HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYAibQSIOrnOrn
(SEQ ID NO:489) HSDAVFTEQY(OMe)TOrnLRK(W)QVAAAibOrnYLQSIOrnOrn (SEQ
ID NO:490) HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLK(W)SIOrnOrn (SEQ ID
NO:491) HSDAVFTEQY(OMe)TOrnLRAibQK(W)AAAibOrnYLQSIOrnOrn (SEQ ID
NO:492) HSDAVFTEQY(OMe)TOrnLRK CO(CH.sub.2).sub.2SH)QVAAAibOrnYLQ
SIOrnOrn (SEQ ID NO:493)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibK(W)YLQSIOrnOrn (SEQ ID NO:494)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibCYLQSIOrnOrn (SEQ ID NO:495)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibIOrnOrn (SEQ ID NO:496)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLQSK(W)OrnOrn (SEQ ID NO:497)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibIOrnC Orn (SEQ ID NO:498)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibCOrn Orn (SEQ ID NO:499)
HSDAVFTEQY(OMe)TOrnLRAibQCAAbuAibOrnYLQAibIOrnOrn (SEQ ID NO:500)
HSDAVFTEQY(OMe)TOrnLRCQLAAbuAibOrnYLQAibIOrnOrn (SEQ ID NO:501)
HSDAVFTEQY(OMe)TOrnLRAibQVK CO(CH.sub.2).sub.2SH)AAibOrn
YLQSIOrnOrn (SEQ ID NO:502)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSIOrnCOrn (SEQ ID NO:503)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSCOrnOrn (SEQ ID NO:504)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibIOrn K
CO(CH.sub.2).sub.2SH)Orn (SEQ ID NO:505)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSIOrn K
CO(CH.sub.2).sub.2SH)Orn (SEQ ID NO:506)
HSDAVFTEQY(OMe)TOrnLRK(W)QLAAbuAibOrnYLQAibIOrn Orn (SEQ ID NO:507)
HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYLQSIOrnOrnC (SEQ ID NO:508)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLQSIOrnOrnC (SEQ ID NO:509)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSIOrnOrnC (SEQ ID NO:510)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnY(OMe)LQAibI OrnOrn (SEQ ID
NO:511) HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnY(OMe)LQAibI OrnCOrn
(SEQ ID NO:512) HSDAVFTEQY(OMe)TOrnLRAibQCAAbuAibOrnY(OMe)LQAibI
OrnOrn (SEQ ID NO:513)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibIOrn OrnC (SEQ ID NO:514)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnY(OMe)LQSI OrnOrn (SEQ ID
NO:515) HSDAVFTEQY(OMe)TOrnLRAibQCAAbuAibOrnY(OMe)LQSI OrnOrn (SEQ
ID NO:516) HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnY(OMe)LQSI OrnCOrn
(SEQ ID NO:517) HSDAVFTEQY(OMe)TOrnLRAibQLAbuAAibOrnYLQSIOrnOrn
(SEQ ID NO:518) HSDAVFTEQY(OMe)TOrnLRAibQK
CO(CH.sub.2).sub.2SH)AAbu AibOrnYLQAibIOrnOrn (SEQ ID NO:519)
HSDAVFTEQY(OMe)TOrnLRAibQK(W)AAbuAibOrnYLQ AibIOrnOrn 3 pituitary
adenylate cyclase-activating polypeptide precursor {Homosapiens}
>gi|153266792|ref|NP_0010932031|pituitary adenylate
cyclase-activating polypeptide precursor {Homosapiens} (SEQ ID
NO:520)
MTMCSGARLALLVYGIIMHSSVYSSPAAAGLRFPGIRPEEEAYGEDGNPLPDFDGSEPPGAGS
PASAPRAAAAWYRPAGRRDVAHGILNEAYRKVLDQLSAGKHLQSLVARGVGGSLGGGAGD
DAEPLSKRHSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNKGRRIAYL Residues
132-158 constitute the active form PACAP-27:
HSDGIFTDSYSRYRKQMAVKKYLAAVL Residues 132-158 constitute the active
form PACAP-38: HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK 4 pituitary
adenylate cyclase-activating polypeptide precursor {Homosapiens}
(SEQ ID NO:521) >gi|153266795|ref|NP_0011082| pituitary
adenylate cyclase-activating polypeptide precursor {Homosapiens }
MTMCSGARLALLVYGIIMHSSVYSSPAAAGLRFPGIRPEEEAYGEDGNPLPDFDGSEPPGAGS
PASAPRAAAAWYRPAGRRDVAHGILNEAYRKVLDQLSAGKHLQSLVARGVGGSLGGGAGD
DAEPLSKRHSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNKGRRIAYL Residues
132-158 constitute the active form PACAP-27:
HSDGIFTDSYSRYRKQMAVKKYLAAVL Residues 132-158 constitute the active
form PACAP-38: HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK (SEQ ID
NO:522) 39 PACAP-Antagonist FTSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK (SEQ
ID NO:523) 40 Maxadilan peptide >US6462016_1 Sequence 1 from
Patent US 6462016 inClaims gi: 27279414
CDATCQERKAIDDCQKQAHHSNVLQTSVQTTATETSMDTSQLPGNSVEKECMKQKKKEEKA (SEQ
ID NO:525) 40 Maxadilan peptide 2
CDATCQERKAIDDCQKQAHHSNVLQTSVQTTATETSMDTSQLPGNSVEKECMKQKKKEESS GK
(SEQ ID NO:525) 40 M65 peptide
CDATCQERKAIDDCQKQAHHSNVLPGNSVEKECMKQKKKEEKA (SEQ ID NO:526) 40 M65
peptide v2 CDATCQERKAIDDCQKQAHHSNVLGNSVEKECMKQKKKEEKA (SEQ ID
NO:527) 41 M65 peptide >U56462016_10 Sequence 10 from Patent US
6462016 inClaims gi: 27279423
GSCDATCQERKAIDDCQKQAHHSNVPGNSVEKECMKQKKKEEKAGK The contents of this
Table 4 also include relate to analogs comprising any agonist
listed in US2009-US Application Serial \10/586124, filed on Jun 24,
2008 5 glucagon preproprotein gi|4503945|ref|NP_0020451| glucagon
preproprotein {Homosapiens} (SEQ ID NO:528)
MKSIYEVAGLEVMLVQGSWQRSLQDTEEKSRSESASQADPLSDPDQMNEDKRHSQGTETSD
YSKYLDSRRAQDEVQWLMNTKRNRNNIAKRHDEFERHAEGTETSDVSSYLEGQAAKEFIAW
LVKGRGRRDEPEEVAIVEELGRRHADGSFSDEMNTILDNLAARDEINWLIQTKITDRK (SEQ ID
NO:529) Residues 21-50 constitute an active form Glicentin-related
polypeptide (GRPP): RSLQDTEEKSRSFSASQADPLSDPDQMNED (SEQ ID NO:530)
Residues 53-81 constitute an active form Glucagon:
HSQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO:531) Residues 92-128
constitute the pro-form of GLP-1
HDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG Residues 98 - 128 constitute
an active form of GLP-1 HAEGTETSDVSSYLEGQAAKEFIAWLVKGRG Residues
98-125 constitute an active form of GLP-1
HAEGTETSDVSSYLEGQAAKEFIAWLVK (SEQ ID NO:532) Residues 146-178
constitute an active form GLP-2: HADGSFSDEMNTILDNLAARDEINWLIQTKITD
(SEQ ID NO:533) 6 Apolipoprotein-mimetic peptide (D4F,
DWFKAFYDKVAEKFKEAF) and other family members: (SEQ ID NO:534) 3F-2
(Ac-DKWKAVYDKFAEAFKEFL-NH2) (SEQ ID NO:535) 3F14
(Ac-DWLKAFYDKVAEKFREAF-NH2 The baseline sequence of 18A is
DWLKAFYDKVAEKLKEAF Ac-18A-NH2 Ac-{F318A}NH2 Ac-{F1418A}NH2
Ac-}F3,1418A}NH2 Ac-{F11,14,1718A}NH2 Ac-{F10,11,14,1718A}NH2
Ac-{F3,10,11,14,1718A}NH2 4F=Ac-DWEKAFYDKVAEKEKEAF-NH2 (18 mer)
4F-KVEPIRA-4F (43 mer) 4F-P-4F (37 mer) 4F-A-4F (37 mer)
apoA-IMilano (R173C) and apoA-IParis (R151C) apolipoprotein A-I
{Homosapiens (SEQ ID NO:536) gi|4557321|ref|NP_0000301|
apolipoprotein A-I preproprotein {Homosapiens}
MKAAVLTLAVLFLTGSQARHFVVQQDEPPQSPWDRVKDLATVYVDVLKDSGRDYVSQFEGS
ALGKQLNLKLLDNWDSVTSTFSKLREQLGPVTQEFVVDNLEKETEGLRQEMSKDLEEVKAKV
QPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLGEEMRDRARAHVD
ALRTHLAPYSDELRQRLAARLEALKENGGARLAEYHAKATEHLSTLSEKAKPALEDLRQGL
LPVLESFKVSFLSALEEYTKKLNTQ I apolipoprotein E {Homosapiens} (SEQ ID
NO:537) >gi|178853|gb|AAB593971| apolipoprotein E {Homosapiens}
MKVLWAALLVTFLAGCQAKVEQAVETEPEPELRQQTEWQSGQRWELALGRFWDYLRWVQ
TLSEQVQEELLSSQVTQELRALMDETMKELKAYKSELEEQLTPVAEETRARLSKELQAAQAR
LGADMEDVRGRLVQYRGEVQAMLGQSTEELRVRLASHLRKLRKRLLRDADDLQKRLAVY
QAGAREGAERGLSAIRERLGPLVEQGRVRAATVGSLAGQPLQERAQAWGERLRARMEEMG
SRTRDRLDEVKEQVAEVRAKLEEQAQQIRLQAEAFQARLKSWFEPLVEDMQRQWAGLVEK
VQAAVGTSAAPVPSDNH II Ac-L V GRQLEEFL-NH III
Ac-LLEQLNEQFNWVSRLANLTQGE-NH2 Ac--PSGVTEVVVKLFDS-NHsub2 IV Ac-Q
QTHMLDVMQD-NHsub2 V Apolipoprotein C-I {Homosapiens} (SEQ ID
NO:538) >gi|32822890|gb|AAH550931| Apolipoprotein C-I
{Homosapiens}
MRLFLSLPVLVVVLSIVLEGPAPAQGTPDVSSALDKLKEFGNTLEDKARELISRIKQSELSAK
MREWFSETFQKVKEKLKIDS VI apolipoprotein I {Homosapiens} (SEQ ID
NO:539) >gi|27373753|gb|AAN873471| apolipoprotein J
{Homosapiens}
CSTNNPSQAKLRRELDESLQVAERLTRKYNELLKSYQWKMLNTSSLLEQLNEQFNVVVSRLA
NLTQGEDQYYLRVTT apoJ peptide
336--D-J336+32Ac-LLEQLNEQFNVVVSRLANTQGE-NH.sub.2 (SEQ ID NO:540)
ANP >gi|23510319|ref|NP_0061631| atrial natriuretic factor
preproprotein {Homo sapiens}
MSSFSTTTVSFLLLLAFQLLGQTRANPMYNAVSNADLMDFKNLLDHLEEKMPLEDEVVPPQ
VLSEPNEEAGAALSPLPEVPPWTGEVSPAQRDGGALGRGPWDSSDRSALLKSKLRALLTAPR
SLRRSSCFGGRMDRIGAQSGLGCNSFRY (SEQ ID NO:541) Active form:
RSLRRSSCFGGRMDRIGAQSGLGC (SEQ ID NO:542) Active form:
RSLRRSSCFGGRMDRIGAQSGLGCNSFRY (SEQ ID NO:543) Active form:
SLRRSSCFGGRMDRIGAQSGLGCNSFRY (SEQ ID NO:544) cardiodilatin
>gi|23510319:26-92 atrial natriuretic factor preproprotein
{Homosapiens}
NPMYNAVSNADLMDFKNLLDHLEEKMPLEDEVVPPQVLSEPNEEAGAALSPLPEVPPWTGE
VSPAQR (SEQ ID NO:545) BNP natriuretic peptides B preproprotein
{Homosapiens} >gi|4505433|ref|NP_0025121| natriuretic peptides B
preproprotein {Homo sapiens}
MDPQTAPSRALLLLLFLHLAFLGGRSHPLGSPGSASDLETSGLQEQRNHLQGKLSELQVEQTS
LEPLQESPRPTGVVVKSREVATEGIRGHRKMVLYTLRAPRSPKMVQGSGCFGRKMDRISSSSG
LGCKVLRRH (SEQ ID NO:546) Active form:
SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH (SEQ ID NO:547) CNP natriuretic
peptide precursor C precursor {Homosapiens}
>gi|13249346|ref|NP_0777201| natriuretic peptide precursor C
precursor {Homo sapiens}
MHLSQLLACALLLTLLSLRPSEAKPGAPPKVPRTPPAEELAEPQAAGGGQKKGDKAPGGGG
ANLKGDRSRLLRDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSM SGLGC
(SEQ ID NO:548) Active form: GLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO:549)
urodilatin >gi|226320|prf||1506430A urodilatin
TAPRSLRRSSCFGGRMDRIGAQSGLGCNSFRY (SEQ ID NO:550) Urodilatin
RPATSLRRSSCFGGRMDRIGAQSGLGCNSFRY (SEQ ID NO:551) neuropeptide Y
preproprotein {Homosapiens} >gi|4505449|ref|NP_0008961|
neuropeptide Y preproprotein {Homosapiens}
MLGNKRLGLSGLTLALSLLVCLGALAEAYPSKPDNPGEDAPAEDMARYYSALRHYINLITRQ (SEQ
ID NO:552) RYGKRSSP (SEQ ID NO:553) ETLISDLLMRESTENVPRTRLEDPAMW
(SEQ ID NO:554) Active form: >gi|4505449:29-64 neuropeptide Y
preproprotein {Homosapiens} YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY
PYY peptide YY precursor {Homosapiens} (SEQ ID NO:555)
>gi|71361686|ref|NP_0041512| Human peptide YY precursor
MVFVRRPWPALTTVLLALLVCLGALVDAYPIKPEAPREDASPEELNRYYASLRHYLNLVTRQ (SEQ
ID NO:556) RYGKRDGP (SEQ ID NO:557) DTLLSKTFFPDGEDRPVRSRSEGPDLW
(SEQ ID NO:558) Active form: IKPEAPREDASPEELNRYYASLRHYLNLVTRQRY
(SEQ ID NO:559) Active form: IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY
(SEQ ID NO:560) Active form: YPIKPEAPREDASPEELNRYYASLRHYLNLVTRQRY
(SEQ ID NO:561) Active form: YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY
adrenomedullin {Homosapiens} (SEQ ID NO:562) Active form:
YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY (SEQ ID
NO:563) Pro-Adrenomedullin (N-20): ARLDVAAEFRKKWNKWALSR (SEQ ID
NO:564) PrePro-Adrenornedullin:
ELRMSSSYPTGLADVKAGPAQTLIRPQDMKGASRSPEDSSPDAARTRV (SEQ ID NO:565)
Ghrelin analog, sequences {Ala1, D-Trp2,4, Leu6}-Ghrelin Receptor
Agonist AwFwLL (SEQ ID NO:566) {D-Trp1,3, Leu5}-Ghrelin Core-Ligand
wFwLL (SEQ ID NO:567) {Des-octanoyl}-Ghrelin, human
GSSFLSPEHQRVQQRKESKKPPAKLQPR (SEQ ID NO:568) Biotin-GS-S
(n-octanoyl)-FLSPEHQRVQQRKESKKPPAKLQPR
FAM-GS-S(n-octanoyl)-FLSPEHQRVQQRKESKKPPAKLQPR
TAMRA-GS-S(n-octanoyl)-FLSPEHQRVQQRKESKKPPAKLQPR (SEQ ID NO:569)
human Obestatin analog seteteences FNAPFDVGIKLSGVQYQQHSQAL-NH2 (SEQ
ID NO:570) PTH analog sequences Parathyroid Hormone (1-34), human
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVIINF (SEQ ID NO:571) Parathyroid
Hormone (1-34), human, biotinylated
Biotin-SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF Parathyroid Hormone (1-34
human, C-Terminal FAM-labeled
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFK(FAM) Parathyroid Hormone
(1-34)-Lys(Biotin), human
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFK(Biotin) Parathyroid Hormone
(1-34)-Lys(Biotin), human, FAM-labeled
FAM-SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFK(Biotin) (SEQ ID NO:572)
Parathyroid Hormone-Related Protein, PTHrP (107-111) TRSAW (SEQ ID
NO:573) TIP 39, Tuberoinfundibular Neuropeptide
SLALADDAAFRERARLLAALERRHWLNSYMHKLLVLDAP (SEQ ID NO:574)
Hypercalcemia Malignancy Factor (1-40)
AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATS (SEQ ID NO:575) Acetalin
analog sequences Acetalin 1, Opioid Receptor Antagonist 1
Ac-RFMWMR-NH2 (SEQ ID NO:576) Acetalin 2, Opioid Receptor
Antagonist 2 Ac-RFMWMK-NH2 (SEQ ID NO:577) Acetalin 3, Opioid
Receptor Antagonist 3 Ac-RFMWMT-NH2 (SEQ ID NO:578) ACTH analog
sequences {Glu10}-ACTH (1-17) SYSMEHFRWEKPVGKKR (SEQ ID NO:579)
{Phe2, Nle4}-ACTH (1-24) SFS-Nle-EHFRWGKPVGKKRRPVKVYP (SEQ ID
NO:580) ACTH (1-10) SYSMEHFRWG (SEQ ID NO:581) ACTH (1-13), human
SYSMEHFRWGKPV (SEQ ID NO:582) ACTH (1-24), human
SYSMEHFRWGKPVGKKRRPVKVYP (SEQ ID NO:583) ACTH (1-39), human
SYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF (SEQ ID NO:584) ACTH
(18-39), human (CLIP) RPVKVYPNGAEDESAEAFPLEF (SEQ ID NO:585) ACTH
(22-39) VYPNGAEDESAEAFPLEF (SEQ ID NO:586) ACTH (7-38), human
FRWGKPVGKKRRPVKVYPNGAEDESAEAFPLE Biotin-ACTH (1-39), human
Biotin-SYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF (SEQ ID NO:587)
Sauvagine Pyr-GPPISIDLSLELLRKMIEIEKQEKEKQQAANNRLLLDTI-NH2 (SEQ ID
NO:588) AGRP (25-51) LAPMEGIRRPDQALLPELPGLGLRAPL (SEQ ID NO:589)
AGRP (54-82)
TTAEQAEEDLLQEAQALAEVLDLQDREPR (SEQ ID NO:590) AGRP (87-132), human
Ac-CVRLHESCLGQQVPCCDPCATCYCRFFNAFCYCRKLGTAMNPCSRT (SEQ ID NO:591)
AGRP fragment (83-132), amide
SSRRCVRLHESCLGQQVPCCDPCATCYCRFFNAFCYCRKLGTAMNPCSRT-NH2 (5 disulfide
bridges (SEQ ID NO:592) Allatostatin I (free acid) APSGAQRLYGFGL
(SEQ ID NO:593) Allatostatin I, Dip-AST7, cockroach
APSGAQRLYGFGL-NH2 (SEQ ID NO:594) Allatostatin II GDGRLYAFGL-NH2
(SEQ ID NO:595) Allatostatin III GGSLYSFGL-NH2 (SEQ ID NO:596)
Altatostatin IV DRLYSFGL-NH2 (SEQ ID NO:597) Allatostatin VI
YPQEHRFSFGL-NH2 (SEQ ID NO:598) Allatostatin VII DGRMYSFGL-NH2 (SEQ
ID NO:599) Allatotropin, Mas-AT GFKNVEMMTARGF-NH2 (SEQ ID NO:600)
{Ala16, 17, 20}-beta- Amyloid (1-28) DAEFRHDSGYEVHHQAAVFAAEDVGSN
(SEQ ID NO:601) {Gln22}-beta-Amyloid (15-23) QKLVFFAQD (SEQ ID
NO:602) {NMeG24, NMeI26} Human Islet Amyloid Polypeptide (IAPP)
(22-27) NF-(NMe-G)-A-(NMe-I)-L (SEQ ID NO:603) Amylin (1-13), human
KCNTATCATQRLA (Disulfide bridge: 2-7) (SEQ ID NO:604) Amylin
(1-37), human KCNTATCATQRLANFLVHSSNNFGAILSSTVGSNTY (Disulfide
bridge: 2-7) (SEQ ID NO:605) Amylin (20-29), human SNNFGAILSS (SEQ
ID NO:606) Amylin (8-37), human ATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2
(SEQ ID NO:607) Beta-Amyloid (12-24) VHHQKLVFFAEDV (SEQ ID NO:608)
Beta-Amyloid (13-23) HHQKLVFFAED (SEQ ID NO:609) Beta-Amyloid
(7-29) DSGYEVHHQKLVFFAEDVGSNKG (SEQ ID NO:610) Angiotensin
{Des-Asp1}-Angiotensin I, human RVYIHPFHL (SEQ ID NO:611) {Sar1,
Ala8}-Angiotensin II Sar-RVYIHPA (SEQ ID NO:612) {Sar1, Va15,
A1a8}-Angiotensin II, Saralasin Sar-RVYVHPA Angiotensin Converting
Enzyme Inhibitor, BPP 9a Pyr-WPRPQIPP (SEQ ID NO:613) Angiotensin I
Converting Enzyme 2, ACE-2/Caspase-1 Substrate Mca-YVADAPK(Dnp)
(SEQ ID NO:614) Angiotensin I human DRVYIHPFHL (SEQ ID NO:615)
Angiotensin II Antipeptide EGVYVHPV (SEQ ID NO:616) Angiotensin
I/II (3-8) VYIHPF (SEQ ID NO:617) Angiotensin I/II (4-8) YIHPF (SEQ
ID NO:618) Angiotensin I/II (5-8) IHPF (SEQ ID NO:619) Angiotensin
II Substrate DRV-pY-IHPF (SEQ ID NO:620) Angiotensin II, human
DRVYIHPF (SEQ ID NO:621) Angiotensin III RVYIHPF (SEQ ID NO:622)
Prorenin Peptide (33-42) RIFLKRMPSI (SEQ ID NO:623) Renin
Substrate, human DRVYIHPFHLVIHN (SEQ ID NO:624) Renin Inhibitor III
RRPFH-Sta-IHK-NH2 (SEQ ID NO:625) Annexin 1 (ANXA-1, Ac 2-12)
Ac-AMVSEFLKQAW (SEQ ID NO:626) Anti-Inflammatory Peptide 1
MQMKKVLDS (SEQ ID NO:627) Anti-Inflavornatory Peptide 2 HDMNKVLDL
(SEQ ID NO:628) Anti-Inflammatory Peptide 3 MQMNKVLDS (SEQ ID
NO:629) Interleukin-6 Receptor Peptide TSLPVQDSSSVP WP9QY,
TNF-alpha Antagonist YCWSQYLCY (Disulfide bridge: between amino
acid numbers between 2 8) (SEQ ID NO:630) {A1a13}-Apelin-13
QRPRLSHKGPMPA (SEQ ID NO:631) {Phe17}-Apelin 17 KFRRQRPRLSHKGPMPF
(SEQ ID NO:632) {Pyr1}-Apelin-13 Pyr-RPRLSHKGPMPF-OH (SEQ ID
NO:633) Apelin 12 RPRLSHKGPMPF (SEQ ID NO:634) Apelin-15 (63-75)
RRQRPRLSHKGPM (SEQ ID NO:635) Apelin-16, human, bovine
FRRQRPRLSHKGPMPF (SEQ ID NO:636) Apelin-36, human
LVQPRGSRNGPGPWQGGRRKFRRQRPRLSHKGPMPF (SEQ ID NO:637) Bak BH3, Bcl2
(72-87) KGGGQVGRQLAIIGDDINR) Bcl 9-2
GSEGLSKEQLEHRERSLQTLRDIERLLLRSGETEPFLKGPPGGAG-NH2 (SEQ ID NO:638)
PR39, Anti-Apoptotic Factor RRRPRPPYLPRPRPPPFFPPRLPPRIPPGFPPRFPPRFP
(SEQ ID NO:639) Proapoptotic Peptide, (klaklak)2
klaklakklaklak-NH2, wherein all amino acid residues are D-amino
acid residues (SEQ ID NO:640) PUMA BH3 EEQWAREIGAQLRRMADDLNAQYER
(SEQ ID NO:641) RGD-targeted Proapoptotic Peptide
ACDCRGDCFC-GG-klaklakklakak-NH2 (S-S bonded C1-C4 & C2-C3) (SEQ
ID NO:642) 26Rfa, Hpothalamic Peptide, human
TSGPLGNLAEELNGYSRKKGGFSFRF-NH2 (SEQ ID NO:643) Catch-Relaxing
Peptide (CARP) AMPMLRL-NH2 (SEQ ID NO:644) Neuropeptide AF (hNPAF),
Human AGEGLNSQFWSLAAPQRF-NH2 (SEQ ID NO:646) NPSF (1-37),
Neuropeptide SF (1-37) SLNFEELKDWGPKNVIKMSTPAVNKMPHSFANLPLRF-NH2
(SEQ ID NO:646) AKH/RPCH family of arthropod neuropeptides LOCUST
(AKH-I): pELNFTPNWGT (SEQ ID NO:647) CARAUSIUS (HTF-II):
pELTFTPNWGT (SEQ ID NO:648) SYNTHETIC: LTFTPNWGT (SEQ ID NO:649)
SYNTHETIC: pELTFTPNWG Mandauca/Heliothis (AKH) pELTFTSSWG
(SEQ ID NO:650) CRUSTACEAN (RPCH) pELNFSPGW (SEQ ID NO:651) LOCUSTA
(AKH-II) pELNFSAGW (SEQ ID NO:652) SCHISTOCERCA pELNFSTGW (SEQ ID
NO:653) PERIPLANETA M-I pEVNFSPNW (SEQ ID NO:654) PERIPLANETA M-II
pELTFTPNW (SEQ ID NO:655) NEUPHOETA/BLABERUS HTH pEVNFS PGWT (SEQ
ID NO:656) ROMALEA-I pEVNFTPNWGT (SEQ ID NO:657) ROMALEA-II/Gryllus
pEVNFS AGW insulin receptor substrate 1 {Homosapiens} (SEQ ID
NO:658) >gi|5031805|ref|NP_0055351| insulin receptor substrate 1
{Homosapiens}
MASPPESDGFSDVRKVGYLRKPKSMHKRFFVLRAASEAGGPARLEYYENEKKWRHKSSAPK
RSIPLESCFNINKRADSKNKHLVALYTRDEHFAIAADSEAEQDSWYQALLQLHNRAKGHHD
GAAALGAGGGGGSCSGSSGLGEAGEDLSYGDVPPGPAFKEVWQVILKPKGLGQTKNLIGIYR
LCLTSKTISFVKLNSEAAAVVLQLMNIRRCGHSENFFFIEVGRSAVTGPGEFWMQVDDSVVA
QNMHETILEAMRAMSDEFRPRSKSQSSSNCSNPISVPLRRHHLNNPPPSQVGLTRRSRTESITA
TSPASMVGGKPGSFRVRASSDGEGTMSRPASVDGSPVSPSTNRTHAHRHRGSARLHPPLNHS
RSIPMPASRCSPSATSPVSLSSSSTSGHGSTSDCLFPRRSSASVSGSPSDGGFISSDEYGSSPCDF
RSSFRSVTPDSLGHTPPARGEEELSNYICMGGKGPSTLTAPNGHYILSRGGNGHRCTPGTGLG
TSPALAGDEAASAADLDNRFRKRTHSAGTSPTITHQKTPSQSSVASIEEYTEMMPAYPPGGGS
GGRLPGHRHSAFVPTRSYPEEGLEMHPLERRGGHHRPDSSTLHTDDGYMPMSPGVAPVPSG
RKGSGDYMPMSPKSVSAPQQIINPIRRHPQRVDPNGYMMMSPSGGCSPDIGGGPSSSSSSSNA
VPSGTSYGKLWTNGVGGHHSHVLPHPKPPVESSGGKLLPCTGDYMNMSPVGDSNTSSPSDC
YYGPEDPQHKPVLSYYSLPRSFKHTQRPGEPEEGARHQHLRLSTSSGRLLYAATADDSSSSTS
SDSLGGGYCGARLEPSLPHPHHQVLQPHLPRKVDTAAQTNSRLARPTRLSLGDPKASTLPRA
REQQQQQQPLLHPPEPKSPGEYVNIEFGSDQSGYLSGPVAFHSSPSVRCPSQLQPAPREEETGT
EEYMKMDLGPGRRAAWQESTGVEMGRLGPAPPGAASICRPTRAVPSSRGDYMTMQMSCPR
QSYVDTSPAAPVSYADMRTGIAAEEVSLPRATMAAASSSSAASASPTGPQGAAELAAHSSLL
GGPQGPGGMSAFTRVNLSPNRNQSAKVIRADPQGCRRRHSSETFSSTPSATRVGNTVPFGAG
AAVGGGGGSSSSSEDVKRHSSASFENVWLRPGELGGAPKEPAKLCGAAGGLENGLNYIDLD
LVKDFKQCPQECTPEPQPPPPPPPHQPLGSGESSSTRRSSEDLSAYASISFQKQPEDRQ (SEQ ID
NO:659) insulin {Homosapiens} >gi|386828|gb|AAA591721| insulin
{Homosapiens }
MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAED
LQVGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN (SEQ ID NO:660)
ACTIVE (human) INSULIN fragment: Chain A: GIVEQCCTSICSLYQLENYCN
(SEQ ID NO:661) Chain B: FVNQHLCGSHLVEALYLVCGERGFFYTPKT
(Modifications: Disulfide bridge between amino acid numbers 6-11, 7
-7*, 20-19*) (SEQ ID NO:662) Insulin Glargine >A chain
GIVEQCCTSICSLYQLENYCG (SEQ ID NO:666) >B chain
FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR In some embodiments the C-terminus
is amidated In some embodiments the N terminus is acylated (SEQ ID
NO:670) Insulin Lispro >A chain GIVEQCCTSICSLYQLENYCN (SEQ ID
NO:673) >B chain FVNQHLCGSHLVEALYLVCGERGFFYTKPT In some
embodiments the C-terminus is amidated in some embodiments the N
terminus is acylated (SEQ ID NO:677) Insulin Aspart >A chain
GIVEQCCTSICSLYQLENYCN >B chain FVNQHLCGSHLVEALYLVCGERGFFYTDKT In
some embodiments the C-terminus is amidated in some embodiments the
N terminus is acylated Oxyntomodulin >gi|125987831|sp|P012753|
MKSIYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNEDKRHSQGTFTSD
YSKYLDSRRAQDFVQWLMNTKRNRNNIAKRHDEFERHAEGTFTSDVSSYLEGQAAKEFIAW
LVKGRGRRDFPEEVAIVEELGRRHADGSFSDEMNTILDNLAARDFINWLIQTKITDRK (SEQ ID
NO:681) Oxm
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValG-
ln TrpLeuMetAsnThrLysArgAsnArgAsnAsnIleAla (SEQ ID NO:682)
DHis1-Oxm
dHisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinT-
r pLeuMetAsnThrLysArgAsnArgAsnAsnIleAla (SEQ ID NO:683) Ala2-Oxm
HisAlaGinGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAla (SEQ ID NO:684)
DHis1-Ala2-Oxm
dHisAlaGinGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinT-
rpL euMetAsnThrLysArgAsnArgAsnAsnIleAla (SEQ ID NO:686)
Oxm(ex15-18)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaAlaGlnAspPheValGlnTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAla (SEQ ID NO:687) Oxm(ex15-21)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaValArgLeuPheValG1nTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAla (SEQ ID NO:688) Oxm(ex15-23)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaValArgLeuPheIleGlnTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAla (SEQ ID NO:689) Oxm(ex15-24)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaValArgLeuPheIleGluTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAla (SEQ ID NO:690) Oxm(ex27-33)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTr-
p LeuLysAsnGlyGlyProSerSerAsnAsnIleAla (SEQ ID NO:691) Oxm(ex29-33)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTr-
p LeuMetAsnGlyGlyProSerSerAsnAsnIleAla (SEQ ID NO:692) Oxm(ex30-33)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTr-
p LeuMetAsnThrGlyProSerSerAsnAsnIleAla (SEQ ID NO:693) Oxm(ex27-30)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg
Arg AlaGln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Arg Asn Arg Asn
Asn Ile Ala (SEQ ID NO:694) Oxm19-37
AlaGlnAspPheValG1nTrpLeuMetAsnThrLysArgAsnArgAsnAsnIleAla (SEQ ID
NO:695) Oxm30-37 LysArgAsnArgAsnAsnIleAla (SEQ ID NO:698) Oxm-Ala38
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTr
pLeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAla (SEQ ID NO:699)
Oxm-Ala38,39
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAlaAla (SEQ ID NO:700)
Oxm-Ala38-42
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValG1nTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAlaAlaAlaAlaAla (SEQ ID
NO:701) Oxm-Lys38-Laur
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAla(LysLAUROYL) (SEQ ID NO:702)
Oxm-Lys38-Palm
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAla(LysPALMITOYL) (SEQ ID
NO:703) Oxm-Ala38,39-Lys40Laur
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinTr-
p LeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAlaAla(LysLAUROYL) (SEQ ID
NO:704) Oxm-Ala38,39-Lys40Palm
HisSerGinGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGin
TrpLeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAlaAla(LysPALMITOYL)-(D-His1)-Ala2-
(SEQ ID NO:705) Oxm(ex15-23)
dHisAlaGinGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaValArgLeuPheIleGinT-
r
pLysAsnGlyGlyProSerSerArgAsnAsnIleAlaAlaAla(LysLAUROYL)(ex27-33)-Ala38,39-
Lys40-LAUROYL (SEQ ID NO:706) MC-4R Agonist (Cyclo
(B-Ala-His-D-Phe-Arg-Trp-Glu)-NH.sub.2)
Ac-Nle-Asp-His-D-Tyr-Arg-Trp-Lys-NH2 (SEQ ID NO:707)
Ac-Lys-Tyr-Val-Nle-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly-NH.sub.2
(SEQ ID NO:709) Ac- Ser Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro
Val NH.sub.2 (SEQ ID NO:710) Biotin-.beta.- Endomorphin, human
Biotin-YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE (SEQ ID NO:711) {Ala1,3, 11,
16}-Endothelin 1, human ASASSLMDKEAVYFAHLDIIW Big Endothelin-1
(1-38), human CSCSSLMDKECVYFCHLDIIVVVNTPEHVVPYGLGSPRS (Disulfide
bridge: 1-15 and 3-11)
(SEQ ID NO:713) Endothelin 1, human, porcine CSCSSLMDKECVYFCHLDIIW
(Disulfide bridge: 1-15 and 3-11 (SEQ ID NO:714) Endothelin 2,
human CSCSSWLDKECVYFCHLDIIW (Disulfide bridge: 1-15 and 3-11) (SEQ
ID NO:715) Orphanin FQ2, (OFQ2, NOCII) FSEFMRQYLVLSMQSSQ (SEQ ID
NO:716) {Des-His1, Glu8}-Exendin-4
GEGTPTSELSKQMEEEAVRLPIEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO:718)
Biotin-Exendin 4 Biotin-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
(SEQ ID NO:718) Exendin (10-39) LSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
(SEQ ID NO:719) Exendin (4-39)
GTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO:720) Exendin
(5-39) TFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO:721)
Exendin (7-39) TSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID
NO:722) Exendin (9-39) DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID
NO:723) Exendin (9-39) DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID
NO:724) Exendin 3 HSDGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ
ID NO:725) Glicentin-Related Peptide (21-50), human
RSLQDTEEKSRSFSASQADPLSDPDQMNED-NH2 (SEQ ID NO:726) .alpha.1 (I)
Collagen (614-639), Type I Collagen .alpha.1 (I) C-Telopeptide,
human SAGFDFSFLPQPPQEKAHDGGRYYRA (SEQ ID NO:727) FDC-SP (30-85),
human SISDSDELASGFFVFPYPYPFRPLPPIPFPRFPWFRRNFPIPIPESAPTTPLPSEK (SEQ
ID NO:728) FDC-SP (61-85), human FPWFRRNFPIPIPESAPTTPLPSEK (SEQ ID
NO:729) Fibrinopeptide A, human ADSGEGDFLAEGGGVR (SEQ ID NO:730)
Fibrinopeptide B, human Pyr-GVNDNEEGFFSAR (SEQ ID NO:731)
Gamma-Fibrinogen (377-395) YSMKETTMKIIPFNRLSIG (SEQ ID NO:732)
{Glu1}-Fibrinopeptide B Glufib EGVNDNEEGFFSAR (SEQ ID NO:733)
EAK16-II AEAEAKAKAEAEAKAK-NH2 (SEQ ID NO:734) Elastin-Like
Octapeptide GVGVPGVGVPGVGVPGVG (SEQ ID NO:735) Fibrinogen
.beta.-Chain (24-42) EEAPSLRPAPPPISGGGYR (SEQ ID NO:736) Fibrinogen
.gamma.-Chain (117-133) NNQKIVNLKEKVAQLEA (SEQ ID NO:737)
Fibrinogen .gamma.-Chain (397-411) GQQHHLGGAKQAGDV (SEQ ID NO:738)
Fibrinogen Binding Inhibitor Peptide HHLGGAKQAGDV (SEQ ID NO:739)
Fibrinogen-Binding Peptide EHIPA (SEQ ID NO:740)
{Ala6,D-Trp8}-Galanin (1-15)-ol GWTLNAAwYLLGPHA-ol (SEQ ID NO:741)
{D-Trp6,8,9}-Galanin (1-15)-ol GWTLNwAwwLLGPHA-ol (SEQ ID NO:742)
Biotin-Galanin, human Biotin-GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS
Biotin-Galanin, human Biotin-GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS (SEQ ID
NO:743) Galanin (1-13)-Bradykinin (2-9), amide, M35
GWTLNSAGYLLGPPPGFSPFR-NH2 (SEQ ID NO:744) Galanin
(1-13)-Neuropeptide Y (25-36), amide, M32
GWTLNSAGYLLGPRHYINLITRQRY-NH2 (SEQ ID NO:745) Galanin
(1-13)-Pro-Pro-(Ala-Leu)2-Ala, amide GWTLNSAGYLLGPPPALALA- NH2 (SEQ
ID NO:746) Galanin (1-13)-Spantide I, C7
GWTLNSAGYLLGPrPKPQQwFwLL-NH2 (SEQ ID NO:747) Galanin
(1-13)-Spantide I, C8 GWTLNSAGYLLGPrPKPQQwFwLL-NH2 (SEQ ID NO:748)
Galanin (1-13)-Substance P (5-11), amide, Galantide
GWTLNSAGYLLGPQQFFGLM-NH2 (SEQ ID NO:749) Galanin (1-13)/Galanin
Like Peptide (GALP) (9-21), common GWTLNSAGYLLGP (SEQ ID NO:750)
Galanin Message Associated Peptide, GMAP (1-41), amide
ELEPEDEARPGGFDRLQSEDKAIRTIMEFLAFLHLKEAGAL-NH2 (SEQ ID NO:751)
Galanin Message Associated Peptide, GMAP (16-41), amide
LQSEDKAIRTIMEFLAFLHLKEAGAL-NH2 (SEQ ID NO:752) Galanin Message
Associated Peptide, GMAP (25-41), amide TIMEFLAFLHLKEAGAL-NH2 (SEQ
ID NO:753) Galanin Message Associated Peptide, GMAP (44-59), amide
LPGLPSAASSEDAGQS-NH2 Galanin, human GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS
(SEQ ID NO:754) Galanin-Lys(Biotin), human
GWTLNSAGYLLGPHAVGNHRSFSDKNGLTSK(Biotin) Galanin-Lys(Biotin), human,
FAM-labeled FAM-GWTLNSAGYLLGPHAVGNHRSFSDKNGLTSK(Biotin) (SEQ ID
NO:755) Leptin (57-74) VTGLDFIPGLHPILTLSK GIP (1-42), human
YAEGTFISDYSIAMDKIHQQDFVNVVLLAQKGKKNDWKHNITQ (SEQ ID NO:756) GIP
(3-42), human EGTFISDYSIAMDKIHQQDFVNVVLLAQKGKKNDWKHNITQ (SEQ ID
NO:757) (Leu15)-Gastrin-1, human Pyr-GPWLEEEEEAYGWLDF-NH2 (SEQ ID
NO:758) Big Gastrin-1, human
Pyr-LGPQGPPHLVADPSKKQGPWLEEEEEAYGWMDF-NH2 (SEQ ID NO:759)
Biotin-Gastrin (1-17) Biotin-EGPWLEEEEEAYGWMDF-NH2 (SEQ ID NO:760)
Biotin-Gastrin (1-17), phosphorylated
Biotin-EGPWLEEEEEA-pY-GWMDF-NH2 (SEQ ID NO:761) Biotin-Gastrin
Releasing Peptide, human Biotin-VPLPAGGGTVLTKMYPRGNHWAVGHLM-NH2
(SEQ ID NO:762) Gastrin derived peptide GPWLEEEEEAYGWMDFK-NH2 (SEQ
ID NO:763) Gastrin Releasing Peptide (14-27), porcine and human
MYPRGNHWAVGHLM-NH2 (SEQ ID NO:764) Gastrin Releasing Peptide
(20-27), porcine and human, acetylated Ac-HWAVGHLM-NH2 (SEQ ID
NO:765) Gastrin Releasing Peptide, human
VPLPAGGGTVLTKMYPRGNHWAVGHLM-NH2 Gastrin Releasing
Peptide-Lys(Biotin), human VPLPAGGGTVLTKMYPRGNHWAVGHLMK(Biotin)
(SEQ ID NO:766) Gastrin-1, human Pyr-GPWLEEEEEAYGWMDF-NH2 (SEQ ID
NO:767) Gastrin-Releasing Peptide (1-17) VPLPAGGGTVLTKMYPR (SEQ ID
NO:768) GRP10, Gastrin-releasing Peptide 10/Neuromedin C, amidated
GNHWAVGHLM-NH2 (SEQ ID NO:769) {Des-His1, Glu9}-Glucagon (1-29),
amide SQGTFTSEYSKYLDSRRAQDFVQWLMNT-NH2 Glucagon-like Peptide-2,
GLP-2 (146-178), human HADGSFSDEMNTILDNLAARDFINWLIQTKITD (SEQ ID
NO:770) Peptide Histidine Isoleucinamide (PHI), Porcine (1-27)
HADGVFTSDFSRLLGQLSAKKYLESLI-NH2
(SEQ ID NO:771) Glucagon-Like Peptide 1, GLP-1 (7-17)-Cys
HAEGTFTSDVSC (SEQ ID NO:772) {GalNAc-Ser}-Erythropoietin (Epo)
(117-131) EAISPPDAA-*S-AAPLR (*S=GalNAc-Ser) (SEQ ID NO:773)
EGFR-1148, EGFR (1140-1152) QISLDNPDYQQDF (SEQ ID NO:774) Growth
Hormone Releasing Factor, GRF (1-29), amide, human
YADAIFTNSYRKVLGQLSARKLLQDIMSR-NH2 (SEQ ID NO:775) Growth Hormone
Releasing Factor, GRF (1-40), amide, human
YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGA-NH2 (SEQ ID NO:776) Growth
Hormone Releasing Factor, GRF (1-44), amide, human
YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH2 (SEQ ID NO:777)
{D-Ala2}-Growth Hormone Releasing Factor, GRF (1-29), amide, human
YaDAIFTNSYRKVLGQLSARKLLQDIMSR-NH2 (SEQ ID NO:778) PEP1--inhibits
membrane association of NS5A, hence impairing HCV replication
SGSWLRDVVVDWICTVLTDFKTWLQSKLDYKD-NH2 (SEQ ID NO:779) Pep 4A
GSVVIVGRIILSGR-NH2 (SEQ ID NO:780) Pep 4AK KKKGSVVIVGRIILSGR-NH2
(SEQ ID NO:781) HMGA N-Terminal Fragment GAGQPSTSAQGQ (SEQ ID
NO:782) AKT/PKB/Rac-Protein Kinase Substrate {ARKRERTYSFGHHA},
Biotinylated Biotin-ARKRERTYSFGHHA (SEQ ID NO:783)
5-TMR-ARKRERTYSFGHHA Competitively inhibits histone H2B
phosphorylation (Ki=12 .mu.M) by AKT 5-TMR-ARKRERTYSFGHHA (SEQ ID
NO:784) T20 Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 (SEQ ID
NO:785) T22 ({Tyr5,12, Lys7}-polyphemusin II) RRWCYRKCYKGYCYRKCR
(SEQ ID NO:786) Skeletal Dihydropyridine Receptor (671-690)
TSAQKAKAEERKRRKMSRGL (SEQ ID NO:787) Luteinizing Hormone-Releasing
Hormone (LH-RH), human, Pyr-HWSYGLRPG-NH2 (SEQ ID NO:788) .beta.-
MSH, human AEKKDEGPYRMEHFRWGSPPKD (SEQ ID NO:789) .gamma.-2-MSH
(41-58) YVMGHFRWDRFG (SEQ ID NO:790) {D-Phe7}-ACTH, .alpha.-MSH
(1-13), amide SYSMEHfRWGKPV-NH2 (SEQ ID NO:791) {Nle4,
D-Phe7}-.alpha.-MSH, amide Ac-SYS-Nle-EHfRWGKPV-NH2 (SEQ ID NO:792)
Melanin Concentrating Hormone, human, mouse, rat
DFDMLRCMLGRVYRPCWQV (Disulfide bridge: 7-16) (SEQ ID NO:793)
VA-.beta.- MSH, Lipotropin-.gamma., Proopiomelanocortin-derived
VAAEKKDEGPYRMEHFRWGSPPKD (SEQ ID NO:794) Apolipoprotein B-100
(3136-3155), human KTTKQSFDLSVKAQYKKNKH (SEQ ID NO:795) alpha-9
Gliadin Peptide QVLQQSTYQLLQELCCQHLW (SEQ ID NO:796) MOG (8-21)
PGYPIRALVGDEAE (SEQ ID NO:797) MOG (97-108) TCFFRDHSYQEE (SEQ ID
NO:798) MOG (14-39), human ALVGDEVELPCRISPGKNATGMELGW (SEQ ID
NO:799) MOG (50-74), human LYRNGKDQDGDAPEYRGRTELLKD (SEQ ID NO:800)
MOG (27-50), human SPGKNATGMELGWYRPPFSRVVHL (SEQ ID NO:801) MOG
(76-100), human IGEGKVTLRIRNVRFSDEGGFTCFF (SEQ ID NO:802) MOG
(89-113), human RFSDEGGFTCFFRDHSYQEEAAMEL (SEQ ID NO:803) MOG
(35-51) MEVGWYRSPFSRVVHLY (SEQ ID NO:804) MOG (35-52)
MEVGWYRSPFSRVVHLYR (SEQ ID NO:805) MOG (35-53) MEVGWYRSPFSRVVHLYRN
(SEQ ID NO:806) MOG (35-55), human MEVGWYRPPFSRVVHLYRNGK (SEQ ID
NO:807) MOG (101-120), human, mouse RDHSYQEEAAMELKVEDPFY (SEQ ID
NO:808) {A1a4}-MBP (1-11) Ac-ASQARPSQRHG (SEQ ID NO:809) {Tyr4}-MBP
(1-11) Ac-ASQYRPSQRHG (SEQ ID NO:810) MBP (1-17) ASQKRPSQRSKYLATAS
(SEQ ID NO:811) MBP (1-20), Myelin Basic Protein (1-20)
ASQKRPSQRSKYLATASTMD (SEQ ID NO:812) MBP (111-129)
LSRFSWGAEGQRPGFGYGG (SEQ ID NO:813) MBP (131-155)
ASDYKSAHKGLKGVDAQGTLSKIFK (SEQ ID NO:814) Vasonatrin Peptide (1-27)
GLSKGCFGLKLDRIGSMSGLGCNSFRY (Disulfide bridge: 6-22) (SEQ ID
NO:815) {Ala5, .beta.-Ala8}-Neurokinin A (4-10)
DAFV-(.beta.-A)-LM-NH2 (SEQ ID NO:816) {D-Pro2, D-Trp6,8,
Nle10}-Neurokinin B DpHDFwVwL-NIe-NH2 (SEQ ID NO:817) {Lys5,
NMeLeu9, NIe10}-Neurokinin A (4-10) DKFVG-(NMeL)-NIe-NH2 (SEQ ID
NO:818) Neurokinin A, Substance K, Neuromedin L, NKA HKTDSFVGLM-NH2
(SEQ ID NO:819) Neuromedin (B-30)
LSWDLPEPRSRAGKIRVHPRGNLWATGHFM-NH2 (SEQ ID NO:820)
{Ser2}-Neuromedin C GSHWAVGHLM-NH2 (SEQ ID NO:821)
.beta.-Neuroprotectin (D-Ala1) aDLIAYL-NH2 (SEQ ID NO:822)
{Ala16,17,20}-beta-Amyloid (1-28) DAEFRHDSGYEVHHQAAVFAAEDVGSNK
26Rfa, Hypothalamic Peptide, human TSGPLGNLAEELNGYSRKKGGFSFRF-NH2
(SEQ ID NO:823) Brain Neuropeptide I AGEGLSSPFWSLAAPQRF-NH2 (SEQ ID
NO:824) Erythropoietin, Human (hEPO) Fragment
MEVGQQAVEVWQGLALLSEAVLR (SEQ ID NO:825) Neuropeptide NPW-23 (Human)
WYKHVASPRYHTVGRAAGLLMGL (SEQ ID NO:826) VGF Protein Precursor
(491-507) PPEPVPPPRAAPAPTHV (SEQ ID NO:827) {Gln4}-Neurotensin
Pyr-LYQNKPRRPYIL (SEQ ID NO:828) {D-Tyr11}-Neurotensin
Pyr-LYENKPRRPyIL (SEQ ID NO:829) {D-Trp11}-Neurotensin
Pyr-LYENKPRRPwIL (SEQ ID NO:830) {D-Phe11}-Neurotensin
Pyr-LYENKPRRPfIL (SEQ ID NO:831) Neurotensin Pyr-LYENKPRRPYIL
(SEQ ID NO:832) Neuropeptide F
PDKDFIVNPSDLVLDNKAALRDYLRQINEYFAIIGRPRF-NH2 (SEQ ID NO:833) PTD-p50
(NLS) Inhibitory Peptide DRQIKIVVFQNRRMKWKKVQRKRQKLMP (SEQ ID
NO:834) PTD-p65-P1 Peptide DRQIKIVVFQNRRMKWKKQLRRPSDRELSE (SEQ ID
NO:835) PTD-p65-P6 (Ser529/536) Inhibitory Peptide
DRQIKIVVFQNRRMKWKKNGLLSGDEDFSS (SEQ ID NO:836) PTD-TRAF6 Inhibitory
Peptide DRQIKIFQNRRMKWKKRKIPTEDEY (SEQ ID NO:837) RNase S Complex
Peptide Ac-KETAAAKFERQHMDSSTSA-NH2 (SEQ ID NO:838) IKK.gamma. NEMO
Binding Domain (NBD) Inhibitory Peptide
DRQIKIVVFQNRRMKWKKTALDWSWLQTE (SEQ ID NO:839) {Trp5}-Oryzatensin
(5-9), rice WPLPR (SEQ ID NO:840) LVV-Hemorphin-6,
Leu-Valorphin-Arg LVVYPWTQR (SEQ ID NO:841) LVV-Hemorphin-7
LVVYPWTQRF (SEQ ID NO:842) Nociceptin (1-11), (Orphanin FQ, or
OFQ/N) (1-11) FGGFTGARKSA (SEQ ID NO:843) Nociceptin (1-13), amide
FGGFTGARKSARK (SEQ ID NO:844) Nociceptin (1-7), (Orphanin FQ, or
OFQ/N) (1-7) FGGFTGA (SEQ ID NO:845) Prepronociceptin (169-176),
human TLHQNGNV (SEQ ID NO:846) Serorphin, BSA (399-404) YGFQNA (SEQ
ID NO:847) Valorphin VVYPWTQ (SEQ ID NO:848) Orexin A, bovine,
human, mouse, rat Pyr-PLPDCCRQKTCSCRLYELLHGAGNHAAGILTL-NH2
(Disulfide bridge: 6-12 and 7-14) (SEQ ID NO:849) Orexin B, human
RSGPPGLQGRLQRLLQASGNHAAGILTM-NH2 (SEQ ID NO:851)
{Gla17,21,24}-Osteocalcin (1-49)
YLYQWLGAPVPYPDPL-Gla-PRR-Gla-VC-Gla-LNPDCDELDHIGFQEAYRRFYGPV
(Gla=.gamma.-Carboxyglutamic Acid; Disulfide bridge: 23-29) (SEQ ID
NO:852) Osteocalcin (37-49), human GFQEAYRRFYGPV (SEQ ID NO:853)
Osteocalcin (7-19), human GAPVPYPDPLEPR (SEQ ID NO:854) Lys-OVA
(257-264), KSIINFEKL KSIINFEKL (SEQ ID NO:855) {Arg8}-Vasopressin
(AVP) CYFQNCPRG-NH2 (Disulfide bridge: 1-6) (SEQ ID NO:856)
{Deamino-Cys1, D-Arg8}-Vasopressin, free acid
3-Mercaptopropionyl-YFQNCPrG (Disulfide bridge: 1-6) (SEQ ID
NO:857) Oxytocin CYIQNCPLG-NH2 (Disulfide bridge: 1-6) (SEQ ID
NO:858) Serum Albumin (102-226) ADDKETCFAEEGKKLVAASQAALGL (SEQ ID
NO:859) Apolipoprotein J (215-222) RPHFFFPK (SEQ ID NO:860)
Apolipoprotein L (306-316) VNEPSILEMSR (SEQ ID NO:861) Catestatin,
human SSMKLSFRARAYGFRGPGPL (SEQ ID NO:862) Pancreastatin (37-52),
Human EEEEEMAVVPQGLFRG-NH2 (SEQ ID NO:863) Pancreatic Polypeptide
(30-53), human APLEPVYPGDNATPEQMAQYAADL (SEQ ID NO:864)
{Tyr0}-Hypercalcemia Malignancy Factor (1-40)
YAVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATS (SEQ ID NO:865)
Hypercalcemia Malignancy Factor (1-34), (PLP) amide, human
AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTA-NH2 (SEQ ID NO:866) TIP 39,
Tuberoinfundibular Neuropeptide
SLALADDAAFRERARLLAALERRHWLNSYMHKLLVLDAP (SEQ ID NO:867)
PACAP-Related Peptide (PRP), human DVAHGILNEAYRKVLDQLSAGKHLQSLVA
(SEQ ID NO:868) Prolactin Releasing Peptide (1-31), human
SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NH2 (SEQ ID NO:869) Prolactin
Releasing Peptide (12-31), human TPDINPAWYASRGIRPVGRF-NH2 (SEQ ID
NO:870) Calpain Inhibitor Peptide, B27-WT
DPMSSTYIEELGKREVTIPPKYRELLA 105Y, .alpha.1-antitrypsin (359-374)
SIPPEVKFNKPFVYLI (SEQ ID NO:871) Acetyl-Calpastatin (184-210), CS
peptide, human Ac-DPMSSTYIEELGKREVTIPPKYRELLA-NH2 (SEQ ID NO:872)
{Ala144}-PLP (139-151) A144-PLP(139-151) HSLGKALGHPDKF (SEQ ID
NO:873) PLP (190-209) SKTSASIGSLCADARMYGVL (SEQ ID NO:874) PLP
(48-70) TYFSKNYQDYEYLINIHAFQYV (SEQ ID NO:875)
Acetyl-Tetradecapeptide Renin Substrate, Acetyl-Angiotensinogen
(1-14), human Ac-DRVYIHPFHLVIHN (SEQ ID NO:876) TP508,
Thrombin-derived Peptide AGYKPDEGKRGDACEGDSGGPFV (SEQ ID NO:877)
Salusin-alpha SGALPPAPAAPRPALRAQRAGPAGPGAK-NH2 (SEQ ID NO:878)
Salusin-beta AIFIFIRWLLKLGHHGRAPP (SEQ ID NO:879) Prosaptide 769P
(D-Ala2) CaFLVKEVTKLIDNNKTEKEIL (SEQ ID NO:880) Prosaptide TX14(A)
(D-Ala2) TaLIDNNATEEILY (SEQ ID NO:881) Prosaptide, wild type
TKLIDNNKTEKEIL (SEQ ID NO:882) Saposin C12 LIDNNKTEKEIL (SEQ ID
NO:883) Saposin C18 VKEVTKLIDNNKTEKEIL (SEQ ID NO:884) Saposin C22
CEFLVKEVTKLIDNNKTEKEIL (SEQ ID NO:885) Secretin, human
HSDGTFTSELSRLREGARLQRLLQGLV-NH2 (SEQ ID NO:886) CC Chemokine
Receptor 3 Fragment I, amide MTTSLDTVETFGTTSYYDDVGLLCEKADTR-NH2
(SEQ ID NO:887) CC Chemokine Receptor 3 Fragment II
MTTSLDTVETFGTTSYYDDVGLLC (SEQ ID NO:888) DAP10 Signaling Fragment
PAQEDGKVYINMPGRG (SEQ ID NO:889) Erythropoietin-Mimetic Peptide 17
(EMP17) TYSCHFGPLTWVCKPQGG (SEQ ID NO:890) Hsp Heat shock protein
(3-13) KTIAYDEEARR (SEQ ID NO:891) iNOS (507-531), human
RPKRREIPLKVLVKAVLFACMLMRK (SEQ ID NO:892) Notch 1(1735-1752)
VLLFFVGCGVLLSRKRRR (SEQ ID NO:893) SmMLCKp, Smooth-Muscle Myosin
Light-Chain Kinase (796-815), Calmodulin Binding
ARRKWQKTGHAVRAIGRLSS (SEQ ID NO:894)
Tau-Protein (1-16) MAEPRQEFEVMEDHAG (SEQ ID NO:895) Tau-Protein
(323-335) GSLGNIHHKPGGG (SEQ ID NO:896) Caveolin-1 Scaffolding
Domain (82-101) DGIVVKASFTTFTVTKYWFYR (SEQ ID NO:897) Caveolin-3
(Cay-3), (55-74) DGVWRVSYTTFTVSKYVVCYR (SEQ ID NO:898) {Gly35,
Asp37}-beta-Amyloid (1-42)
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLGVDGVVIA (SEQ ID NO:899)
{Cys7}-beta-Amyloid (1-40) DAEFRHCSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV
(SEQ ID NO:900) beta-Amyloid (1-40)
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV (SEQ ID NO:901) {Cys3,6,
Tyr8, Pro9}-Substance P RPCPQCFYPLM-NH2 (Disulfide bridge: 3-6)
(SEQ ID NO:902) {4-Chloro-Phe}7,8-Substance P
RPKPQQ-F(4-Cl-F)-GLM-NH2 (SEQ ID NO:903) {Cys3,6, Tyr8,
Pro10}-Substance P RPCPQCFYGPM-NH2 (Disulfide bridge: 3-6) (SEQ ID
NO:904) Ranakinin KPNPERFYGLM-NH2 (SEQ ID NO:905) Scyliorhinin I,
Scy I, Shark Substance P Related Peptide AKFDKFYGLM (SEQ ID NO:906)
Substance P RPKPQQFFGLM-NH2 (SEQ ID NO:907) SFLLRNPNDKYEPF, human
Thrombin Receptor 42-55 SFLLRNPNDKYEPF (SEQ ID NO:908) Tumor
Necrosis Factor Receptor, TNFR (159-178) Analog
QEKQNTVATAHGFFLRENEG (SEQ ID NO:909) CDIP2 KISLQRLKSYVITTSRCPQ (SEQ
ID NO:910) Pro-TNF-.alpha.+0(71-82), human SPLAQAVRSSSR (SEQ ID
NO:911) TNF-.alpha. (10-36), human DKPVAHVVANPQAEGQLQWLNRRANAL (SEQ
ID NO:912) TNF-.alpha. (31-5), human RRANALLANGVELRD (SEQ ID
NO:913) Brevinin-2Eg GIMDTLKNLAKTAGKGALQSLLNHASCKLSGQC (Disulfide
bridge 27-33) (SEQ ID NO:914) Brevinin-2Eh
GIMDTLKNLAKTAGKGALQSLLNHASCKLSKQC (Disulfide bridge 27-33) (SEQ ID
NO:915) Caloxin 1b1 TAWSEVLHLLSRGGG (SEQ ID NO:916) Caloxin 2A1
VSNSNWPSFPSSGGG (SEQ ID NO:917) Caloxin 3A1 WSSTSSVSAPLEFGGGGSAK
(SEQ ID NO:918) Delta-Toxin (1-26), Staphylococcus aureus
MAQDIISTIGDLVKWIIDTVNKFTKK (SEQ ID NO:919) Delta-Toxin (5-20),
Staphylococcus aureus IISTIGDLVKWIIDTV (SEQ ID NO:920) Sarafotoxin
6c CTCNDMTDEECLNFCHQDVIVV (Disulfide bridge: 1-15 and 3-11) (SEQ ID
NO:921) Vesicle-Associated Membrane Protein, VAMP (60-94)
LSELDDRADALQAGASQFETSAAKLKRKYWWKNLK (SEQ ID NO:922
Vesicle-Associated Membrane Protein, VAMP (77-94)
SQFETSAAKLKRKYWWKNLK (SEQ ID NO:923) Helodermin
HSDAIFTQQYSKLLAKLALQKYLASILGSRTSPPP (SEQ ID NO:924) highly
selective CRF2 receptor antagonist K41498
dFHLLRKNleIEIEKQEKEKQQAANNRLLLDTI-NH2 (SEQ ID NO:925)
Corticotrooin-releasing factor receptor antagonist
DLTFHLLREMLEMAKAEQEAEQAALNRLLLEEA-NH2 (SEQ ID NO:926) Astressin CAS
No: {170809-51-5} Potent cortieotropin-releasing factor (CRF)
receptor antagonist (K.sub.i values are 2, 15 and 1 nM at
CRF.sub.1, CRF.sub.2.alpha. and CRF.sub.2.beta.) Reduces ACTH
secretion, blocks delayed gastric emptying and is neuroprotective
in vivo dFfHLLREVLENleARAEQLAQE*AHKg*NRKLNleEII-NH2 E*-Kg* are
cyclized The cyclic structure has been fixed by amide bond between
gamma-COOH group of glutamicacid and alpha-NH2 group of glycine
coupled to the epsilon-NH2 group of lysine (SEQ ID NO:927) Stressin
I Potent and selective corticotropin releasing factor receptor-1
(CRF.sub.1) agonist (K.sub.i values are15 and 224 nM for CRF.sub.1
and CRF.sub.2 receptors respectively) Increases ACTH levels
andincreases faecal pellet output in vivo following ip
administration Ac-PPISLDLTFHLIREVLENleARAEQIAQQE*HSK*AKLNleEII-NH2
E*-K* are cyclized The cyclic structure has been fixed by amide
bond between gamma-COOH groupof glutamic acid and epsilon-NH2 group
of lysine (SEQ ID NO:928) Human urocortin III ?+0like sequences
MLMPVHFLLLLLLLLGGPRTGLPHKFYKAKPIFSCLNTALSEAEKGQWEDASLLSKR
SFHYLRSRDASSGEEEEGKEKKTFPISGARGGAGGTRYRYVSQAQPRGKPRQDTAKS
PHRTKFTLSLDVPTNIMNLLFNIAKAKNLRAQAAANAHLMAQIGRKK (SEQ ID NO:929)
Active Form: 120-137 urocortin III {Homosapiens} FTLSLDVPTNIMNLLFNI
FTLSLDVPTNIMNLLFNIAKAKNLRAQAAANAHLMAQI (SEQ ID NO:930) Human
urocortin-2 IVLSLDVPIGLLQILLEQARARAAREQATTNARILARV Human Growth
Hormone Releasing Factor (GHRF), GRF
YADAIFTNSYRKVLGQLSARKLLQDIMSR-NH2 JI-22 {Dat1, Orn12,21, Abu15,
Nle27, Agm29} GHRF-(1-29) JI-34 {Dat1, Orn12,21 ,Abu15, N1e27,
Asp28, Agm29} GHRF-(1-29) JI-36 {Dat1, Thr8, Orn12,21, Abu15,
N1e27, Asp28, Agm29} GHRF-(1-29) JI-38 {Dat1, Gln8, Orn12,21,
Abu15, N1e27, Asp28, Agm29} GHRF-(1-29) Dat=desaminotyrosine
Agm=agmatine .alpha.-CGRP (human)
ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH2 Optional Disulfide bridge
between C2 and C7 (SEQ ID NO:931) CGRP (rat)
SCNTATCVTHRLAGLLSRSFFVKDNFVPTNVGSEAF-NH2 Optional Disulfide bridge
between C2 and C7 (SEQ ID NO:932) PTHrP (Human) 1-37
AVSEHQLLHDKGKSIQDLRRFFLHHLIAEIHTAEIR (SEQ ID NO:933) PTH (human)
1-34 SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN (SEQ ID NO:934) TIP 39,
Tuberoinfundibular Neuropeptide (human)
SLALADDAAFRERARLLAALERRHWLNSYMHKLLVLDAP TIP 39, Tuberoinfundibular
Neuropeptide (mouse) SLALADDAAFRERARLLAALERRRWLDSYMQKLLLLDAP PTH2
Agonists {His5}-PTH 1-34 (human) {Ile5}-PTHrP 1-36
{Ile5,Trp23}-PTHrP 1-36 (human) {Ile5,Trp23}-PTHrP 2-36 (human)
{Ile5,Trp23}-PTHrP 3-36 (human) {Ile5,Trp23}-PTHrP 4-36 (human)
{Ile5,Trp23}-PTHrP 5-36 (human) {Ile5,Trp23,Tyr36}-PTHrP 1-36-NH2
(human)1-34 (human) {Phe23}-PTH (human) PTH 1-34 PTH 1-34 (rat)
PTHrP 1-34 PTHrP 1-36 (human) {125I} {Nle8,21,Tyr34}-PTH 1-34-NH2
(rat) TIP39 (human/bovine) TIP39 (mouse) {Trp23}-PTHrP 1-36 (human)
{Trp23,Tyr36}-PTHrP1-36-NH2 (human) PTH2 Antagonists
{D-Trp12+56-PTH 7-34 (bovine {D-Trp12,Tyr34}-PTH 7-34 (bovine)
{Ile5,Trp23}-PTHrP 5-36 PTHrP 1-21/PTH 22-34 PTHrP 7-34 TIP39 7-39
(human/bovine) TIP39 7-39 (mouse) (SEQ ID NO:935) AF 12198 (Potent
and selective antagonist for the human type I interleukin-1 (IL-1)
receptor)Ac-FEWTPGWYQXYALPL-NH2 X=2-Carboxyazetidine (SEQ ID
NO:936) human epidermal growth factor >gi|46242544|gb|AAS833951|
epidermal growth factor {Homosapiens }
NSDSECPLSHDGYCLHDGVCMYIEALDKYACNCVVGYIGERCQYRDLKWWELR (SEQ ID
NO:937) {cPP1-7,NPY19-23,A1a31,Aib32,G1n34}-hPancreatic Polypeptide
GPSQPTYPGDNATPEQMARYYSALRRYINMAXRQRY-NH X=Aib (SEQ ID NO:938) Xenin
8 C-Terminal fragment of xenin, a neurotensin-like peptide;
modulates pancreatic insulin and glucagon secretion/effects
HPKRPWIL
(SEQ ID NO:939) >gi|29725609|ref|NP_0052192| epidermal growth
factor receptor isoform a precursor {Homosapiens}
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVV
LGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSN
YDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGS
CQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESD
CLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSC
VRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLH
ILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQ
FSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCK
ATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPEC
LPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHP
NCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQE
RELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELRE
ATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGS
QYLLNVVCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHA
EGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLP
QPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNF
YRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPI
KEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDP
HYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPN
GIFKGSTAENAEYLRVAPQSSEFIGA (SEQ ID NO:940)
>gi|41327736|ref|NP_9584411| epidermal growth factor receptor
isoform d precursor {Homosapiens}
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVV
LGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSN
YDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGS
CQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESD
CLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSC
VRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLH
ILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQ
FSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCK
ATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPEC
LPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHP
NCTYGPGNESLKAMLFCLFKLSSCNQSNDGSVSHQSGSPAAQESCLGWIPSLLPSEFQLGWG
GCSHLHAWPSASVIITASSCH (SEQ ID NO:941)
>gi|41327732|ref|NP_9584391| epidermal growth factor receptor
isoform b precursor {Homosapiens}
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVV
LGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSN
YDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGS
CQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESD
CLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSC
VRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLH
ILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQ
FSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCK
ATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPEC
LPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHP NCTYGS
(SEQ ID NO:942) >gi|41327734|ref|NP_9584401| epidermal growth
factor receptor isoform c precursor {Homosapiens}
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVV
LGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSN
YDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGS
CQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESD
CLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSC
VRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLH
ILPVAFRGDSFTHTPPLDPQELDILKTVKEITGLS (SEQ ID NO:943) PHM 27 (human)
Endogenous peptide product of human prepro-VIP and analog of
porcine PHI-27; potent agonist for the human calcitonin receptor
(EC50=11 nM) HADGVFTSDFSKLLGQLSAKKYLESLM-NH2 (SEQ ID NO:944)
Calcitoninreceptor-stimulating peptide-1 (Endogenous central
calcitonin (CT) receptor agonist agonist that stimulates cAMP
formation at a potency 350-fold greater than CT (ED50 values are 02
and 71 nM respectively) Displays no activity at calcitonin-gene
related peptide (CGRP) and adrenomedullin receptors Inhibits
formation of multinuclear osteoclasts with similar efficacy to CT
in vitro Suppresses food intake and increases body temperature in
free-feeding rats, and significantly decreases plasma calcium
levels in vivo) SCNTATCMTHRLVGLLSRSGSMVRSNLLPTKMGFKVFG-NH2 (SEQ ID
NO:945) AC 187 (Orally active, potent amylin receptor antagonist
(IC50=048 nM) that displays 38-fold and 400-foldselectivity over
calcitonin and CGRP receptors respectively Blocks amyloid
.beta.-induced neurotoxicity by attenuating the activation of
initiator and effector caspases in vitro Increases glucagon
secretion, accelerates gastric emptying, alters plasma glucose
levels and increases food intake in vivo)
Ac-VLGKLSQQLHKLQTYPRTNTGSNTY-NH2 (SEQ ID NO:946) VIP (guinea pig)
(Neuropeptide with many biological actions; plays a role in
neurotransmission, smooth musclerelaxation and has trophic and
mitogenic actions)HSDALFTDTYTRLRKQMAMKKYLNSVLN-NH2 (SEQ ID NO:947)
{Ala2,8,9,11,19,22,24,25,27,28}-VIP (Highly selective agonist for
the VPAC1 receptor (IC50 values are~115-132 and >30000 nM for
VPAC1 and VPAC2 receptors respectively)))
HADAVFTAAYARLRKQMAAKKALAAIAA-NH2 (SEQ ID NO:948)
{Ac-Tyr1,D-Phe2}GRF 1-29, amide (human) (VIP antagonist; inhibits
{125I}iodo-VIP binding and selectively inhibits VIP- and
GRF-induced effects on adenylyl cyclase)
Ac-YdFDAIFTNSYRKVLGQLSARKLLQDIMSR-NH2 (SEQ ID NO:949) VIP (6-28)
(human, rat, porcine, bovine) (VIP antagonist)
FTDNYTRLRKQMAVKKYLNSILN-NH2 (SEQ ID NO:950) {D-p-Cl-Phe6,Leu17}-VIP
(Selective vasoactive intestinal peptide (VIP) antagonist
(IC50=1258 nM) Displays no activity on glucagon, secretin or GRF
receptors) HSDAVFTDNYTRLRKQLAVKKYLNSILN-NH2 Phe-6=p-Cl-D-Phe (SEQ
ID NO:951) Neurotensin XLYENKPRRPYIL X=Pyroglutamic acid (Pyr)
(pGlu) N-stearyl-{Nle17} neurotensin(6-11)/VIP (7-28)
neurotensin(6-11)/P ACAP (6-38) (SEQ ID NO:952) human pancreatic
polypeptide APLEPVYPGDNATPEQMAQYAADLRRYINMLTRPRY (SEQ ID NO:953)
Kinetensin (human) (Endogenous neurotensin-like peptide, originally
isolated from pepsin-treatedhuman plasma Induces histamine release
from rat peritoneal mast cells in vitro (ED50~10 mM))IARRHPYFL (SEQ
ID NO:954) JMV 449 (Potent, metabolically stable neurotensin
receptor agonist peptide (IC50=015 nM for inhibition of{125I}-NT
binding to neonatal mouse brain; EC50=19 nM for contraction of
guinea pigleum)Produces long-lasting hypothermic, neuroprotective
and analgesic effects in mice following central administration in
vivo)KKPYIL(Note: Lys-1-Lys-2 peptide bond replace with
Psi(CH2-NH))) (SEQ ID NO:955) Neuromedin N (rat, mouse, porcine,
canine) (Endogenous neurotensin-like neuropeptide, originally
isolated from porcine spinal cord. Binds toneurotensin receptors
(IC50=167 nM for inhibition of {Trp11}-NT bindingto rat brain
receptors) Regulates guinea pig intestinal smooth muscle
contraction and produces hypotension inrats Alsoinduces hypothermia
following central administration in rats in vivo) KIPYIL (SEQ ID
NO:956) des-His1-{Glu9}-Glucagon (1-29) amide (Glucagon receptor
antagonist (pA2=72 for inhibition of glucagon-induced adenylyl
cyclaseactivation in rat liver membranes); displays no agonist
activity Enhances glucose-stimulatedpancreatic insulin release in
vitro In vivo, blocks added glucagon-induced hyperglycemia in
normal rabbits without affecting glycogenolysis Also blocks
endogenous glucagon- induced hyperglycemia in streptozocin diabetic
rats) SQGTFTSEYSKYLDSRRAQDFVQWLMNT-NH2 (SEQ ID NO:957)
Antisauvagine-30 (Potent, selective and competitive
corticotropin-releasing factor CRF2 receptor antagonist (Kd
valuesare 14 and 1536 nM for binding to mouse CRF2.beta. and rat
CRF1 receptors respectively) Inhibitssauvagine-stimulated cAMP
accumulation in HEK-mCRF2.beta. cells (pA2=849) Prevents stress-
enhanced fear conditioning and MEK 1/2-dependent activation of
ERK1/2 in mice in vivo) dFHLLRKMIEIEKQEKEKQQAANNRLLLDTI-NH2 (SEQ ID
NO:958) >gi|76781480|ref|NP_0010205372| vascular endothelial
growth factor A isoform a {Homosapiens}
TDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFV
QLLGCSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVYVGARCCLMPWSLPGPHPCGPC
SERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR (SEQ ID NO:959)
>gi|76781481|ref|NP_0033674| vascular endothelial growth factor
A isoform b {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVPCGPCSERRKHLFVQDPQTCKC
SCKNTDSRCKARQLELNERTCRCDKPRR (SEQ ID NO:960)
gi|76781482|ref|NP_0010205382| vascular endothelial growth factor A
isoform c {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQEKKSVRGKGKGQKRKRKKSRPCGPCSERRKHLFVQDPQTCKCSCKNTDS
RCKARQLELNERTCRCDKPRR >gi|76781483|ref|NP_0010205392| vascular
endothelial growth factor A isoform d {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDK PRR
(SEQ ID NO:961) >gi|76781487|ref|NP_0010289281| vascular
endothelial growth factor A isoform g {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRSLTR
KD (SEQ ID NO:962) >gi|76781484|ref|NP_0010205402| vascular
endothelial growth factor A isoform e {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKM (SEQ ID NO:963)
>gi|76781485|ref|NP_0010205412| vascular endothelial growth
factor A isoform f {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQEKCDKPRR (SEQ ID NO:964) >gi|4507887|ref|NP_0033681|
vascular endothelial growth factor B precursor {Homosapiens}
MSPLLRRLLLAALLQLAPAQAPVSQPDAPGHQRKVVSWIDVYTRATCQPREVVVPLTVELM
GTVAKQLVPSCVTVQRCGGCCPDDGLECVPTGQHQVRMQILMIRYPSSQLGEMSLEEHSQC
ECRPKKKDSAVKPDRAATPHHRPQPRSVPGWDSAPGAPSPADITHPTPAPGPSAHAAPSTTSA
LTPGPAAAAADAAASSVAKGGA (SEQ ID NO:965)
>gi|4885653|ref|NP_0054201| vascular endothelial growth factor C
preproprotein {Homosapiens}
MHLLGFFSVACSLLAAALLPGPREAPAAAAAFESGLDLSDAEPDAGEATAYASKDLEEQLRS
VSSVDELMTVLYPEYWKMYKCQLRKGGWQHNREQANLNSRTEETIKFAAAHYNTEILKSID
NEWRKTQCMPREVCIDVGKEFGVATNTFFKPPCVSVYRCGGCCNSEGLQCMNTSTSYLSKT
LFEITVPLSQGPKPVTISFANHTSCRCMSKLDVYRQVHSIIRRSLPATLPQCQAANKTCPTNYM
WNNHICRCLAQEDFMFSSDAGDDSTDGFHDICGPNKELDEETCQCVCRAGLRPASCGPHKEL
DRNSCQCVCKNKLFPSQCGANREFDENTCQCVCKRTCPRNQPLNPGKCACECTESPQKCLL
KGKKFHHQTCSCYRRPCTNRQKACEPGFSYSEEVCRCVPSYVVKRPQMS (SEQ ID NO:966)
A-71623 (Potent CCK1 agonist (IC50=37 nM) with 1200-fold
selectivity over the CCK2 receptor Suppresses food intake following
central or peripheral administration) XWKDF-NH2 Trp-1=Boc-Trp,
Lys-3=Lys(Tac), Phe-5=N-methyl-Phe (SEQ ID NO:967) Enterostatin (N'
terminal peptide fragment of procolipase that binds to the
.beta.-subunit of F1-ATPase Activates the ERK and cAMP signaling
pathways, and downregulates expression of Krtippel-like factor 4
(KLF4) and agouti-related peptide (AgRP) in vitro Inhibits insulin
secretion from pancreatic .beta.-cells bydownregulating expression
of dynamin2 and altering via activation of CCK1, induces satiety,
enhances memory-consolidation and exhibits hypocholesterolemic
activity in vivo Orally active)) APGPR Ac2-12 (Annexin/lipocortin
1-mimetic peptide; inhibits leukocyte extravasation Reduces
neutrophil adhesion and emigration, and promotes detachment of
neutrophils from activated mesenteric endothelium in mice in vivo)
Ac-AMVSEFLKQAW (SEQ ID NO:968) Ac2-26 (Annexin/lipocortin 1-mimetic
peptide; inhibits leukocyte extravasation Reduces neutrophil
adhesion and emigration, and promotes detachment of neutrophils
from activated mesenteric endothelium in mice in vivo
Anti-inflammatory) Ac-AMVSEFLKQAWFIENEEQEYVQTVK (SEQ ID NO:969)
Peptide F9 (Peptide derived from the heparin-binding domain in the
B1 chain of laminin Binds to heparin, promotes cell adhesion, and
inhibits the migration towards, and adhesion of metastatic
fibrosarcoma cells to laminin) RYVVLPRPVCFEKGMNYTVR (SEQ ID NO:970)
R18 (Antagonist of 1433 proteins (KD .apprxeq.80 nM) Competitively
inhibits 1433-ligand interactions without requiring phosphorylation
Blocks the ability of 1433 to bind to target proteins such as
Raf-1, Bad, ASK1 and exoenzyme S Induces apoptosis)
PHCVPRDLSWLDLEANMCLP (SEQ ID NO:971) Thymosin .beta.34 (Naturally
occuring, potent regulator of actin polymerization present in human
platelets at a concentration of 200-500 .mu.M Sequesters G-actin
monomers in a 1:1 ratio (Kd=07-10 .mu.M) and allows rapid filament
polymerization in the presence of profilin Implicated in wound
healing,MMPs, chemotaxis, angiogenesis, inflammatory processes and
tumor progression induction of
Ac-SDKPDMAEIEKFDKSKLKKTETQEKNPLPSKETIEQEKQAGES (SEQ ID NO:972)
Anti-GluR4 blocking peptide (Synthetic peptide
({K}-HTGTAIRQSSGLAVIASDLP) corresponding to the C-terminal amino
acids883-902 of rat precursor GluR4 (Accession No P19493) with a
lysine added at the N-terminus of the peptide Immunogen used for
anti-GluR4) KHTGTAIRQSSGLAVIASDLP (SEQ ID NO:973)
Anti-phospho-GluR1(Ser831) phosphorylated blocking peptide 826-836
of rat mature(Synthetic peptide (LIPQQ(pS)INEA1{K}) corresponding
to amino acids GluR1 (Accession No P19490), with a phosphorylated
serine at position 831, and a lysine added to the C-terminus for
conjugation Immunogen used for anti- phospho-GluR1 (5er831))
LIPQQSINEAI Ser-6=phosphorylated Ser (SEQ ID NO:974) PHV (1-42)
HADGVFTSDFSKLLGQLSAKKYLESLMGKRVSSNISEDPVPV (SEQ ID NO:975) PRP
DVAHGILNQAYRKVLDQLSAGKHLQSLVA PHM HADGVFTSDFSKLLGQLSAKKYLESLM (SEQ
ID NO:976) >gi|4501947|ref|NP_0006651| adenosine receptor A1
{Homosapiens}
MPPSISAFQAAYIGIEVLIALVSVPGNVLVIVVAVKVNQALRDATFCFIVSLAVADVAVGALVI
PLAILINIGPQTYFHTCLMVACPVLILTQSSILALLAIAVDRYLRVKIPLRYKMVVTPRRAAVAI
AGCWILSFVVGLTPMFGWNNLSAVERAWAANGSMGEPVIKCEFEKVISMEYMVYFNFFVW
VLPPLLLMVLIYLEVFYLIRKQLNKKVSASSGDPQKYYGKELKIAKSLALILFLFALSWLPLHI
LNCITLFCPSCHKPSILTYIAIFLTHGNSAMNPIVYAFRIQKFRVTFLKIVVNDHFRCQPAPPIDED
LPEERPDD (SEQ ID NO:977) >gi|4501951|ref|NP_0006671| adenosine
receptor A2b {Homosapiens}
MLLETQDALYVALELVIAALSVAGNVLVCAAVGTANTLQTPTNYFLVSLAAADVAVGLFAI
PFAITISLGFCTDFYGCLFLACFVLVLTQSSIFSLLAVAVDRYLAICVPLRYKSLVTGTRARGVI
AVLWVLAFGIGLTPFLGWNSKDSATNNCTEPWDGTTNESCCLVKCLFENVVPMSYMVYFNF
FGCVLPPLLIMLVIYIKIFLVACRQLQRTELMDHSRTTLQREIHAAKSLAMIVGIFALCWLPVH
AVNCVTLFQPAQGKNKPKWAMNMAILLSHANSVVNPIVYAYRNRDFRYTFHKIISRYLLCQ
ADVKSGNGQAGVQPALGVGL (SEQ ID NO:978) >gi|4501953|ref|NP_0006681|
adenosine receptor A3 isoform 2 {Homosapiens}
MPNNSTALSLANVTYITMEIFIGLCAIVGNVLVICVVKLNPSLQTTTFYFIVSLALADIAVGVL
VMPLAIVVSLGITIHFYSCLFMTCLLLIFTHASIMSLLAIAVDRYLRVKLTVRYKRVTTHRRIVV
LALGLCWLVSFLVGLTPMFGWNMKLTSEYHRNVTFLSCQFVSVMRMDYMVYFSFLTWIFIP
LVVMCAIYLDIFYIIRNKLSLNLSNSKETGAFYGREFKTAKSLFLVLFLFALSWLPLSHNCIIYF
NGEVPQLVLYMGILLSHANSMMNPIVYAYKIKKFKETYLLILKACVVCHPSDSLDTSIEKNSE
(SEQ ID NO:979) >gi|4501957|ref|NP_0006691| alpha-1D adrenergic
receptor {Homosapiens}
MTFRDLLSVSFEGPRPDSSAGGSSAGGGGGSAGGAAPSEGPAVGGVPGGAGGGGGVVGAGS
GEDNRSSAGEPGSAGAGGDVNGTAAVGGLVVSAQGVGVGVFLAAFILMAVAGNLLVILSV
ACNRHLQTVTNYFIVNLAVADLLLSATVLPFSATMEVLGFWAFGRAFCDVWAAVDVLCCT
ASILSLCTISVDRYVGVRHSLKYPAIMTERKAAAILALLWVVALVVSVGPLLGWKEPVPPDE
RFCGITEEAGYAVFSSVCSFYLPMAVIVVMYCRVYVVARSTTRSLEAGVKRERGKASEVVLR
IHCRGAATGADGAHGMRSAKGHTFRSSLSVRLLKFSREKKAAKTLAIVVGVFVLCWFPFFFV
LPLGSLFPQLKPSEGVFKVIFWLGYFNSCVNPLIYPCSSREFKRAFLRLLRCQCRRRRRRRPLW
RVYGHHWRASTSGLRQDCAPSSGDAPPGAPLALTALPDPDPEPPGTPEMQAPVASRRKPPSA
FREWRLLGPFRRPTTQLRAKVSSLSHKIRAGGAQRAEAACAQRSEVEAVSLGVPHEVAEGAT
CQAYELADYSNLRETDI (SEQ ID NO:980) >gi|4501959|ref|NP_0006701|
alpha-1B adrenergic receptor {Homosapiens}
MNPDLDTGHNTSAPAHWGELKNANFTGPNQTSSNSTLPQLDITRAISVGLVLGAFILFAIVGN
ILVILSVACNRHLRTPTNYFIVNLAMADLLLSFTVLPFSAALEVLGYWVLGRIFCDIVVAAVDV
LCCTASILSLCAISIDRYIGVRYSLQYPTLVTRRKAILALLSVWVLSTVISIGPLLGWKEPAPND
DKECGVTEEPFYALFSSLGSFYIPLAVILVMYCRVYIVAKRTTKNLEAGVMKEMSNSKELTL
RIHSKNFHEDTLSSTKAKGHNPRSSIAVKLFKFSREKKAAKTLGIVVGMFILCWLPFFIALPLG
SLFSTLKPPDAVFKVVFWLGYFNSCLNPIIYPCSSKEFKRAFVRILGCQCRGRGRRRRRRRRRL
GGCAYTYRPWTRGGSLERSQSRKDSLDDSGSCLSGSQRTLPSASPSPGYLGRGAPPPVELCAF
PEWKAPGALLSLPAPEPPGRRGRHDSGPLFTFKLLTEPESPGTDGGASNGGCEAAADVANGQ
PGFKSNMPLAPGQF (SEQ ID NO:981) >gi|4501969|ref|NP_0000151|
adrenergic, beta-2-, receptor, surface {Homosapiens}
MGQPGNGSAFLLAPNRSHAPDHDVTQQRDEVWVVGMGIVMSLIVLAIVFGNVLVITAIAKFE
RLQTVTNYFITSLACADLVMGLAVVPFGAAHILMKMWTFGNFWCEFWTSIDVLCVTASIETL
CVIAVDRYFAITSPFKYQSLLTKNKARVIILMVWIVSGLTSFLPIQMHWYRATHQEAINCYAN
ETCCDFFTNQAYAIASSIVSFYVPLVIMVFVYSRVFQEAKRQLQKIDKSEGRFHVQNLSQVEQ
DGRTGHGLRRSSKFCLKEHKALKTLGIIMGTFTLCWLPFFIVNIVHVIQDNLIRKEVYILLNWI
GYVNSGFNPLIYCRSPDFRIAFQELLCLRRSSLKAYGNGYSSNGNTGEQSGYHVEQEKENKLL
CEDLPGTEDFVGHQGTVPSDNIDSQGRNCSTNDSLL (SEQ ID NO:982)
>gi|4501997|ref|NP_0006761| type-1 angiotensin II receptor
{Homosapiens}
MILNSSTEDGIKRIQDDCPKAGRHNYIFVMIPTLYSIIFVVGIFGNSLVVIVIYFYMKLKTVASV
FLLNLALADLCFLLTLPLWAVYTAMEYRWPFGNYLCKIASASVSFNLYASVFLLTCLSIDRYL
AIVHPMKSRLRRTMLVAKVTCIIIVVLLAGLASLPAIIHRNVFFIENTNITVCAFHYESQNSTLPI
GLGLTKNILGFLFPFLIILTSYTLIVVKALKKAYEIQKNKPRNDDIFKIIMAIVLFFFFSWIPHQIFT
FLDVLIQLGIIRDCRIADIVDTAMPITICIAYFNNCLNPLFYGFLGKKFKRYFLQLLKYIPPKAKS
HSNLSTKMSTLSYRPSDNVSSSTKKPAPCFEVE (SEQ ID NO:983)
>gi|4502331|ref|NP_0006971| vasopressin V1a receptor
{Homosapiens}
MRLSAGPDAGPSGNSSPWWPLATGAGNTSREAEALGEGNGPPRDVRNEELAKLEIAVLAVT
FAVAVLGNSSVLLALHRTPRKTSRMHLFIRHLSLADLAVAFFQVLPQMCWDITYRFRGPDWL
CRVVKHLQVFGMFASAYMLVVMTADRYIAVCHPLKTLQQPARRSRLMIAAAWVLSFVLST
PQYFVFSMIEVNNVTKARDCWATFIQPWGSRAYVTWMTGGIFVAPVVILGTCYGFICYNIVVC
NVRGKTASRQSKGAEQAGVAFQKGFLLAPCVSSVKSISRAKIRTVKMTFVIVTAYIVCWAPF
FIIQMWSVWDPMSVVVTESENPTITITALLGSLNSCCNPWIYMFFSGHLLQDCVQSFPCCQNM
KEKFNKEDTDSMSRRQTFYSNNRSPTNSTGMWKDSPKSSKSIKFIPVST (SEQ ID NO:984)
>gi|4502333|ref|NP_0006981| vasopressin V1b receptor
{Homosapiens}
MDSGPLWDANPTPRGTLSAPNATTPWLGRDEELAKVEIGVLATVLVLATGGNLAVLLTLGQ
LGRKRSRMHLFVLHLALTDLAVALFQVLPQLLWDITYRFQGPDLLCRAVKYLQVLSMFAST
YMLLAMTLDRYLAVCHPLRSLQQPGQSTYLLIAAPWLLAAIFSLPQVFIFSLREVIQGSGVLD
CWADFGFPWGPRAYLTWTTLAIFVLPVTMLTACYSLICHEICKNLKVKTQAWRVGGGGWR
TWDRPSPS TLAATTRGLPSRVSSINTISRAKIRTVKMTFVIVLAYIACWAPFFSVQMWSVVVDK
NAPDEDSTNVAFTISMLLGNLNSCCNPWIYMGFNSHLLPRPLRHLACCGGPQPRMRRRLSDG
SLSSRHTTLLTRSSCPATLSLSLSLTLSGRPRPEESPRDLELADGEGTAETIIF (SEQ ID
NO:985) >gi|4502359|ref|NP_0016951| brain-specific angiogenesis
inhibitor 3 precursor {Homosapiens}
MKAVRNLLIYIFSTYLLVMFGFNAAQDFWCSTLVKGVIYGSYSVSEMFPKNFTNCTVVTLENP
DPTKYSIYLKFSKKDLSCSNFSLLAYQFDHFSHEKIKDLLRKNHSIMQLCNSKNAFVFLQYDK
NFIQIRRVFPTNFPGLQKKGEEDQKSFFEFLVLNKVSPSQFGCHVLCTVVLESCLKSENGRTESC
GIMYTKCTCPQHLGEWGIDDQSLILLNNVVLPLNEQTEGCLTQELQTTQVCNLTREAKRPPK
EEFGMMGDHTIKSQRPRSVHEKRVPQEQADAAKFMAQTGESGVEEWSQWSTCSVTCGQGS
QVRTRTCVSPYGTHCSGPLRESRVCNNTALCPVHGVWEEWSPWSLCSFTCGRGQRTRTRSC
TPPQYGGRPCEGPETHHKPCNIALCPVDGQWQEWSSWSQCSVTCSNGTQQRSRQCTAAAHG
GSECRGPWAESRECYNPECTANGQWNQWGHWSGCSKSCDGGWERRIRTCQGAVITGQQCE
GTGEEVRRCSEQRCPAPYEICPEDYLMSMVWKRTPAGDLAFNQCPLNATGTTSRRCSLSLHG
VAFWEQPSFARCISNEYRHLQHSIKEHLAKGQRMLAGDGMSQVTKTLLDLTQRKNFYAGDL
LMSVEILRNVTDTFKRASYIPASDGVQNFFQIVSNLLDEENKEKWEDAQQIYPGSIELMQVIE
DFIHIVGMGMMDFQNSYLMTGNVVASIQKLPAASVLTDINFPMKGRKGMVDWARNSEDRV
VIPKSIFTPVSSKELDESSVFVLGAVLYKNLDLILPTLRNYTVINSKIIVVTIRPEPKTTDSFLEIE
LAHLANGTLNPYCVLWDDSKTNESLGTWSTQGCKTVLTDASHTKCLCDRLSTFAILAQQPR
EIIMESSGTPSVTLIVGSGLSCLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQT
HNKSICTTTTAFLHFFFLASFCWVLTEAWQSYMAVTGKIRTRLIRKRFLCLGWGLPALVVAT
SVGFTRTKGYGTDHYCWLSLEGGLLYAFVGPAAAVVLVNMVIGILVFNKLVSRDGILDKKL
KHRAGQMSEPHSGLTLKCAKCGVVSTTALSATTASNAMASLWSSCVVLPLLALTWMSAVL
AMTDKRSILFQILFAVFDSLQGFVIVMVHCILRREVQDAFRCRLRNCQDPINADSSSSFPNGH
AQIMTDFEKDVDIACRSVLHKDIGPCRAATITGTLSRISLNDDEEEKGTNPEGLSYSTLPGNVI
SKVIIQQPTGLHMPMSMNELSNPCLKKENSELRRTVYLCTDDNLRGADMDIVHPQERMMES
DYIVMPRSSVNNQPSMKEESKMNIGMETLPHERLLHYKVNPEFNMNPPVMDQFNMNLEQH
LAPQEHMQNLPFEPRTAVKNFMASELDDNAGLSRSETGSTISMSSLERRKSRYSDLDFEKVM
HTRKRHMELFQELNQKFQTLDRFRDIPNTSSMENPAPNKNPWDTFKNPSEYPHYTTINVLDT
EAKDALELRPAEWEKCLNLPLDVQEGDFQTEV (SEQ ID NO:986)
>gi|4502415|ref|NP_0017071|Burkitt lymphoma receptor 1 isoform 1
{Homosapiens}
MNYPLTLEMDLENLEDLFVVELDRLDNYNDTSLVENHLCPATEGPLMASFKAVFVPVAYSLIF
LLGVIGNVLVLVILERHRQTRSSTETFLFHLAVADLLLVFILPFAVAEGSVGWVLGTFLCKTVI
ALHKVNFYCSSLLLACIAVDRYLAIVHAVHAYRHRRLLSIHITCGTIVVLVGFLLALPEILFAKV
SQGHHNNSLPRCTFSQENQAETHAWFTSRFLYHVAGFLLPMLVMGWCYVGVVHRLRQAQR
RPQRQKAVRVAILVTSIFFLCWSPYHIVIFLDTLARLKAVDNTCKLNGSLPVAITMCEFLGLA
HCCLNPMLYTFAGVKFRSDLSRLLTKLGCTGPASLCQLFPSWRRSSLSESENATSLTTF (SEQ ID
NO:987) >gi|4502455|ref|NP_0017181| bombesin receptor subtype-3
{Homosapiens}
MAQRQPHSPNQTLISITNDTESSSSVVSNDNTNKGWSGDNSPGIEALCAIYITYAVIISVGILGN
AILIKVFFKTKSMQTVPNIFITSLAFGDLLLLLTCVPVDATHYLAEGWLFGRIGCKVLSFIRLTS
VGVSVFTLTILSADRYKAVVKPLERQPSNAILKTCVKAGCVWIVSMIFALPEAIFSNVYTFRD
IPNKNMTFESCTSYPVSKKLLQEIHSLLCFLVFYIIPLSIISVYYSLIARTLYKSTLNIPTEEQSHAR
KQIESRKRIARTVLVLVALFALCWLPNHLLYLYHSFTSQTYVDPSAMHFIFTIFSRVLAFSNSC
VNPFALYWLSKSFQKHFKAQLFCCKAERPEPPVADTSLTTLAVMGTVPGTGSIQMSEISVTSF
TGCSVKQAEDRF (SEQ ID NO:988) >gi|4502509|ref| NP_0017271| C5a
anaphylatoxin chemotactic receptor {Homosapiens}
MNSFNYTTPDYGHYDDKDTLDLNTPVDKTSNTLRVPDILALVIFAVVFLVGVLGNALVVWV
TAFEAKRTINAIWFLNLAVADFLSCLALPILFTSIVQHHHWPFGGAACSILPSLILLNMYASILL
LATISADRFLLVFKPIVVCQNFRGAGLAWIACAVAWGLALLLTIPSFLYRVVREEYFPPKVLCG
VDYSHDKRRERAVAIVRLVLGFLWPLLTLTICYTFILLRTWSRRATRSTKTLKVVVAVVASFF
IIFVVLPYQVTGIMMSFLEPSSPTFLLLNKLDSLCVSFAYINCCINPIIYVVAGQGFQGRLRKSLPS
LLRNVLTEESVVRESKSFTRSTVDTMAQKTQAV (SEQ ID NO:989)
>gi|4502547|ref|NP_0017331| calcitonin receptor isoform 2
precursor {Homosapiens}
MRFTFTSRCLALFLLLNHPTPILPAFSNQTYPTIEPKPFLYVVGRKKMMDAQYKCYDRMQQL
PAYQGEGPYCNRTWDGWLCWDDTPAGVLSYQFCPDYFPDFDPSEKVTKYCDEKGVVVFKHP
ENNRTWSNYTMCNAFTPEKLKNAYVLYYLAIVGHSLSIFTLVISLGIFVFFRSLGCQRVTLHK
NMFLTYILNSMIIIIHLVEVVPNGELVRRDPVSCKILHFFHQYMMACNYFVVMLCEGIYLHTLI
VVAVFTEKQRLRWYYLLGWGFPLVPTTIHAITRAVYFNDNCWLSVETHLLYIIHGPVMAAL
VVNFFFLLNIVRVLVTKMRETHEAESHMYLKAVKATMILVPLLGIQFVVFPWRPSNKMLGKI
IYDYVMHSLIHFQGFFVATIYCFCNNEVQTTVKRQWAQFKIQWNQRWGRRPSNRSARAAAA
AAEAGDIPIYICHQELRNEPANNQGEESAEIIPLNIIEQESSA (SEQ ID NO:990)
>gi|4502607|ref|NP_0007211| cholecystokinin receptor type A
{Homosapiens}
MDVVDSLLVNGSNITPPCELGLENETLFCLDQPRPSKEWQPAVQILLYSLIFLLSVLGNTLVIT
VLIRNKRMRTVTNIFLLSLAVSDLMLCLFCMPFNLIPNLLKDFIFGSAVCKTTTYFMGTSVSVS
TFNLVAISLERYGAICKPLQSRVVVQTKSHALKVIAATWCLSFTIMTPYPIYSNLVPFTKNNNQ
TANMCRFLLPNDVMQQSWHTFLLLILFLIPGIVMMVAYGLISLELYQGIKFEASQKKSAKERK
PSTTSSGKYEDSDGCYLQKTRPPRKLELRQLSTGSSSRANRIRSNSSAANLMAKKRVIRMLIVI
VVLFFLCWMPIFSANAWRAYDTASAERRLSGTPISFILLLSYTSSCVNPIIYCFMNKRFRLGFM
IATFPCCPNPGPPGARGEVGEEEEGGTTGASLSRFSYSHMSASVPPQ (SEQ ID NO:991)
>gi|4502631|ref|NP_0012861| C-C chemokine receptor type 1
{Homosapiens}
METPNTTEDYDTTTEFDYGDATPCQKVNERAFGAQLLPPLYSLVFVIGLVGNILVVLVLVQY
KRLKNMTSIYLLNLAISDLLFLFTLPFWIDYKLKDDWVFGDAMCKILSGFYYTGLYSEIFFIIL
LTIDRYLAIVHAVFALRARTVTFGVITSIIIVVALAILASMPGLYFSKTQWEFTHHTCSLHFPHES
LREWKLFQALKLNLFGLVLPLLVMIICYTGIIKILLRRPNEKKSKAVRLIFVIMIIFFLFVVTPYN
LTILISVFQDFLFTHECEQSRHLDLAVQVTEVIAYTHCCVNPVIYAFVGERFRKYLRQLFHRR
VAVHLVKWLPFLSVDRLERVSSTSPSTGEHELSAGF (SEQ ID NO:992)
>gi|4502637|ref|NP_0018281| C-C chemokine receptor type 3
isoform 1 {Homosapiens}
MTTSLDTVETFGTTSYYDDVGLLCEKADTRALMAQFVPPLYSLVFTVGLLGNVVVVMILIKY
RRLRIMTNIYLLNLAISDLLFLVTLPFWIHYVRGHNVVVFGHGMCKLLSGFYHTGLYSEIFFIIL
LTIDRYLAIVHAVFALRARTVTFGVITSIVTWGLAVLAALPEFIFYETEELFEETLCSALYPEDT
VYSWRHFHTLRMTIFCLVLPLLVMAICYTGIIKTLLRCPSKKKYKAIRLIFVIMAVFFIFVVTPY
NVAILLSSYQSILFGNDCERSKHLDLVMLVTEVIAYSHCCMNPVIYAFVGERFRKYLRHFFHR
HLLMHLGRYIPFLPSEKLERTSSVSPSTAEPELSIVF (SEQ ID NO:993)
>gi|4502639|ref|NP_0005701| chemokine (C-C motif) receptor 5
{Homosapiens}
MDYQVSSPIYDINYYTSEPCQKINVKQIAARLLPPLYSLVFIFGFVGNMLVILILINCKRLKSMT
DIYLLNLAISDLFFLLTVPFWAHYAAAQWDFGNTMCQLLTGLYFIGFFSGIFFIILLTIDRYLAV
VHAVFALKARTVTFGVVTSVITWVVAVFASLPGIIFTRSQKEGLHYTCSSHFPYSQYQFVVKN
FQTLKIVILGLVLPLLVMVICYSGILKTLLRCRNEKKRHRAVRLIFTIMIVYFLFWAPYNIVLLL
NTFQEFFGLNNCSSSNRLDQAMQVTETLGMTHCCINPIIYAFVGEKFRNYLLVFFQKHIAKRF
CKCCSIFQQEAPERASSVYTRSTGEQEISVGL (SEQ ID NO:994)
>gi|4502641|ref|NP_0018291| chemokine (C-C motif) receptor 7
precursor {Homosapiens}
MDLGKPMKSVLVVALLVIFQVCLCQDEVTDDYIGDNTTVDYTLFESLCSKKDVRNFKAWFL
PIMYSIICFVGLLGNGLVVLTYIYFKRLKTMTDTYLLNLAVADILFLLTLPFVVAYSAAKSWVF
GVHFCKLIFAIYKMSFFSGMLLLLCISIDRYVAIVQAVSAHRHRARVLLISKLSCVGIVVILATV
LSIPELLYSDLQRSSSEQAMRCSLITEHVEAFITIQVAQMVIGFLVPLLAMSFCYLVIIRTLLQA
RNFERNKAIKVIIAVVVVFIVFQLPYNGVVLAQTVANFNITSSTCELSKQLNIAYDVTYSLACV
RCCVNPFLYAFIGVKFRNDLFKLFKDLGCLSQEQLRQWSSCRHIRRSSMSVEAETTTTFSP (SEQ
ID NO:995) >gi|4502817|ref|NP_0007301| cholinergic receptor,
muscarinic 2 {Homosapiens}
MNNSTNSSNNSLALTSPYKTFEVVFIVLVAGSLSLVTIIGNILVMVSIKVNRHLQTVNNYFLFS
LACADLIIGVFSMNLYTLYTVIGYWPLGPVVCDLWLALDYVVSNASVMNLLIISFDRYFCVT
KPLTYPVKRTTKMAGMMIAAAWVLSFILWAPAILFVVQFIVGVRTVEDGECYIQFFSNAAVTF
GTAIAAFYLPVIIMTVLYWHISRASKSRIKKDKKEPVANQDPVSPSLVQGRIVKPNNNNMPSS
DDGLEHNKIQNGKAPRDPVTENCVQGEEKESSNDSTSVSAVASNMRDDEITQDENTVSTSLG
HSKDENSKQTCIRIGTKTPKSDSCTPTNTTVEVVGSSGQNGDEKQNIVARKIVKMTKQPAKK
KPPPSREKKVTRTILAILLAFIITWAPYNVMVLINTFCAPCIPNTVVVTIGYWLCYINSTINPACY
ALCNATFKKTFKHLLMCHYKNIGATR (SEQ ID NO:996)
>gi|4502819|ref|NP_0007311| cholinergic receptor, muscarinic 3
{Homosapiens}
MTLHNNSTTSPLFPNISSSWIHSPSDAGLPPGTVTHFGSYNVSRAAGNFSSPDGTTDDPLGGHT
VWQVVFIAFLTGILALVTIIGNILVIVSFKVNKQLKTVNNYFLLSLACADLIIGVISMNLFTTYII
MNRWALGNLACDLWLAIDYVASNASVMNLLVISFDRYFSITRPLTYRAKRTTKRAGVMIGL
AWVISFVLWAPAILFWQYFVGKRTVPPGECFIQFLSEPTITFGTAIAAFYMPVTIMTILYWRIY
KETEKRTKELAGLQASGTEAETENFVHPTGSSRSCSSYELQQQSMKRSNRRKYGRCHFVVFTT
KSWKPSSEQMDQDHSSSDSWNNNDAAASLENSASSDEEDIGSETRAIYSIVLKLPGHSTILNS
TKLPSSDNLQVPEEELGMVDLERKADKLQAQKSVDDGGSFPKSFSKLPIQLESAVDTAKTSD
VNSSVGKSTATLPLSFKEATLAKRFALKTRSQITKRKRMSLVKEKKAAQTLSAILLAFIITWTP
YNIMVLVNTFCDSCIPKTFVVNLGYWLCYINSTVNPVCYALCNKTFRTTFKMLLL
CQCDKKKRRKQQYQQRQSVIFHKRAPEQAL (SEQ ID NO:997)
>gi|4502929|ref|NP_0018321| cannabinoid receptor 2 {Homosapiens}
MEECWVTEIANGSKDGLDSNPMKDYMILSGPQKTAVAVLCTLLGLLSALENVAVLYLILSSH
QLRRKPSYLFIGSLAGADFLASVVFACSFVNFHVFHGVDSKAVFLLKIGSVTMTFTASVGSLL
LTAIDRYLCLRYPPSYKALLTRGRALVTLGIMWVLSALVSYLPLMGWTCCPRPCSELFPLIPN
DYLLSWLLFIAFLFSGIIYTYGHVLWKAHQHVASLSGHQDRQVPGMARMRLDVRLAKTLGL
VLAVLLICWFPVLALMAHSLATTLSDQVKKAFAFCSMLCLINSMVNPVIYALRSGEIRSSAHH
CLAHWKKCVRGLGSEAKEEAPRSSVTETEADGKITPWPDSRDLDLSDC (SEQ ID NO:998)
>gi|4503171|ref|NP_0013281| CX3C chemokine receptor 1 isoform b
{Homosapiens}
MDQFPESVTENFEYDDLAEACYIGDIVVFGTVFLSIFYSVIFAIGLVGNLLVVFALTNSKKPKS
VTDIYLLNLALSDLLFVATLPFWTHYLINEKGLHNAMCKFTTAFFFIGFFGSIFFITVISIDRYL
AIVLAANSMNNRTVQHGVTISLGVWAAAILVAAPQFMFTKQKENECLGDYPEVLQEIVVPVL
RNVETNFLGFLLPLLIMSYCYFRIIQTLFSCKNHKKAKAIKLILLVVIVFFLFVVTPYNVMIFLET
LKLYDFFPSCDMRKDLRLALSVTETVAFSHCCLNPLIYAFAGEKFRRYLYHLYGKCLAVLCG
RSVHVDFSSSESQRSRHGSVLSSNFTYHTSDGDALLLL (SEQ ID NO:999)
>gi|4503175|ref|NP_0034581| chemokine (C-X-C motif) receptor 4
isoform b {Homosapiens}
MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGLVILVMG
YQKKLRSMTDKYRLHLSVADLLFVITLPFVVAVDAVANWYFGNFLCKAVHVIYTVNLYSSVL
ILAFISLDRYLAIVHATNSQRPRKLLAEKVVYVGVWIPALLLTIPDFIFANVSEADDRYICDRF
YPNDLWVVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKTTVILILAFFACWLP
YYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPILYAFLGAKFKTSAQHALTSV
SRGSSLKILSKGKRGGHSSVSTESESSSFHSS (SEQ ID NO:1000)
>gi|4503383|ref|NP_0007851| d(1A) dopamine receptor
{Homosapiens}
MRTLNTSAMDGTGLVVERDFSVRILTACFLSLLILSTLLGNTLVCAAVIRFRHLRSKVTNFFVI
SLAVSDLLVAVLVMPWKAVAEIAGFWPFGSFCNIWVAFDIMCSTASILNLCVISVDRYWAISS
PFRYERKMTPKAAFILISVAWTLSVLISFIPVQLSWHKAKPTSPSDGNATSLAETIDNCDSSLSR
TYAISSSVISFYIPVAIMIVTYTRIYRIAQKQIRRIAALERAAVHAKNCQTTTGNGKPVECSQPE
SSFKMSFKRETKVLKTLSVIMGVFVCCWLPFFILNCILPFCGSGETQPFCIDSNTFDVFVVVFGW
ANSSLNPIIYAFNADFRKAFSTLLGCYRLCPATNNAIETVSINNNGAAMFSSHHEPRGSISKEC
NLVYLIPHAVGSSEDLKKEEAAGIARPLEKLSPALSVILDYDTDVSLEKIQPITQNGQHPT (SEQ
ID NO:1001) >gi|4503385|ref|NP_0007861| d(2) dopamine receptor
isoform long {Homosapiens}
MDPLNLSWYDDDLERQNWSRPFNGSDGKADRPHYNYYATLLTLLIAVIVFGNVLVCMAVS
REKALQTTTNYLIVSLAVADLLVATLVMPWVVYLEVVGEWKFSRIHCDIFVTLDVMMCTAS
ILNLCAISIDRYTAVAMPMLYNTRYSSKRRVTVMISIVWVLSFTISCPLLFGLNNADQNECIIA
NPAFVVYSSIVSFYVPFIVTLLVYIKIYIVLRRRRKRVNTKRSSRAFRAHLRAPLKGNCTHPED
MKLCTVIMKSNGSFPVNRRRVEAARRAQELEMEMLSSTSPPERTRYSPIPPSHHQLTLPDPSH
HGLHSTPDSPAKPEKNGHAKDHPKIAKIFEIQTMPNGKTRTSLKTMSRRKLSQQKEKKATQM
LAIVLGVFIICWLPFFITHILNIHCDCNIPPVLYSAFTWLGYVNSAVNPHYTTFNIEFRKAFLKIL
HC (SEQ ID NO:1002) >gi|4503391|ref|NP_0007891| d(1B) dopamine
receptor {Homosapiens}
MLPPGSNGTAYPGQFALYQQLAQGNAVGGSAGAPPLGPSQVVTACLLTLLIIVVTLLGNVLVC
AAIVRSRHLRANMTNVFIVSLAVSDLFVALLVMPWKAVAEVAGYWPFGAFCDVWVAFDIM
CSTASILNLCVISVDRYVVAISRPFRYKRKMTQRMALVMVGLAWTLSILISFIPVQLNWHRDQ
AASWGGLDLPNNLANVVTPWEEDFWEPDVNAENCDSSLNRTYAISSSLISFYIPVAIMIVTYTR
IYRIAQVQIRRISSLERAAEHAQSCRSSAACAPDTSLRASIKKETKVLKTLSVIMGVFVCCWLP
FFILNCMVPFCSGHPEGPPAGFPCVSETTFDVFVVVFGWANSSLNPVIYAFNADFQKVFAQLLG
CSHFCSRTPVETVNISNELISYNQDIVFHKEIAAAYIHMMPNAVTPGNREVDNDEEEGPFDRM
FQIYQTSPDGDPVAESVWELDCEGEISLDKITPFTPNGFH (SEQ ID NO:1003)
>gi|4503459|ref|NP_0037661| sphingosine-1-phosphate receptor 4
precursor {Homosapiens}
MNATGTPVAPESCQQLAAGGHSRLIVLHYNHSGRLAGRGGPEDGGLGALRGLSVAASCLVV
LENLLVLAAITSHMRSRRWVYYCLVNITLSDLLTGAAYLANVLLSGARTFRLAPAQWFLREG
LLFTALAASTFSLLFTAGERFATMVRPVAESGATKTSRVYGFIGLCWLLAALLGMLPLLGWN
CLCAFDRCSSLLPLYSKRYILFCLVIFAGVLATIMGLYGAIFRLVQASGQKAPRPAARRKARR
LLKTVLMILLAFLVCWGPLFGLLLADVFGSNLWAQEYLRGMDWILALAVLNSAVNPIIYSFR
SREVCRAVLSFLCCGCLRLGMRGPGDCLARAVEAHSGASTTDSSLRPRDSFRGSRSLSFRMR
EPLSSISSVRSI (SEQ ID NO:1004) >gi|4503465|ref|NP_0019481|
endothelin-1 receptor isoform a precursor {Homosapiens}
METLCLRASFVVLALVGCVISDNPERYSTNLSNHVDDFTTFRGTELSFLVTTHQPTNLVLPSNG
SMHNYCPQQTKITSAFKYINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDL
IYVVIDLPINVFKLLAGRWPFDHNDFGVFLCKLFPFLQKSSVGITVLNLCALSVDRYRAVASW
SRVQGIGIPLVTAIEIVSIVVILSFILAIPEAIGFVMVPFEYRGEQHKTCMLNATSKFMEFYQDVK
DWWLFGFYFCMPLVCTAIFYTLMTCEMLNRRNGSLRIALSEHLKQRREVAKTVFCLVVIFAL
CWFPLHLSRILKKTVYNEMDKNRCELLSFLLLMDYIGINLATMNSCINPIALYFVSKKFKNCF
QSCLCCCCYQSKSLMTSVPMNGTSIQWKNHDQNNHNTDRSSHKDSMN (SEQ ID NO:1005)
>gi|4503779|ref|NP_0020201| fMet-Leu-Phe receptor {Homosapiens}
METNSSLPTNISGGTPAVSAGYLFLDIITYLVFAVTFVLGVLGNGLVIWVAGFRMTHTVTTIS
YLNLAVADFCFTSTLPFFMVRKAMGGHWPFGWFLCKFVFTIVDINLFGSVFLIALIALDRCVC
VLHPVWTQNHRTVSLAKKVIIGPWVMALLLTLPVIIRVTTVPGKTGTVACTFNFSPWTNDPK
ERINVAVAMLTVRGIIRFIIGFSAPMSIVAVSYGLIATKIHKQGLIKSSRPLRVLSFVAAAFFLC
WSPYQVVALIATVRIRELLQGMYKEIGIAVDVTSALAFFNSCLNPMLYVFMGQDFRERLIHA
LPASLERALTEDSTQTSDTATNSTLPSAEVELQAK (SEQ ID NO:1006)
>gi|4503781|ref|NP_0014531| N-formyl peptide receptor 2
{Homosapiens}
METNFSTPLNEYEEVSYESAGYTVLRILPLVVLGVTFVLGVLGNGLVIVVVAGFRMTRTVTTI
CYLNLALADFSFTATLPFLIVSMAMGEKWPFGWFLCKLIHIVVDINLFGSVFLIGFIALDRCIC
VLHPVWAQNHRTVSLAMKVIVGPWILALVLTLPVFLFLTTVTIPNGDTYCTFNFASWGGTPE
ERLKVAITMLTARGIIRFVIGFSLPMSIVAICYGLIAAKIHKKGMIKSSRPLRVLTAVVASFFIC
WFPFQLVALLGTVWLKEMLFYGKYKIIDILVNPTSSLAFFNSCLNPMLYVFVGQDFRERLIHS
LPTSLERALSEDSAPTNDTAANSASPPAETELQAM (SEQ ID NO:1007)
>gi|4503905|ref|NP_0038481| galanin receptor type 2
{Homosapiens}
MNVSGCPGAGNASQAGGGGGWHPEAVIVPLLFALIFLVGTVGNTLVLAVLLRGGQAVSTTN
LFILNLGVADLCFILCCVPFQATIYTLDGWVFGSLLCKAVHFLIFLTMHASSFTLAAVSLDRYL
AIRYPLHSRELRTPRNALAAIGLIVVGLSLLFSGPYLSYYRQSQLANLTVCHPAWSAPRRRAM
DICTFVFSYLLPVLVLGLTYARTLRYLWRAVDPVAAGSGARRAKRKVTRMILIVAALFCLCW
MPHHALILCVWFGQFPLTRATYALRILSHLVSYANSCVNPIVYALVSKHFRKGFRTICAGLLG
RAPGRASGRVCAAARGTHSGSVLERESSDLLHMSEAAGALRPCPGASQPCILEPCPGPSWQG
PKAGDSILTVDVA
(SEQ ID NO:1008) >gi|4503907|ref|NP_0036051| galanin receptor
type 3 {Homosapiens}
MADAQNISLDSPGSVGAVAVPVVFALIFLLGTVGNGLVLAVLLQPGPSAWQEPGSTTDLFIL
NLAVADLCFILCCVPFQATIYTLDAWLFGALVCKAVHLLIYLTMYASSFTLAAVSVDRYLAV
RHPLRSRALRTPRNARAAVGLVWLLAALFSAPYLSYYGTVRYGALELCVPAWEDARRRAL
DVATFAAGYLLPVAVVSLAYGRTLRFLWAAVGPAGAAAAEARRRATGRAGRAMLAVAAL
YALCWGPHHALILCFWYGRFAFSPATYACRLASHCLAYANSCLNPLVYALASRHFRARFRR
LWPCGRRRRHRARRALRRVRPASSGPPGCPGDARPSGRLLAGGGQGPEPREGPVHGGEAAR GPE
(SEQ ID NO:1009) >gi|4503947|ref|NP_0001511| glucagon receptor
precursor {Homosapiens}
MPPCQPQRPLLLLLLLLACQPQVPSAQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTF
DKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQC
QMDGEEIEVQKEVAKMYSSFQVMYTVGYSLSLGALLLALAILGGLSKLHCTRNAIHANLFAS
FVLKASSVLVIDGLLRTRYSQKIGDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANYCWLLV
EGLYLHNLLGLATLPERSFFSLYLGIGWGAPMLFVVPWAVVKCLFENVQCWTSNDNMGFVV
WILRFPVFLAILINFFIFVRIVQLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGVHEVVFAFV
TDEHAQGTLRSAKLFFDLFLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRLGKVLWEERN
TSNHRASSSPGHGPPSKELQFGRGGGSQDSSAETPLAGGLPRLAESPF (SEQ ID NO:1010)
>gi|4503999|ref|NP_0001551| gastric inhibitory polypeptide
receptor precursor {Homosapiens}
MTTSPILQLLLRLSLCGLLLQRAETGSKGQTAGELYQRWERYRRECQETLAAAEPPSGLACN
GSFDMYVCWDYAAPNATARASCPWYLPWHHHVAAGFVLRQCGSDGQWGLWRDHTQCEN
PEKNEAFLDQRLILERLQVMYTVGYSLSLATLLLALLILSLFRRLHCTRNYIHINLFTSFMLRA
AAILSRDRLLPRPGPYLGDQALALWNQALAACRTAQIVTQYCVGANYTWLLVEGVYLHSLL
VLVGGSEEGHFRYYLLLGWGAPALFVIPWVIVRYLYENTQCWERNEVKAIWWIIRTPILMTI
LINFLIFIRILGILLSKLRTRQMRCRDYRLRLARSTLTLVPLLGVHEVVFAPVTEEQARGALRF
AKLGFEIFLSSFQGFLVSVLYCFINKEVQSEIRRGWHHCRLRRSLGEEQRQLPERAFRALPSGS
GPGEVPTSRGLSSGTLPGPGNEASRELESYC (SEQ ID NO:1011)
>gi|4504059|ref|NP_0003971| gonadotropin-releasing hormone
receptor isoform 1 {Homosapiens}
MANSASPEQNQNHCSAINNSIPLMQGNLPTLTLSGKIRVTVTFFLFLLSATFNASFLLKLQKW
TQKKEKGKKLSRMKLLLKHLTLANLLETLIVMPLDGMWNITVQWYAGELLCKVLSYLKLFS
MYAPAFMMVVISLDRSLAITRPLALKSNSKVGQSMVGLAWILSSVFAGPQLYIFRMIHLADSS
GQTKVFSQCVTHCSFSQWWHQAFYNFFTFSCLFHPLFIMLICNAKIIFTLTRVLHQDPHELQL
NQSKNNIPRARLKTLKMTVAFATSFTVCWTPYYVLGIVVYWFDPEMLNRLSDPVNHFFFLFAF
LNPCFDPLIYGYFSL (SEQ ID NO:1012) >gi|4504091|ref|NP_0014961|
G-protein coupled estrogen receptor 1 {Homosapiens}
MDVTSQARGVGLEMYPGTAQPAAPNTTSPELNLSHPLLGTALANGTGELSEHQQYVIGLFLS
CLYTIFLFPIGFVGNILILVVNISFREKMTIPDLYFINLAVADLILVADSLIEVFNLHERYYDIAV
LCTFMSLFLQVNMYSSVFFLTVVMSFDRYIALARAMRCSLFRTKHHARLSCGLIVVMASVSAT
LVPFTAVHLQHTDEACFCFADVREVQWLEVTLGFIVPFAIIGLCYSLIVRVLVRAHRHRGLRP
RRQKALRMILAVVLVFFVCWLPENVFISVHLLQRTQPGAAPCKQSFRHAHPLTGHIVNLAAF
SNSCLNPLIYSFLGETFRDKLRLYIEQKTNLPALNRFCHAALKAVIPDSTEQSDVRFSSAV (SEQ
ID NO:1013) >gi|4504093|ref|NP_0014971| G protein-coupled
receptor 32 {Homosapiens}
MNGVSEGTRGCSDRQPGVLTRDRSCSRKMNSSGCLSEEVGSLRPLTVVILSASIVVGVLGNG
LVLWMTVFRMARTVSTVCFFHLALADFMLSLSLPIAMYYIVSRQWLLGEWACKLYITFVFLS
YFASNCLLVFISVDRCISVLYPVVVALNHRTVQRASWLAFGVWLLAAALCSAHLKFRTTRKW
NGCTHCYLAFNSDNETAQIVVIEGVVEGHIIGTIGHFLLGFLGPLAIIGTCAHLIRAKLLREGWV
HANRPKRLLLVLVSAFFIFVVSPFNVVLLVHLWRRVMLKEIYHPRMLLILQASFALGCVNSSL
NPFLYVFVGRDFQEKFFQSLTSALARAFGEEEFLSSCPRGNAPRE (SEQ ID NO:1014)
>gi|4504095|ref|NP_0014981| motilin receptor {Homosapiens}
MGSPWNGSDGPEGAREPPWPALPPCDERRCSPFPLGALVPVTAVCLCLFVVGVSGNVVTVM
LIGRYRDMRTTTNLYLGSMAVSDLLILLGLPFDLYRLWRSRPWVFGPLLCRLSLYVGEGCTY
ATLLHMTALSVERYLAICRPLRARVLVTRRRVRALIAVLWAVALLSAGPFLFLVGVEQDPGI
SVVPGLNGTARIASSPLASSPPLWLSRAPPPSPPSGPETAEAAALFSRECRPSPAQLGALRVML
WVTTAYFFLPFLCLSILYGLIGRELWSSRRPLRGPAASGRERGHRQTVRVLLVVVLAFIICWL
PFHVGRIIYINTEDSRMMYFSQYFNIVALQLFYLSASINPILYNLISKKYRAAAFKLLLARKSRP
RGFHRSRDTAGEVAGDTGGDTVGYTETSANVKTMG (SEQ ID NO:1015)
>gi|4504097|ref|NP_0014991| G-protein coupled receptor 39
{Homosapiens}
MASPSLPGSDCSQIIDHSHVPEFEVATWIKITLILVYLIIFVMGLLGNSATIRVTQVLQKKGYLQ
KEVTDHMVSLACSDILVFLIGMPMEFYSIIVVNPLTTSSYTLSCKLHTFLFEACSYATLLHVLTL
SFERYIAICHPFRYKAVSGPCQVKLLIGFVWVTSALVALPLLFAMGTEYPLVNVPSHRGLTCN
RSSTRHHEQPETSNMSICTNLSSRWTVFQSSIFGAFVVYLVVLLSVAFMCWNMMQVLMKSQ
KGSLAGGTRPPQLRKSESEESRTARRQTIIFLRLIVVTLAVCWMPNQIRRIMAAAKPKHDWTR
SYFRAYMILLPFSETFFYLSSVINPLLYTVSSQQFRRVFVQVLCCRLSLQHANHEKRLRVHAH
STTDSARFVQRPLLFASRRQSSARRTEKIFLSTFQSEAEPQSKSQSLSLESLEPNSGAKPANSAA
ENGFQEHEV (SEQ ID NO:1016) >gi|4504099|ref|NP_0014951| C-X-C
chemokine receptor type 3 isoform A {Homosapiens}
MVLEVSDHQVLNDAEVAALLENFSSSYDYGENESDSCCTSPPCPQDFSLNFDRAFLPALYSLL
FLLGLLGNGAVAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLC
KVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRGPPARVTLTCLAVWGLCLLFALPD
FIFLSAHHDERLNATHCQYNFPQVGRTALRVLQLVAGFLLPLLVMAYCYAHILAVLLVS RGQ
RRLRAMRLVVVVVVAFALCWTPYHLVVLVDILMDLGALARNCGRESRVDVAKSVTSGLGY
MHCCLNPLLYAFVGVKFRERMWMLLLRLGCPNQRGLQRQPSSSRRDSSWSETSEASYSGL (SEQ
ID NO:1017) >gi|4504141|ref|NP_0008321| metabotropic glutamate
receptor 4 precursor {Homosapiens}
MPGKRGLGWWWARLPLCLLLSLYGPWMPSSLGKPKGHPHMNSIRIDGDITLGGLFPVHGRG
SEGKPCGELKKEKGIHRLEAMLFALDRINNDPDLLPNITLGARILDTCSRDTHALEQSLTFVQ
ALIEKDGTEVRCGSGGPPIITKPERVVGVIGASGSSVSIMVANILRLFKIPQISYASTAPDLSDNS
RYDFFSRVVPSDTYQAQAMVDIVRALKWNYVSTVASEGSYGESGVEAFIQKSREDGGVCIA
QSVKIPREPKAGEFDKIIRRLLETSNARAVIIFANEDDIRRVLEAARRANQTGHFFVVMGSDSW
GSKIAPVLHLEEVAEGAVTILPKRMSVRGFDRYFSSRTLDNNRRNIVVFAEFVVEDNFHCKLSR
HALKKGSHVKKCTNRERIGQDSAYEQEGKVQFVIDAVYAMGHALHAMHRDLCPGRVGLCP
RMDPVDGTQLLKYIRNVNFSGIAGNPVTFNENGDAPGRYDIYQYQLRNDSAEYKVIGSWTD
HLHLRIERMHWPGSGQQLPRSICSLPCQPGERKKTVKGMPCCWHCEPCTGYQYQVDRYTCK
TCPYDMRPTENRTGCRPIPIIKLEWGSPWAVLPLFLAVVGIAATLFVVITFVRYNDTPIVKASG
RELSYVLLAGIFLCYATTFLMIAEPDLGTCSLRRIFLGLGMSISYAALLTKTNRIYRIFEQGKRS
VSAPRFISPASQLAITFSLISLQLLGICVWFVVDPSHSVVDFQDQRTLDPRFARGVLKCDISDLS
LICLLGYSMLLMVTCTVYAIKTRGVPETFNEAKPIGFTMYTTCIVWLAFIPIFFGTSQSADKLY
IQTTTLTVSVSLSASVSLGMLYMPKVYIILFHPEQNVPKRKRSLKAVVTAATMSNKFTQKGN
FRPNGEAKSELCENLEAPALATKQTYVTYTNHAI (SEQ ID NO:1018)
>gi|4504143|ref|NP_0008331| metabotropic glutamate receptor 5
isoform b precursor {Homosapiens}
MVLLLILSVLLLKEDVRGSAQSSERRVVAHMPGDIIIGALFSVHHQPTVDKVHERKCGAVRE
QYGIQRVEAMLHTLERINSDPTLLPNITLGCEIRDSCWHSAVALEQSIEFIRDSLISSEEEEGLV
RCVDGSSSSFRSKKPIVGVIGPGSSSVAIQVQNLLQLFNIPQIAYSATSMDLSDKTLFKYFMRV
VPSDAQQARAMVDIVKRYNWTYVSAVHTEGNYGESGMEAFKDMSAKEGICIAHSYKIYSN
AGEQSFDKLLKKLTSHLPKARVVACFCEGMTVRGLLMAMRRLGLAGEFLLLGSDGWADRY
DVTDGYQREAVGGITIKLQSPDVKWFDDYYLKLRPETNHRNPWFQEFVVQHRFQCRLEGFPQ
ENSKYNKTCNSSLTLKTHHVQDSKMGFVINAIYSMAYGLHNMQMSLCPGYAGLCDAMKPI
DGRKLLESLMKTNFTGVSGDTILFDENGDSPGRYEIMNFKEMGKDYFDYINVGSWDNGELK
MDDDEVWSKKSNIIRSVCSEPCEKGQIKVIRKGEVSCCWTCTPCKENEYVFDEYTCKACQLG
SWPTDDLTGCDLIPVQYLRWGDPEPIAAVVFACLGLLATLFVTVVFIIYRDTPVVKSSSRELC
YIILAGICLGYLCTFCLIAKPKQIYCYLQRIGIGLSPAMSYSALVTKTNRIARILAGSKKKICTK
KPRFMSACAQLVIAFILICIQLGIIVALFIMEPPDIMHDYPSIREVYLICNTTNLGVVTPLGYNGL
LILSCTFYAFKTRNVPANFNEAKYIAFTMYTTCHWLAFVPIYFGSNYKIITMCFSVSLSATVAL
GCMFVPKVYIILAKPERNVRSAFTTSTVVRMHVGDGKSSSAASRSSSLVNLWKRRGSSGETL
SSNGKSVTWAQNEKSSRGQHLWQRLSIHINKKENPNQTAVIKPFPKSTESRGLGAGAGAGGS
AGGVGATGGAGCAGAGPGGPESPDAGPKALYDVAEAEEHFPAPARPRSPSPISTLSHRAGSA
SRTDDDVPSLHSEPVARSSSSQGSLMEQISSVVTRFTANISELNSMMLSTAAPSPGVGAPLCSS
YLIPKEIQLPTTMTTFAEIQPLPAIEVTGGAQPAAGAQAAGDAARESPAAGPEAAAAKPDLEE
LVALTPPSPFRDSVDSGSTTPNSPVSESALCIPSSPKYDTLIIRDYTQSSSSL (SEQ ID
NO:1019) >gi|4504147|ref|NP_0008351| metabotropic glutamate
receptor 7 isoform a precursor {Homosapiens}
MVQLRKLLRVLTLMKFPCCVLEVLLCALAAAARGQEMYAPHSIRIEGDVTLGGLFPVHAKG
PSGVPCGDIKRENGIHRLEAMLYALDQINSDPNLLPNVTLGARILDTCSRDTYALEQSLTFVQ
ALIQKDTSDVRCTNGE PVFVKPEKVVGVIGASGSSVSIMVANILRLFQIPQISYASTAPELSD
DRRYDFFSRVVPPDSFQAQAMVDIVKALGWNYVSTLASEGSYGEKGVESFTQISKEAGGLCI
AQSVRIPQERKDRTIDFDRIIKQLLDTPNSRAVVIFANDEDIKQILAAAKRADQVGHFLWVGS
DSWGSKINPLHQHEDIAEGAITIQPKRATVEGFDAYFTSRTLENNRRNVVVFAEYWEENFNCK
LTISGSKKEDTDRKCTGQERIGKDSNYEQEGKVQFVIDAVYAMAHALHHMNKDLCADYRG
VCPEMEQAGGKKLLKYIRNVNFNGSAGTPVMFNKNGDAPGRYDIFQYQTTNTSNPGYRLIG
QWTDELQLNIEDMQWGKGVREIPASVCTLPCKPGQRKKTQKGTPCCWTCEPCDGYQYQFD
EMTCQHCPYDQRPNENRTGCQDIPIIKLEWHSPWAVIPVFLAMLGIIATIFVMATFIRYNDTPI
VRASGRELSYVLLTGIFLCYIITFLMIAKPDVAVCSFRRVFLGLGMCISYAALLTKTNRIYRIFE
QGKKSVTAPRLISPTSQLAITSSLISVQLLGVFIVVFGVDPPNIIIDYDEHKTMNPEQARGVLKCD
ITDLQIICSLGYSILLMVTCTVYAIKTRGVPENFNEAKPIGFTMYTTCIVWLAFIPIFFGTAQSAE
KLYIQTTTLTISMNLSASVALGMLYMPKVYIIIFHPELNVQKRKRSFKAVVTAATMSSRLSHK
PSDRPNGEAKTELCENVDPNSPAAKKKYVSYNNLVI (SEQ ID NO:1020)
>gi|4504379|ref|NP_0036581| leucine-rich repeat-containing G
protein-coupled receptor 5 precursor{Homosapiens}
MDTSRLGVLLSLPVLLQLATGGSSPRSGVLLRGCPTHCHCEPDGRMLLRVDCSDLGLSELPS
NLSVFTSYLDLSMNNISQLLPNPLPSLRFLEELRLAGNALTYIPKGAFTGLYSLKVLMLQNNQ
LRHVPTEALQNLRSLQSLRLDANHISYVPPSCFSGLHSLRHLWLDDNALTEIPVQAFRSLSAL
QAMTLALNKIHHIPDYAFGNLSSLVVLHLHNNRIHSLGKKCFDGLHSLETLDLNYNNLDEFP
TAIRTLSNLKELGFHSNNIRSIPEKAFVGNPSLITIHFYDNPIQFVGRSAFQHLPELRTLTLNGAS
QITEFPDLTGTANLESLTLTGAQISSLPQTVCNQLPNLQVLDLSYNLLEDLPSFSVCQKLQKID
LRHNEIYEIKVDTFQQLLSLRSLNLAWNKIAIIHPNAFSTLPSLIKLDLSSNLLSSFPITGLHGLT
HLKLTGNHALQSLISSENFPELKVIEMPYAYQCCAFGVCENAYKISNQWNKGDNSSMDDLH
KKDAGMFQAQDERDLEDFLLDFEEDLKALHSVQCSPSPGPFKPCEHLLDGWLIRIGVWTIAV
LALTCNALVTSTVFRSPLYISPIKLLIGVIAAVNMLTGVSSAVLAGVDAFTFGSFARHGAWWE
NGVGCHVIGFLSIFASESSVFLLTLAALERGFSVKYSAKFETKAPFSSLKVIILLCALLALTMA
AVPLLGGSKYGASPLCLPLPFGEPSTMGYMVALILLNSLCFLMMTIAYTKLYCNLDKGDLEN
IVVDCSMVKHIALLLFTNCILNCPVAFLSFSSLINLTFISPEVIKFILLVVVPLPACLNPLLYILFNP
HFKEDLVSLRKQTYVWTRSKHPSLMSINSDDVEKQSCDSTQALVTFTSSSITYDLPPSSVPSPA
YPVTESCHLSSVAFVPCL (SEQ ID NO:1021) >gi|4504491|ref|NP_0008521|
histamine H1 receptor {Homosapiens}
MSLPNSSCLLEDKMCEGNKTTMASPQLMPLVVVLSTICLVTVGLNLLVLYAVRSERKLHTV
GNLYIVSLSVADLIVGAVVMPMNILYLLMSKWSLGRPLCLFVVLSMDYVASTASIFSVFILCID
RYRSVQQPLRYLKYRTKTRASATILGAWFLSFLWVIPILGWNHFMQQTSVRREDKCETDFYD
VTWFKVMTAIINFYLPTLLMLWFYAKIYKAVRQHCQHRELINRSLPSFSEIKLRPENPKGDAK
KPGKESPWEVLKRKPKDAGGGSVLKSPSQTPKEMKSPVVFSQEDDREVDKLYCFPLDIVHM
QAAAEGSSRDYVAVNRSHGQLKTDEQGLNTHGASEISEDQMLGDSQSFSRTDSDTTTETAPG
KGKLRSGSNTGLDYIKFTVVKRLRSHSRQYVSGLHMNRERKAAKQLGFIMAAFILCWIPYFIFF
MVIAFCKNCCNEHLHMFTIVVLGYINSTLNPLIYPLCNENFKKTFKRILHIRS (SEQ ID
NO:1022) >gi|4504533 |ref|NP_000854 1| 5-hydroxytryptamine
receptor 1B {Homosapiens }
MEEPGAQCAPPPPAGSETWVPQANLSSAPSQNCSAKDYIYQDSISLPWKVLLVMLLALITLAT
TLSNAFVIATVYRTRKLHTPANYLIASLAVTDLLVSILVMPISTMYTVTGRWTLGQVVCDFVV
LSSDITCCTASILHLCVIALDRYWAITDAVEYSAKRTPKRAAVMIALVWVFSISISLPPFFVVRQ
AKAEEEVSECVVNTDHILYTVYSTVGAFYFPTLLLIALYGRIYVEARSRILKQTPNRTGKRLT
RAQLITDSPGSTSSVTSINSRVPDVPSESGSPVYVNQVKVRVSDALLEKKKLMAARERKATKT
LGIILGAFIVCWLPFFIISLVMPICKDACWFHLAIFDFFTVVLGYLNSLINPIIYTMSNEDFKQAFH
KLIRFKCTS (SEQ ID NO:1023) >gi|4504535|ref|NP_0008551|
5-hydroxytryptamine receptor 1D {Homosapiens}
MSPLNQSAEGLPQEASNRSLNATETSEAWDPRTLQALKISLAVVLSVITLATVLSNAFVLTTIL
LTRKLHTPANYLIGSLATTDLLVSILVMPISIAYTITHTWNFGQILCDIVVLSSDITCCTASILHLC
VIALDRYWAITDALEYSKRRTAGHAATMIAIVWAISICISIPPLFVVRQAKAQEEMSCLVNTS
QISYTIYSTCGAFYIPSVLLIILYGRIYRAARNRILNPPSLYGKRFTTAHLITGSAGSSLCSLNSSL
HEGHSHSAGSPLFFNHVKIKLADSALERKRISAARERKATKILGIILGAFIICWLPFFVVSLVLPI
CRDSCWIHPALFDFFTVVLGYLNSLINPHYTVFNEEFRQAFQKIVPFRKAS (SEQ ID
NO:1024) >gi|4504537|ref|NP_0008561| 5-hydroxytryptamine
receptor 1E {Homosapiens}
MNITNCTTEASMAIRPKTITEKMLICMTLVVITTLTTLLNLAVIMAIGTTKKLHQPANYLICSL
AVTDLLVAVLVMPLSIIYIVMDRWKLGYFLCEVVVLSVDMTCCTCSILHLCVIALDRYWAITN
AIEYARKRTAKRAALMILTVWTISIFISMPPLFWRSHRRLSPPPSQCTIQHDHVIYTIYSTLGAF
YIPLTLILILYYRIYHAAKSLYQKRGSSRHLSNRSTDSQNSFASCKLTQTFCVSDFSTSDPTTEF
EKFHASIRIPPFDNDLDHPGERQQISSTRERKAARILGLILGAFILSWLPFFIKELIVGLSIYTVSS
EVADFLTWLGYVNSLINPLLYTSFNEDFKLAFKKLIRCREHT (SEQ ID NO:1025)
>gi|4504541|ref|NP_0008591| 5-hydroxytryptamine receptor 2C
{Homosapiens}
MVNLRNAVHSFLVHLIGLLVWQCDISVSPVAAIVTDIFNTSDGGRFKFPDGVQNWPALSIVIII
IMTIGGNILVIMAVSMEKKLHNATNYFLMSLAIADMLVGLLVMPLSLLAILYDYVWPLPRYL
CPVWISLDVLFSTASIMHLCAISLDRYVAIRNPIEHS RFNS
RTKAIMKIAIVWAISIGVSVPIPVI
GLRDEEKVFVNNTTCVLNDPNFVLIGSFVAFFIPLTIMVITYCLTIYVLRRQALMLLHGHTEEP
PGLSLDFLKCCKRNTAEEENSANPNQDQNARRRKKKERRPRGTMQAINNERKASKVLGIVFF
VFLIMWCPFFITNILSVLCEKSCNQKLMEKLLNVFVWIGYVCSGINPLVYTLFNKIYRRAFSN
YLRCNYKVEKKPPVRQIPRVAATALSGRELNVNIYRHTNEPVIEKASDNEPGIEMQVENLELP
VNPSSVVSERISSV (SEQ ID NO:1026) >gi|4504545|ref|NP_0008621|
5-hydroxytryptamine receptor 6 {Homosapiens}
MVPEPGPTANSTPAWGAGPPSAPGGSGWVAAALCVVIALTAAANSLLIALICTQPALRNTSN
FFLVSLFTSDLMVGLVVMPPAMLNALYGRWVLARGLCLLWTAFDVMCCSASILNLCLISLD
RYLLILSPLRYKLRMTPLRALALVLGAWSLAALASFLPLLLGWHELGHARPPVPGQCRLLAS
LPFVLVASGLTFFLPSGAICFTYCRILLAARKQAVQVASLTTGMASQASETLQVPRTPRPGVE
SADSRRLATKHSRKALKASLTLGILLGMFFVTWLPFFVANIVQAVCDCISPGLFDVLTWLGY
CNSTMNPIIYPLFMRDFKRALGRFLPCPRCPRERQASLASPSLRTSHSGPRPGLSLQQVLPLPLP
PDSDSDSDAGSGGSSGLRLTAQLLLPGEATQDPPLPTRAAAAVNFFNIDPAEPELRPHPLGIPT N
(SEQ ID NO:1027) >gi|4504547|ref|NP_0008631| 5-hydroxytryptamine
receptor 7 isoform a {Homosapiens}
MMDVNSSGRPDLYGHLRSFLLPEVGRGLPDLSPDGGADPVAGSWAPHLLSEVTASPAPTWD
APPDNASGCGEQINYGRVEKVVIGSILTLITLLTIAGNCLVVISVCFVKKLRQPSNYLIVSLALA
DLSVAVAVMPFVSVTDLIGGKWIFGHFFCNVFIAMDVMCCTASIMTLCVISIDRYLGITRPLT
YPVRQNGKCMAKMILSVWLLSASITLPPLFGWAQNVNDDKVCLISQDFGYTIYSTAVAFYIP
MSVMLFMYYQIYKAARKSAAKHKFPGFPRVEPDSVIALNGIVKLQKEVEECANLSRLLKHER
KNISIFKREQKAATTLGIIVGAFTVCWLPFFLLSTARPFICGTSCSCIPLWVERTFLWLGYANSL
INPFIYAFFNRDLRTTYRSLLQCQYRNINRKLSAAGMHEALKLAERPERPEFVLQNADYCRK
KGHDS (SEQ ID NO:1028) >gi|4504681|ref|NP_0006251| C-X-C
chemokine receptor type 1 {Homosapiens}
MSNITDPQMWDFDDLNFTGMPPADEDYSPCMLETETLNKYVVIIAYALVFLLSLLGNSLVML
VILYSRVGRSVTDVYLLNLALADLLFALTLPIVVAASKVNGWIFGTFLCKVVSLLKEVNFYSGI
LLLACISVDRYLAIVHATRTLTQKRHLVKFVCLGCWGLSMNLSLPFFLFRQAYHPNNSSPVC
YEVLGNDTAKWRMVLRILPHTFGFIVPLFVMLFCYGFTLRTLFKAHMGQKHRAMRVIFAVV
LIFLLCWLPYNLVLLADTLMRTQVIQESCERRNNIGRALDATEILGFLHSCLNPIIYAFIGQNFR
HGFLKILAMHGLVSKEFLARHRVTSYTSSSVNVSSNL (SEQ ID NO:1029)
>gi|4504683|ref|NP_0015481| C-X-C chemokine receptor type 2
{Homosapiens}
MEDFNMESDSFEDFVVKGEDLSNYSYSSTLPPFLLDAAPCEPESLEINKYFVVIIYALVFLLSLL
GNSLVMLVILYSRVGRSVTDVYLLNLALADLLFALTLPIVVAASKVNGWIFGTFLCKVVSLLK
EVNFYSGILLLACISVDRYLAIVHATRTLTQKRYLVKFICLSIVVGLSLLLALPVLLFRRTVYSS
NVSPACYEDMGNNTANVVRMLLRILPQSFGFIVPLLIMLFCYGFTLRTLFKAHMGQKHRAMR
VIFAVVLIFLLCWLPYNLVLLADTLMRTQVIQETCERRNHIDRALDATEILGILHSCLNPLIYA
FIGQKFRHGLLKILAIHGLISKDSLPKDSRPSFVGSSSGHTSTTL (SEQ ID NO:1030)
>gi|4505127|ref|NP_0005201| adrenocorticotropic hormone receptor
{Homosapiens}
MKHIINSYENINNTARNNSDCPRVVLPEEIFFTISIVGVLENLIVLLAVFKNKNLQAPMYFFICS
LAISDMLGSLYKILENILIILRNMGYLKPRGSFETTADDIIDSLFVLSLLGSIFSLSVIAADRYITIF
HALRYHSIVTMRRTVVVLTVIVVTFCTGTGITMVIFSHHVPTVITFTSLFPLMLVFILCLYVHMF
LLARSHTRKISTLPRANMKGAITLTILLGVFIFCWAPFVLHVLLMTFCPSNPYCACYMS LFQV
NGMLIMCNAVIDPFIYAFRSPELRDAFKKMIFCSRYW (SEQ ID NO:1031)
>gi|4505445|ref|NP_0009001| neuropeptide Y receptor type 1
{Homosapiens}
MNSTLFSQVENHSVHSNFSEKNAQLLAFENDDCHLPLAMIFTLALAYGAVIILGVSGNLALIII
ILKQKEMRNVTNILIVNLSFSDLLVAIMCLPFTFVYTLMDHWVFGEAMCKLNPFVQCVSITVS
IFSLVLIAVERHQLIINPRGWRPNNRHAYVGIAVIWVLAVASSLPFLIYQVMTDEPFQNVTLD
AYKDKYVCFDQFPSDSHRLSYTTLLLVLQYFGPLCFIFICYFKIYIRLKRRNNMMDKMRDNK
YRSSETKRINIMLLSIVVAFAVCWLPLTIFNTVFDWNHQIIATCNHNLLFLLCHLTAMISTCVN
PIFYGFLNKNFQRDLQFFFNFCDFRSRDDDYETIAMSTMHTDVSKTSLKQASPVAFKKINNND
DNEKI (SEQ ID NO:1032) >gi|4505447|ref|NP_0009011| neuropeptide
Y receptor Y2 {Homosapiens}
MGPIGAEADENQTVEEMKVEQYGPQTTPRGELVPDPEPELIDSTKLIEVQVVLILAYCSIILLG
VIGNSLVIHVVIKFKSMRTVTNFFIANLAVADLLVNTLCLPFTLTYTLMGEWKMGPVLCHLV
PYAQGLAVQVSTITLTVIALDRHRCIVYHLESKISKRISFLIIGLAWGISALLASPLAIFREYSLIE
IIPDFEIVACTEKWPGEEKSIYGTVYSLSSLLILYVLPLGIISFSYTRIVVSKLKNHVSPGAANDH
YHQRRQKTTKMLVCVVVVFAVSWLPLHAFQLAVDIDSQVLDLKEYKLIFTVFHIIAMCSTFA
NPLLYGWMNSNYRKAFLSAFRCEQRLDAIHSEVSVTFKAKKNLEVRKNSGPNDSFTEATNV (SEQ
ID NO:1033) >gi|4505513|ref|NP_0009041| opiate receptor-like 1
{Homosapiens}
MEPLFPAPFVVEVIYGSHLQGNLSLLSPNHSLLPPHLLLNASHGAFLPLGLKVTIVGLYLAVCV
GGLLGNCLVMYVILRHTKMKTATNIYIFNLALADTLVLLTLPFQGTDILLGFVVPFGNALCKT
VIAIDYYNMFTSTFTLTAMSVDRYVAICHPIRALDVRTSSKAQAVNVAIVVALASVVGVPVAI
MGSAQVEDEEIECLVEIPTPQDYWGPVFAICIFLFSFIVPVLVISVCYSLMIRRLRGVRLLSGSR
EKDRNLRRITRLVLVVVAVFVGCWTPVQVFVLAQGLGVQPSSETAVAILRFCTALGYVNSCL
NPILYAFLDENFKACFRKFCCASALRRDVQVSDRVRSIAKDVALACKTSETVPRPA (SEQ ID
NO:1034) >gi|4505557|ref|NP_0025541| P2Y purinoceptor 1
{Homosapiens}
MTEVLWPAVPNGTDAAFLAGPGSSWGNSTVASTAAVSSSFKCALTKTGFQFYYLPAVYILVF
IIGFLGNSVAIWMFVFHMKPWSGISVYMFNLALADFLYVLTLPALIFYYFNKTDWIFGDAMC
KLQRFIFHVNLYGSILFLTCISAHRYSGVVYPLKSLGRLKKKNAICISVLVWLIVVVAISPILFY
SGTGVRKNKTITCYDTTSDEYLRSYFIYSMCTTVAMFCVPLVLILGCYGLIVRALIYKDLDNS
PLRRKSIYLVIIVLTVFAVSYIPFHVMKTMNLRARLDFQTPAMCAFNDRVYATYQVTRGLAS
LNSCVDPILYFLAGDTFRRRLSRATRKASRRSEANLQSKSEDMTLNILPEFKQNGDTSL (SEQ ID
NO:1035) >gi|4505561|ref|NP_0025561| pyrimidinergic receptor
P2Y4 {Homosapiens}
MASTESSLLRSLGLSPGPGSSEVELDCWFDEDFKFILLPVSYAVVFVLGLGLNAPTLWLFIFRL
RPWDATATYMFHLALSDTLYVLSLPTLIYYYAAHNHWPFGTEICKFVRFLFYVVNLYCSVLFL
TCISVHRYLGICHPLRALRWGRPRLAGLLCLAVWLVVAGCLVPNLFFVTTSNKGTTVLCHDT
TRPEEFDHYVHFSSAVMGLLFGVPCLVTLVCYGLMARRLYQPLPGSAQSSSRLRSLRTIAVV
LTVFAVCFVPFHITRTIYYLARLLEADCRVLNIVNVVYKVTRPLASANSCLDPVLYLLTGDKY
RRQLRQLCGGGKPQPRTAASSLALVSLPEDSSCRWAATPQDSSCSTPRADRL (SEQ ID
NO:1036) >gi|4506241|ref|NP_0009431| platelet-activating factor
receptor {Homosapiens}
MEPHDSSHMDSEFRYTLFPIVYSIIFVLGVIANGYVLWVFARLYPCKKFNEIKIFMVNLTMAD
MLFLITLPLWIVYYQNQGNWILPKFLCNVAGCLFFINTYCSVAFLGVITYNRFQAVTRPIKTA
QANTRKRGISLSLVIVVVAIVGAASYFLILDSTNTVPDSAGSGNVTRCFEHYEKGSVPVLIIHIFI
VFSFFLVFLIILFCNLVIIRTLLMQPVQQQRNAEVKRRALWMVCTVLAVFIICFVPHHVVQLP
WTLAELGFQDSKFHQAINDAHQVTLCLLSTNCVLDPVIYCFLTKKFRKHLTEKFYSMRSSRK
CSRATTDTVTEVVVPFNQIPGNSLKN (SEQ ID NO:1037)
>gi|4506259|ref|NP_0009491| prostaglandin E2 receptor EP4
subtype {Homosapiens}
MSTPGVNSSASLSPDRLNSPVTIPAVMFIFGVVGNLVAIVVLCKSRKEQKETTFYTLVC GLAV
TDLLGTLLVSPVTIATYMKGQWPGGQPLCEYSTFILLFFSLSGLSIICAMSVERYLAINHAYFY
SHYVDKRLAGLTLFAVYASNVLFCALPNMGLGSSRLQYPDTVVCFIDWTTNVTAHAAYSYM
YAGFSSFLILATVLCNVLVCGALLRMHRQFMRRTSLGTEQHHAAAAASVASRGHPAASPAL
PRLSDFRRRRSFRRIAGAEIQMVILLIATSLVVLICSIPLVVRVFVNQLYQPSLEREVSKNPDLQ
AIRIASVNPILDPWIYILLRKTVLSKAIEKIKCLFCRIGGSRRERSGQHCSDSQRTSSAMSGHSR
SFISRELKEISSTSQTLLPDLSLPDLSENGLGGRNLLPGVPGMGLAQEDTTSLRTLRISETSDSS
QGQDSESVLLVDEAGGSGRAGPAPKGSSLQVTFPSETLNLSEKCI (SEQ ID NO:1038)
>gi|4506261|ref|NP_0009501| prostaglandin F2-alpha receptor
isoform a precursor {Homosapiens}
MSMNNSKQLVSPAAALLSNTTCQTENRLSVFFSVIFMTVGILSNSLAIAILMKAYQRFRQKSK
ASFLLLASGLVITDFFGHLINGAIAVFVYASDKEWIRFDQSNVLCSIFGICMVFSGLCPLLLGSV
MAIERCIGVTKPIFHSTKITSKHVKMMLSGVCLFAVFIALLPILGHRDYKIQASRTWCFYNTED
IKDWEDRFYLLLFSFLGLLALGVSLLCNAITGITLLRVKFKSQQHRQGRSHHLEMVIQLLAIM
CVSCICWSPFLVTMANIGINGNHSLETCETTLFALRMATWNQILDPWVYILLRKAVLKNLYK
LASQCCGVHVISLHIVVELSSIKNSLKVAAISESPVAEKSAST (SEQ ID NO:1039)
>gi|4506263|ref|NP_0009511| prostaglandin 12 (prostacyclin)
receptor (IP) {Homosapiens}
MADSCRNLTYVRGSVGPATSTLMFVAGVVGNGLALGILSARRPARPSAFAVLVTGLAATDL
LGTSFLSPAVFVAYARNSSLLGLARGGPALCDAFAFAMTFFGLASMLILFAMAVERCLALSH
PYLYAQLDGPRCARLALPAIYAFCVLFCALPLLGLGQHQQYCPGSWCFLRMRWAQPGGAAF
SLAYAGLVALLVAAIFLCNGSVTLSLCRMYRQQKRHQGSLGPRPRTGEDEVDHLILLALMTV
VMAVCSLPLTIRCFTQAVAPDSSSEMGDLLAFRFYAFNPILDPWVFILFRKAVFQRLKLWVCC
LCLGPAHGDSQTPLSQLASGRRDPRAPSAPVGKEGSCVPLSAWGEGQVEPLPPTQQSSGSAV
GTSSKAEASVACSLC (SEQ ID NO:1040) >gi|4506271|ref|NP_0003071|
parathyroid hormone receptor 1 precursor {Homosapiens}
MGTARIAPGLALLLCCPVLSSAYALVDADDVMTKEEQIFLLHRAQAQCEKRLKEVLQRPASI
MESDKGWTSASTSGKPRKDKASGKLYPESEEDKEAPTGSRYRGRPCLPEWDHILCWPLGAP
GEVVAVPCPDYIYDFNHKGHAYRRCDRNGSWELVPGHNRTWANYSECVKFLTNETREREV
FDRLGMIYTVGYSVSLASLTVAVLILAYFRRLHCTRNYIHMHLFLSFMLRAVSIFVKDAVLYS
GATLDEAERLTEEELRAIAQAPPPPATAAAGYAGCRVAVTFFLYFLATNYYWILVEGLYLHS
LIFMAFFSEKKYLWGFTVFGWGLPAVFVAVWVSVRATLANTGCWDLSSGNKKWIIQVPILA
SIVLNFILFINIVRVLATKLRETNAGRCDTRQQYRKLLKSTLVLMPLFGVHYIVFMATPYTEVS
GTLWQVQMHYEMLFNSFQGFFVAIIYCFCNGEVQAEIKKSWSRWTLALDFKRKARSGSSSY
SYGPMVSHTSVTNVGPRVGLGLPLSPRLLPTATTNGHPQLPGHAKPGTPALETLETTPPAMA
APKDDGFLNGSCSGLDEEASGPERPPALLQEEWETVM (SEQ ID NO:1041)
>gi|4506403|ref|NP_0039701| retinoic acid-induced protein 3
{Homosapiens}
MATTVPDGCRNGLKSKYYRLCDKAEAWGIVLETVATAGVVTSVAFMLTLPILVCKVQDSNR
RKMLPTQFLFLLGVLGIFGLTFAFIIGLDGSTGPTRFFLFGILFSICFSCLLAHAVSLTKLVRGRK
PLSLLVILGLAVGFSLVQDVIAIEYIVLTMNRTNVNVFSELSAPRRNEDFVLLLTYVLFLMALT
FLMSSFTFCGSFTGWKRHGAHIYLTMLLSIAIWVAWITLLMLPDFDRRWDDTILSSALAANG
WVFLLAYVSPEFWLLTKQRNPMDYPVEDAFCKPQLVKKSYGVENRAYSQEEITQGFEETGD
TLYAPYSTHFQLQNQPPQKEFSIPRAHAWPSPYKDYEVKKEGS (SEQ ID NO:1042)
>gi|4507343|ref|NP_0010491| substance-P receptor isoform long
{Homosapiens}
MDNVLPVDSDLSPNISTNTSEPNQFVQPAWQIVLWAAAYTVIVVTSVVGNVVVMWIILAHK
RMRTVTNYFLVNLAFAEASMAAFNTVVNFTYAVHNEWYYGLFYCKFHNFFPIAAVFASIYS
MTAVAFDRYMAIIHPLQPRLSATATKVVICVIWVLALLLAFPQGYYSTTETMPSRVVCMIEW
PEHPNKIYEKVYHICVTVLIYFLPLLVIGYAYTVVGITLWASEIPGDSSDRYHEQVSAKRKVV
KMMIVVVCTFAICWLPFHIFFLLPYINPDLYLKKFIQQVYLAIMWLAMSSTMYNPIIYCCLND
RFRLGFKHAFRCCPFISAGDYEGLEMKSTRYLQTQGSVYKVSRLETTISTVVGAHEEEPEDGP
KATPSSLDLTSNCSSRSDSKTMTESFSFSSNVLS (SEQ ID NO:1043)
>gi|4507381|ref|NP_0010511| thromboxane A2 receptor isoform
alpha {Homosapiens}
MWPNGSSLGPCFRPTNITLEERRLIASPWFAASFCVVGLASNLLALSVLAGARQGGSHTRSSF
LTFLCGLVLTDFLGLLVTGTIVVSQHAALFEWHAVDPGCRLCRFMGVVMIFFGLSPLLLGAA
MASERYLGITRPFSRPAVASQRRAWATVGLVWAAALALGLLPLLGVGRYTVQYPGSWCFLT
LGAESGDVAFGLLFSMLGGLSVGLSFLLNTVSVATLCHVYHGQEAAQQRPRDSEVEMMAQL
LGIMVVASVCWLPLLVFIAQTVLRNPPAMSPAGQLSRTTEKELLIYLRVATWNQILDPWVYIL
FRRAVLRRLQPRLSTRPRSLSLQPQLTQRSGLQ (SEQ ID NO:1044)
>gi|4507681|ref|NP_0032921| thyrotropin-releasing hormone
receptor {Homosapiens}
MENETVSELNQTQLQPRAVVALEYQVVTILLVLIICGLGIVGNIMVVLVVMRTKHMRTPTNC
YLVSLAVADLMVLVAAGLPNITDSIYGSWVYGYVGCLCITYLQYLGINASSCSITAFTIERYIA
ICHPIKAQFLCTFSRAKKIIIFVWAFTSLYCMLWFFLLDLNISTYKDAIVISCGYKISRNYYSPIY
LMDFGVFYVVPMILATVLYGFIARILFLNPIPSDPKENSKTWKNDSTHQNTNLNVNTSNRCFN
STVSSRKQVTKMLAVVVILFALLWMPYRTLVVVNSFLSSPFQENWFLLFCRICIYLNSAINPVI
YNLMSQKFRAAFRKLCNCKQKPTEKPANYSVALNYSVIKESDHFSTELDDITVTDTYLSATK
VSFDDTCLASEVSFSQS (SEQ ID NO:1045) >gi|4557265|ref|NP_0006751|
beta-1 adrenergic receptor {Homosapiens}
MGAGVLVLGASEPGNLSSAAPLPDGAATAARLLVPASPPASLLPPASESPEPLSQQWTAGMG
LLMALIVLLIVAGNVLVIVAIAKTPRLQTLTNLFIMSLASADLVMGLLVVPFGATIVVWGRW
EYGSFFCELWTSVDVLCVTASIETLCVIALDRYLAITSPFRYQSLLTRARARGLVCTVWAISAL
VSFLPILMHWWRAESDEARRCYNDPKCCDFVTNRAYAIASSVVSFYVPLCIMAFVYLRVFRE
AQKQVKKIDSCERRFLGGPARPPSPSPSPVPAPAPPPGPPRPAAAAATAPLANGRAGKRRPSR
LVALREQKALKTLGIIMGVFTLCWLPFFLANVVKAFHRELVPDRLFVFFNWLGYANSAFNPII
YCRSPDFRKAFQGLLCCARRAARRRHATHGDRPRASGCLARPGPPPSPGAASDDDDDDVVG
ATPPARLLEPWAGCNGGAAADSDSSLDEPCRPGFASESKV (SEQ ID NO:1046)
>gi|4557267|ref|NP_0000161| adrenergic, beta-3-, receptor
{Homosapiens}
MAPWPHENSSLAPWPDLPTLAPNTANTSGLPGVPWEAALAGALLALAVLATVGGNLLVIVA
IAWTPRLQTMTNVFVTSLAAADLVMGLLVVPPAATLALTGHWPLGATGCELWTSVDVLCV
TASIETLCALAVDRYLAVTNPLRYGALVTKRCARTAVVLVWVVSAAVSFAPIMSQWWRVG
ADAEAQRCHSNPRCCAFASNMPYVLLSSSVSFYLPLLVMLFVYARVFVVATRQLRLLRGEL
GRFPPEESPPAPSRSLAPAPVGTCAPPEGVPACGRRPARLLPLREHRALCTLGLIMGTFTLCWL
PFFLANVLRALGGPSLVPGPAFLALNWLGYANSAFNPLIYCRSPDFRSAFRRLLCRCGRRLPP
EPCAAARPALFPSGVPAARSSPAQPRLCQRLDGASWGV (SEQ ID NO:1047)
>gi|4557345|ref|NP_0000451| vasopressin V2 receptor isoform 1
{Homosapiens} MLMASTTSAVPGHPSLPSLPS
NSSQERPLDTRDPLLARAELALLSIVFVAVALSNGLVLAALA
RRGRRGHWAPIHVFIGHLCLADLAVALFQVLPQLAWKATDRFRGPDALCRAVKYLQMVGM
YASSYMILAMTLDRHRAICRPMLAYRHGSGAHWNRPVLVAWAFSLLLSLPQLFIFAQRNVE
GGSGVTDCWACFAEPWGRRTYVTVVIALMVFVAPTLGIAACQVLIFREIHASLVPGPSERPGG
RRRGRRTGSPGEGAHVSAAVAKTVRMTLVIVVVYVLCWAPFFLVQLWAAWDPEAPLEGAP
FVLLMLLASLNSCTNPWIYASFSSSVSSELRSLLCCARGRTPPSLGPQDESCTTASSSLAKDTS S
(SEQ ID NO:1048) >gi|4557359|ref|NP_0006141| B2 bradykinin
receptor {Homosapiens}
MFSPWKISMFLSVREDSVPTTASFSADMLNVTLQGPTLNGTFAQSKCPQVEWLGWLNTIQPP
FLWVLFVLATLENIFVLSVFCLHKSSCTVAEIYLGNLAAADLILACGLPFVVAITISNNFDWLFG
ETLCRVVNAIISMNLYSSICFLMLVSIDRYLALVKTMSMGRMRGVRWAKLYSLVIVVGCTLLL
SSPMLVFRTMKEYSDEGHNVTACVISYPSLIVVEVFTNMLLNVVGFLLPLSVITFCTMQIMQVL
RNNEMQKFKEIQTERRATVLVLVVLLLFIICWLPFQISTFLDTLHRLGILSSCQDERIIDVITQIA
SFMAYSNSCLNPLVYVIVGKRFRKKSWEVYQGVCQKGGCRSEPIQMENSMGTLRTSISVERQ
IHKLQDWAGSRQ (SEQ ID NO:1049) >gi|4557547|ref|NP_0001061|
endothelin B receptor isoform 1 precursor {Homosapiens}
MQPPPSLCGRALVALVLACGLSRIVVGEERGFPPDRATPLLQTAEIMTPPTKTLWPKGSNASLA
RSLAPAEVPKGDRTAGSPPRTISPPPCQGPIEIKETFKYINTVVSCLVFVLGIIGNSTLLRIIYKN
KCMRNGPNILIASLALGDLLHIVIDIPINVYKLLAEDWPFGAEMCKLVPFIQKASVGITVLSLC
ALSIDRYRAVASWSRIKGIGVPKWTAVEIVLIVVVVSVVLAVPEAIGFDIITMDYKGSYLRICLL
HPVQKTAFMQFYKTAKDWWLFSFYFCLPLAITAFFYTLMTCEMLRKKSGMQIALNDHLKQR
REVAKTVFCLVLVFALCWLPLHLSRILKLTLYNQNDPNRCELLSFLLVLDYIGINMASLNSCI
NPIALYLVSKRFKNCFKSCLCCWCQSFEEKQSLEEKQSCLKFKANDHGYDNFRSSNKYSSS (SEQ
ID NO:1050) >gi|4557857|ref|NP_0010401| somatostatin receptor
type 1 {Homosapiens}
MFPNGTASSPSSSPSPSPGSCGEGGGSRGPGAGAADGMEEPGRNASQNGTLSEGQGSAILISFI
YSVVCLVGLCGNSMVIYVILRYAKMKTATNIYILNLAIADELLMLSVPFLVTSTLLRHWPFGA
LLCRLVLSVDAVNMFTSIYCLTVLSVDRYVAVVHPIKAARYRRPTVAKVVNLGVWVLSLLV
ILPIVVFSRTAANSDGTVACNMLMPEPAQRWLVGFVLYTFLMGFLLPVGAICLCYVLIIAKM
RMVALKAGWQQRKRSERKITLMVMMVVMVFVICWMPFYVVQLVNVFAEQDDATVSQLSV
ILGYANSCANPILYGFLSDNFKRSFQRILCLSWMDNAAEEPVDYYATALKSRAYSVEDFQPE
NLESGGVFRNGTCTSRITTL
(SEQ ID NO:1051) >gi|4557859|ref|NP_0010411| somatostatin
receptor type 2 {Homosapiens}
MDMADEPLNGSHTWLSIPFDLNGSVVSTNTSNQTEPYYDLTSNAVLTFIYFVVCIIGLCGNTL
VIYVILRYAKMKTITNIYILNLAIADELFMLGLPFLAMQVALVHWPFGKAICRVVMTVDGINQ
FTSIFCLTVMSIDRYLAVVHPIKSAKWRRPRTAKMITMAVWGVSLLVILPIMIYAGLRSNQW
GRSSCTINWPGESGAWYTGFIIYTFILGFLVPLTIICLCYLFIIIKVKSSGIRVGSSKRKKSEKKVT
RMVSIVVAVFIFCWLPFYIFNVSSVSMAISPTPALKGMFDFVVVLTYANSCANPILYAFLSDNF
KKSFQNVLCLVKVSGTDDGERSDSKQDKSRLNETTETQRTLLNGDLQTSI (SEQ ID NO:1052)
>gi|4557861|ref|NP_0010421| somatostatin receptor type 3
{Homosapiens}
MDMLHPSSVSTTSEPENASSAWPPDATLGNVSAGPSPAGLAVSGVLIPLVYLVVCVVGLLGN
SLVIYVVLRHTASPSVTNVYILNLALADELFMLGLPFLAAQNALSYWPFGSLMCRLVMAVD
GINQFTSIFCLTVMSVDRYLAVVHPTRSARWRTAPVARTVSAAVWVASAVVVLPVVVFSGV
PRGMSTCHMQWPEPAAAWRAGFHYTAALGFFGPLLVICLCYLLIVVKVRSAGRRVVVAPSCQ
RRRRSERRVTRMVVAVVALFVLCWMPFYVLNIVNVVCPLPEEPAFFGLYFLVVALPYANSC
ANPILYGFLSYRFKQGFRRVLLRPSRRVRSQEPTVGPPEKTEEEDEEEEDGEESREGGKGKEM
NGRVSQITQPGTSGQERPPSRVASKEQQLLPQEASTGEKSSTMRISYL (SEQ ID NO:1053)
>gi|4557865|ref|NP_0010441| somatostatin receptor type 5
{Homosapiens}
MEPLFPASTPSWNASSPGAASGGGDNRTLVGPAPSAGARAVLVPVLYLLVCAAGLGGNTLVI
YVVLRFAKMKTVTNIYILNLAVADVLYMLGLPFLATQNAASFVVPFGPVLCRLVMTLDGVNQ
FTSVFCLTVMSVDRYLAVVHPLSSARWRRPRVAKLASAAAWVLSLCMSLPLLVFADVQEGG
TCNASWPEPVGLWGAVFIIYTAVLGFFAPLLVICLCYLLIVVKVRAAGVRVGCVRRRSERKV
TRMVLVVVLVFAGCWLPFFTVNIVNLAVALPQEPASAGLYFFVVILSYANSCANPVLYGFLS
DNFRQSFQKVLCLRKGSGAKDADATEPRPDRIRQQQEATPPAHRAAANGLMQTSKL (SEQ ID
NO:1054) >gi|4757888|ref|NP_0040451| C3a anaphylatoxin
chemotactic receptor {Homosapiens}
MASFSAETNSTDLLSQPWNEPPVILSMVILSLTFLLGLPGNGLVLWVAGLKMQRTVNTIVVFL
HLTLADLLCCLSLPFSLAHLALQGQWPYGRFLCKLIPSIIVLNMFASVFLLTAISLDRCLVVFK
PIVVCQNHRNVGMACSICGCIVVVVAFVMCIPVFVYREIFTTDNHNRCGYKFGLSSSLDYPDFY
GDPLENRSLENIVQPPGEMNDRLDPSSFQTNDHPWTVPTVFQPQTFQRPSADSLPRGSARLTS
QNLYSNVFKPADVVSPKIPSGFPIEDHETSPLDNSDAFLSTHLKLFPSASSNSFYESELPQGFQD
YYNLGQFTDDDQVPTPLVAITITRLVVGFLLPSVIMIACYSFIVFRMQRGRFAKSQSKTFRVA
VVVVAVFLVCWTPYHIFGVLSLLTDPETPLGKTLMSWDHVCIALASANSCFNPFLYALLGKD
FRKKARQSIQGILEAAFSEELTRSTHCPSNNVISERNSTTV (SEQ ID NO:1055)
>gi|4758014|ref|NP_0040631| chemokine receptor-like 1 isoform b
{Homosapiens}
MEDEDYNTSISYGDEYPDYLDSIVVLEDLSPLEARVTRIFLVVVYSIVCFLGILGNGLVIIIATF
KMKKTVNMVWFLNLAVADFLFNVFLPIHITYAAMDYHWVFGTAMCKISNFLLIHNMFTSVF
LLTIISSDRCISVLLPVVVSQNHRSVRLAYMACMVIWVLAFFLSSPSLVFRDTANLHGKISCFNN
FSLSTPGSSSWPTHSQMDPVGYSRHMVVTVTRFLCGFLVPVLIITACYLTIVCKLQRNRLAKT
KKPFKIIVTIIITFFLCWCPYHTLNLLELHHTAMPGSVFSLGLPLATALAIANSCMNPILYVFMG
QDFKKFKVALFSRLVNALSEDTGHSSYPSHRSFTKMSSMNERTSMNERETGML (SEQ ID
NO:1056) >gi|4758326|ref|NP_0040921| proteinase-activated
receptor 3 precursor {Homosapiens}
MKALIFAAAGLLLLLPTFCQSGMENDTNNLAKPTLPIKTFRGAPPNSFEEFPFSALEGWTGATI
TVKIKCPEESASHLHVKNATMGYLTSSLSTKLIPAIYLLVFVVGVPANAVTLWMLFFRTRSIC
TTVFYTNLAIADFLFCVTLPFKIAYHLNGNNWVFGEVLCRATTVIFYGNMYCSILLLACISINR
YLAIVHPFTYRGLPKHTYALVTCGLVWATVFLYMLPFFILKQEYYLVQPDITTCHDVHNTCE
SSSPFQLYYFISLAFFGFLIPFVLIIYCYAAHRTLNAYDHRWLWYVKASLLILVIFTICFAPSNHL
IIHHANYYYNNTDGLYFIYLIALCLGSLNSCLDPFLYFLMSKTRNHSTAYLTK (SEQ ID
NO:1057) >gi|4758438|ref|NP_0042371| glucagon-like peptide 2
receptor precursor {Homosapiens}
MKLGSSRAGPGRGSAGLLPGVHELPMGIPAPWGTSPLSFHRKCSLWAPGRPFLTLVLLVSIKQ
VTGSLLEETTRKWAQYKQACLRDLLKEPSGIFCNGTFDQYVCWPHSSPGNVSVPCPSYLPW
WSEESSGRAYRHCLAQGTWQTIENATDIVVQDDSECSENHSFKQNVDRYALLSTLQLMYTVG
YSFSLISLFLALTLLLFLRKLHCTRNYIHMNLFASFILRTLAVLVKDVVFYNSYSKRPDNENG
WMSYLSEMSTSCRSVQVLLHYFVGANYLWLLVEGLYLHTLLEPTVLPERRLWPRYLLLGW
AFPVLFVVPWGFARAHLENTGCWTTNGNKKIVVWIIRGPMMLCVTVNFFIFLKILKLLISKLK
AHQMCFRDYKYRLAKSTLVLIPLLGVHEILFSFITDDQVEGFAKLIRLFIQLTLSSFHGFLVAL
QYGFANGEVKAELRKYWVRFLLARHSGCRACVLGKDFRFLGKCPKKLSEGDGAEKLRKLQ
PSLNSGRLLHLAMRGLGELGAQPQQDHARWPRGSSLSECSEGDVTMANTMEEILEESEI (SEQ ID
NO:1058) >gi|4758474|ref|NP_0042391| prolactin-releasing peptide
receptor {Homosapiens}
MASSTTRGPRVSDLFSGLPPAVTTPANQSAEASAGNGSVAGADAPAVTPFQSLQLVHQLKGL
IVLLYSVVVVVGLVGNCLLVLVIARVRRLHNVTNFLIGNLALSDVLMCTACVPLTLAYAFEP
RGWVFGGGLCHLVFFLQPVTVYVSVFTLTTIAVDRYVVLVHPLRRRISLRLSAYAVLAIWAL
SAVLALPAAVHTYHVELKPHDVRLCEEFWGSQERQRQLYAWGLLLVTYLLPLLVILLSYVR
VSVKLRNRVVPGCVTQSQADWDRARRRRTFCLLVVVVVVFAVCWLPLHVFNLLRDLDPHA
IDPYAFGLVQLLCHWLAMSSACYNPFIYAWLHDSFREELRKLLVAWPRKIAPHGQNMTVSV VI
(SEQ ID NO:1059) >gi|4758864|ref|NP_004145 1| pyrimidinergic
receptor P2Y6 {Homosapiens}
MEWDNGTGQALGLPPTTCVYRENFKQLLLPPVYSAVLAAGLPLNICVITQICTSRRALTRTA
VYTLNLALADLLYACSLPLLIYNYAQGDHWPFGDFACRLVRFLFYANLHGSILFLTCISFQRY
LGICHPLAPWHKRGGRRAAWLVCVAVWLAVTTQCLPTAIFAATGIQRNRTVCYDLSPPALA
THYMPYGMALTVIGFLLPFAALLACYCLLACRLCRQDGPAEPVAQERRGKAARMAVVVAA
AFAISFLPFHITKTAYLAVRSTPGVPCTVLEAFAAAYKGTRPFASANSVLDPILFYFTQKKFRR
RPHELLQKLTAKWQRQGR (SEQ ID NO:1060) >gi|4826706|ref|NP_0049421|
G-protein coupled receptor 183 {Homosapiens}
MDIQMANNFTPPSATPQGNDCDLYAHHSTARIVMPLHYSLVFIIGLVGNLLALVVIVQNRKKI
NSTTLYSTNLVISDILFTTALPTRIAYYAMGFDWRIGDALCRITALVFYINTYAGVNFMTCLSI
DRFIAVVHPLRYNKIKRIEHAKGVCIFVWILVFAQTLPLLINPMSKQEAERITCMEYPNFEETK
SLPWILLGACFIGYVLPLIIILICYSQICCKLFRTAKQNPLTEKSGVNKKALNTIILIIVVFVLCFT
PYHVAIIQHMIKKLRFSNFLECSQRHSFQISLHFTVCLMNFNCCMDPFIYFFACKGYKRKVMR
MLKRQVSVSISSAVKSAPEENSREMTETQMMIHSKSSNGK (SEQ ID NO:1061)
>gi|4826954|ref|NP_0050391| parathyroid hormone 2 receptor
precursor {Homosapiens}
MAGLGASLHVWGWLMLGSCLLARAQLDSDGTITIEEQIVLVLKAKVQCELNITAQLQEGEG
NCFPEWDGLICWPRGTVGKISAVPCPPYIYDFNHKGVAFRHCNPNGTWDFMHSLNKTWANY
SDCLRFLQPDISIGKQEFFERLYVMYTVGYSISFGSLAVAILIIGYFRRLHCTRNYIHMHLFVSF
MLRATSIFVKDRVVHAHIGVKELESLIMQDDPQNSIEATSVDKSQYIGCKIAVVMFIYFLATN
YYWILVEGLYLHNLIFVAFFSDTKYLWGFILIGWGFPAAFVAAWAVARATLADARCWELSA
GDIKWIYQAPILAAIGLNFILFLNTVRVLATKIVVETNAVGHDTRKQYRKLAKSTLVLVLVFGV
HYIVFVCLPHSFTGLGWERMHCELFFNSFQGFFVSIIYCYCNGEVQAEVKKMWSRWNLSVD
WKRTPPCGSRRCGSVLTTVTHSTSSQSQVAASTRMVLISGKAAKIASRQPDSHITLPGYVWSN
SEQDCLPHSFHEETKEDSGRQGDDILMEKPSRPMESNPDTEGCQGETEDVL (SEQ ID
NO:1062) >gi|4885057|ref|NP_005152 1| apelin receptor
{Homosapiens}
MEEGGDFDNYYGADNQSECEYTDWKSSGALIPAIYMLVFLLGTTGNGLVLWTVFRSSREKR
RSADIFIASLAVADLTFVVTLPLWATYTYRDYDWPFGTFFCKLSSYLIFVNMYASVFCLTGLS
FDRYLAIVRPVANARLRLRVSGAVATAVLWVLAALLAMPVMVLRTTGDLENTTKVQCYMD
YSMVATVSSEWAWEVGLGVSSTTVGFVVPFTIMLTCYFFIAQTIAGHFRKERIEGLRKRRRLL
SIIVVLVVTFALCWMPYHLVKTLYMLGSLLHWPCDFDLFLMNIFPYCTCISYVNSCLNPFLYA
FFDPRFRQACTSMLCCGQSRCAGTSHSSSGEKSASYSSGHSQGPGPNMGKGGEQMHEKSIPY
SQETLVVD (SEQ ID NO:1063) >gi|4885121|ref|NP_0051921| C-C
chemokine receptor type 8 {Homosapiens}
MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNGKLLLAVFYCLLFVFSLLGNSLVILVLVVC
KKLRSITDVYLLNLALSDLLFVFSFPFQTYYLLDQWVFGTVMCKVVSGFYYIGFYSSMFFITL
MSVDRYLAVVHAVYALKVRTIRMGTTLCLAVWLTAIMATIPLLVFYQVASEDGVLQCYSFY
NQQTLKWKIFTNFKMNILGLLIPFTIFMFCYIKILHQLKRCQNHNKTKAIRLVLIVVIASLLFVV
VPFNVVLFLTSLHSMHILDGCSISQQLTYATHVTEIISFTHCCVNPVIYAFVGEKFKKHLSEIFQ
KSCSQIFNYLGRQMPRESCEKSSSCQQHSSRSSSVDYIL (SEQ ID NO:1064)
>gi|4885295|ref|NP_0052791| G-protein coupled receptor 12
{Homosapiens}
MNEDLKVNLSGLPRDYLDAAAAENISAAVSSRVPAVEPEPELVVNPWDIVLCTSGTLISCEN
AIVVLIIFHNPSLRAPMFLLIGSLALADLLAGIGLITNFVFAYLLQSEATKLVTIGLIVASFSASV
CSLLAITVDRYLSLYYALTYHSERTVTFTYVMLVMLWGTSICLGLLPVMGWNCLRDESTCS
VVRPLTKNNAAILSVSFLFMFALMLQLYIQICKIVMRHAHQIALQHHFLATSHYVTTRKGVST
LAHLGTFAACWMPFTLYSLIADYTYPSIYTYATLLPATYNSIINPVIYAFRNQEIQKALCLICCG
CIPSSLAQRARSPSDV (SEQ ID NO:1065) >gi|4885299|ref|NP_0052811| G
protein-coupled receptor 15 {Homosapiens}
MDPEETSVYLDYYYATSPNSDIRETHSHVPYTSVFLPVFYTAVFLTGVLGNLVLMGALHFKP
GSRRLIDIFIINLAASDFIFLVTLPLWVDKEASLGLWRTGSFLCKGSSYMISVNMHCSVLLLTC
MSVDRYLAIVWPVVSRKFRRTDCAYVVCASIVVFISCLLGLPTLLSRELTLIDDKPYCAEKKAT
PIKLIVVSLVALIFTFFVPLLSIVTCYCCIARKLCAHYQQSGKHNKKLKKSIKIIFIVVAAFLVSW
LPFNTFKFLAIVSGLRQEHYLPSAILQLGMEVSGPLAFANSCVNPFIYYIFDSYIRRAIVHCLCP
CLKNYDFGSSTETSDSHLTKALSTFIHAEDFARRRKRSVSL (SEQ ID NO:1066)
>gi|4885301|ref|NP_0052821| uracil nucleotide/cysteinyl
leukotriene receptor isoform a {Homosapiens }
MSKRSWWAGSRKPPREMLKLSGSDSSQSMNGLEVAPPGLITNFSLATAEQCGQETPLENMLF
ASFYLLDFILALVGNTLALWLFIRDHKSGTPANVFLMHLAVADLSCVLVLPTRLVYHFSGNH
WPFGEIACRLTGFLFYLNMYASIYFLTCISADRFLAIVHPVKSLKLRRPLYAHLACAFLWVVV
AVAMAPLLVSPQTVQTNHTVVCLQLYREKASHHALVSLAVAFTFPFITTVTCYLLIIRSLRQG
LRVEKRLKTKAVRMIAIVLAIFLVCFVPYHVNRSVYVLHYRSHGASCATQRILALANRITSCL
TSLNGALDPIMYFFVAEKFRHALCNLLCGKRLKGPPPSFEGKTNESSLSAKSEL (SEQ ID
NO:1067) >gi|4885307|ref|NP_0052851| G protein-coupled receptor
21 {Homosapiens}
MNSTLDGNQSSHPFCLLAFGYLETVNFCLLEVLIIVFLTVLIISGNIIVIFVFHCAPLLNHHTTSY
FIQTMAYADLFVGVSCVVPSLSLLHHPLPVEESLTCQIFGFVVSVLKSVSMASLACISIDRYIAI
TKPLTYNTLVTPWRLRLCIFLIVVLYSTLVFLPSFFHWGKPGYHGDVFQWCAESWHTDSYFTL
FIVMMLYAPAALIVCFTYFNIFRICQQHTKDISERQARFSSQSGETGEVQACPDKRYAMVLFRI
TSVFYILWLPYIIYFLLESSTGHSNRFASFLTTWLAISNSFCNCVIYSLSNSVFQRGLKRLSGAM
CTSCASQTTANDPYTVRSKGPLNGCHI (SEQ ID NO:1068)
>gi|4885311|ref|NP_0052871| lysophosphatidic acid receptor 4
{Homosapiens}
MGDRRFIDFQFQDSNSSLRPRLGNATANNTCIVDDSFKYNLNGAVYSVVFILGLITNSVSLFV
FCFRMKMRSETAIFITNLAVSDLLFVCTLPFKIFYNFNRHWPFGDTLCKISGTAFLTNIYGSML
FLTCISVDRFLAIVYPFRSRTIRTRRNSAIVCAGVWILVLSGGISASLFSTTNVNNATTTCFEGF
SKRVVVKTYLSKITIFIEVVGFIIPLILNVSCSSVVLRTLRKPATLSQIGTNKKKVLKMITVHMAV
FVVCFVPYNSVLFLYALVRSQAITNCFLERFAKIMYPITLCLATLNCCFDPFIYYFTLESFQKSF
YINAHIRMESLFKTETPLTTKPSLPAIQEEVSDQTTNNGGELMLESTF (SEQ ID NO:1069)
>gi|4885319|ref|NP_0052911| probable G-protein coupled receptor
34 {Homosapiens}
MRSHTITMTTTSVSSWPYSSHRMRFITNHSDQPPQNFSATPNVTTCPMDEKLLSTVLTTSYSVI
FIVGLVGNIIALYVFLGIHRKRNSIQIYLLNVAIADLLLIFCLPFRIMYHINQNKWTLGVILCKV
VGTLFYMNMYISIILLGFISLDRYIKINRSIQQRKAITTKQSIYVCCIVWMLALGGFLTMIILTLK
KGGHNSTMCFHYRDKHNAKGEAIFNFILVVMFVVLIFLLIILSYIKIGKNLLRISKRRSKFPNSG
KYATTARNSFIVLIIFTICFVPYHAFRFIYISSQLNVSSCYVVKEIVHKTNEIMLVLSSFNSCLDPV
MYFLMSSNIRKIMCQLLFRRFQGEPSRSESTSEFKPGYSLHDTSVAVKIQSSSKST (SEQ ID
NO:1070) >gi|4885323|ref|NP_0052931| probable G-protein coupled
receptor 37 precursor {Homosapiens}
MRAPGALLARMSRLLLLLLLKVSASSALGVAPASRNETCLGESCAPTVIQRRGRDAWGPGNS
ARDVLRARAPREEQGAAFLAGPSWDLPAAPGRDPAAGRGAEASAAGPPGPPTRPPGPWRW
KGARGQEPSETLGRGNPTALQLFLQISEEEEKGPRGAGISGRSQEQSVKTVPGASDLFYWPRR
AGKLQGSHHKPLSKTANGLAGHEGWTIALPGRALAQNGSLGEGIHEPGGPRRGNSTNRRVR
LKNPFYPLTQESYGAYAVMCLSVVIFGTGIIGNLAVMCIVCHNYYMRSISNSLLANLAFVVDF
LIIFFCLPLVIFHELTKKWLLEDFSCKIVPYIEVASLGVTTFTLCALCIDRFRAATNVQMYYEMI
ENCSSTTAKLAVIWVGALLLALPEVVLRQLSKEDLGFSGRAPAERCIIKISPDLPDTIYVLALT
YDSARLWWYFGCYFCLPTLFTITCSLVTARKIRKAEKACTRGNKRQIQLESQMNCTVVALTI
LYGFCIIPENICNIVTAYMATGVSQQTMDLLNIISQFLLFFKSCVTPVLLFCLCKPFSRAFMECC
CCCCEECIQKSSTVTSDDNDNEYTTELELSPFSTIRREMSTFASVGTHC (SEQ ID NO:1071)
>gi|4885325|ref|NP_0052721| G protein-coupled receptor 3
{Homosapiens}
MMWGAGSPLAWLSAGSGNVNVSSVGPAEGPTGPAAPLPSPKAWDVVLCISGTLVSCENALV
VAHVGTPAFRAPMFLLVGSLAVADLLAGLGLVLHFAAVFCIGSAEMSLVLVGVLAMAFTASI
GSLLAITVDRYLSLYNALTYYSETTVTRTYVMLALVWGGALGLGLLPVLAWNCLDGLTTCG
VVYPLSKNHLVVLAIAFFMVFGIMLQLYAQICRIVCRHAQQIALQRHLLPASHYVATRKGIAT
LAVVLGAFAACWLPFTVYCLLGDAHSPPLYTYLTLLPATYNSMINPIIYAFRNQDVQKVLWA
VCCCCSSSKIPFRSRSPSDV (SEQ ID NO:1072)
>gi|4885327|ref|NP_0052941| free fatty acid receptor 1
{Homosapiens}
MDLPPQLSFGLYVAAFALGFPLNVLAIRGATAHARLRLTPSLVYALNLGCSDLLLTVSLPLKA
VEALASGAWPLPASLCPVFAVAHFFPLYAGGGFLAALSAGRYLGAAFPLGYQAFRRPCYSW
GVCAAIWALVLCHLGLVFGLEAPGGWLDHSNTSLGINTPVNGSPVCLEAWDPASAGPARFS
LSLLLFFLPLAITAFCYVGCLRALARSGLTHRRKLRAAWVAGGALLTLLLCVGPYNASNVAS
FLYPNLGGSWRKLGLITGAWSVVLNPLVTGYLGRGPGLKTVCAARTQGGKSQK (SEQ ID
NO:1073) >gi|4885329|ref|NP_0052951| free fatty acid receptor 3
{Homosapiens}
MDTGPDQSYFSGNHWFVFSVYLLTFLVGLPLNLLALVVFVGKLQRRPVAVDVLLLNLTASD
LLLLLFLPFRMVEAANGMHWPLPFILCPLSGFIFFTTIYLTALFLAAVSIERFLSVAHPLWYKT
RPRLGQAGLVSVACWLLASAHCSVVYVIEFSGDISHSQGTNGTCYLEFRKDQLAILLPVRLE
MAVVLFVVPLIITSYCYSRLVVVILGRGGSHRRQRRVAGLLAATLLNFLVCFGPYNVSHVVGY
ICGESPAWRIYVTLLSTLNSCVDPFVYYFSSSGFQADFHELLRRLCGLWGQWQQESSMELKE
QKGGEEQRADRPAERKTSEHSQGCGTGGQVACAES (SEQ ID NO:1074)
>gi|4885333|ref|NP_0052971| free fatty acid receptor 2
{Homosapiens}
MLPDWKSSLILMAYIIIFLTGLPANLLALRAFVGRIRQPQPAPVHILLLSLTLADLLLLLLLPFKI
IEAASNFRWYLPKVVCALTSFGFYSSIYCSTVVLLAGISIERYLGVAFPVQYKLSRRPLYGVIAA
LVAWVMSFGHCTIVIIVQYLNTTEQVRSGNEITCYENFTDNQLDVVLPVRLELCLVLFFIPMA
VTIFCYWRFVVVIMLSQPLVGAQRRRRAVGLAVVTLLNFLVCFGPYNVSHLVGYHQRKSPW
WRSIAVVFSSLNASLDPLLFYFSSSVVRRAFGRGLQVLRNQGSSLLGRRGKDTAEGTNEDRG
VGQGEGMPSSDFTTE (SEQ ID NO:1075) >gi|4885335|ref|NP_0052731|
G-protein coupled receptor 4 {Homosapiens}
MGNHTWEGCHVDSRVDHLFPPSLYIFVIGVGLPTNCLALWAAYRQVQQRNELGVYLMNLSI
ADLLYICTLPLWVDYFLHHDNVVIHGPGSCKLFGFIFYTNIYISIAFLCCISVDRYLAVAHPLRF
ARLRRVKTAVAVSSVVWATELGANSAPLFHDELFRDRYNHTFCFEKFPMEGWVAWMNLYR
VFVGFLFPWALMLLSYRGILRAVRGSVSTERQEKAKIKRLALSLIAIVLVCFAPYHVLLLSRS
AIYLGRPWDCGFEERVFSAYHSSLAFTSLNCVADPILYCLVNEGARSDVAKALHNLLRFLAS
DKPQEMANASLTLETPLTSKRNSTAKAMTGSWAATPPSQGDQVQLKMLPPAQ (SEQ ID
NO:1076) >gi|4885339|ref|NP_0052741| chemokine XC receptor 1
{Homosapiens}
MESSGNPESTTFFYYDLQSQPCENQAWVFATLATTVLYCLVFLLSLVGNSLVLWVLVKYESL
ESLTNIFILNLCLSDLVFACLLPVWISPYHWGWVLGDFLCKLLNMIFSISLYSSIFFLTIMTIHRY
LSVVSPLSTLRVPTLRCRVLVTMAVWVASILSSILDTIFHKVLSSGCDYSELTWYLTSVYQHN
LFFLLSLGIILFCYVEILRTLFRSRSKRRHRTVKLIFAIVVAYFLSWGPYNFTLFLQTLFRTQIIRS
CEAKQQLEYALLICRNLAFSHCCFNPVLYVFVGVKFRTHLKHVLRQFVVFCRLQAPSPASIPHS
PGAFAYEGASFY (SEQ ID NO:1077) >gi|4885341|ref|NP_0052751|
G-protein coupled receptor 6 {Homosapiens}
MNASAASLNDSQVVVVAAEGAAAAATAAGGPDTGEWGPPAAAALGAGGGANGSLELSSQ
LSAGPPGLLLPAVNPWDVLLCVSGTVIAGENALVVALIASTPALRTPMFVLVGSLATADLLA
GCGLILHFVFQYLVPSETVSLLTVGFLVASFAASVSSLLAITVDRYLSLYNALTYYSRRTLLGV
HLLLAATWTVSLGLGLLPVLGWNCLAERAACSVVRPLARSHVALLSAAFFMVFGIMLHLYV
RICQVVWRHAHQIALQQHCLAPPHLAATRKGVGTLAVVLGTFGASWLPFAIYCVVGSHEDP
AVYTYATLLPATYNSMINPIIYAFRNQEIQRALWLLLCGCFQSKVPFRSRSPSEV (SEQ ID
NO:1078) >gi|488536 1 |ref|NP_0053051| gastrin-releasing peptide
receptor {Homosapiens}
MALNDCFLLNLEVDHFMHCNISSHSADLPVNDDWSHPGILYVIPAVYGVIILIGLIGNITLIKIF
CTVKSMRNVPNLFISSLALGDLLLLITCAPVDASRYLADRWLFGRIGCKLIPFIQLTSVGVSVF
TLTALSADRYKAIVRPMDIQASHALMKICLKAAFIVVIISMLLAIPEAVFSDLHPFHEESTNQTFI
SCAPYPHSNELHPKIHSMASFLVFYVIPLSIISVYYYFIAKNLIQSAYNLPVEGNIHVKKQIESR
KRLAKTVLVFVGLFAFCWLPNHVIYLYRSYHYSEVDTSMLHFVTSICARLLAFTNSCVNPFA
LYLLSKSFRKQFNTQLLCCQPGLIIRSHSTGRSTTCMTSLKSTNPSVATFSLINGNICHERYV
(SEQ ID NO:1079) >gi|5031621|ref|NP_0057861| calcitonin
gene-related peptide type 1 receptor precursor {Homosapiens}
MEKKCTLYFLVLLPFFMILVTAELEESPEDSIQLGVTRNKIMTAQYECYQKIMQDPIQQAEGV
YCNRTWDGWLCWNDVAAGTESMQLCPDYFQDFDPSEKVTKICDQDGNWFRHPASNRTWT
NYTQCNVNTHEKVKTALNLFYLTIIGHGLSIASLLISLGIFFYFKSLSCQRITLHKNLFFSFVCN
SVVTIIHLTAVANNQALVATNPVSCKVSQFIHLYLMGCNYFVVMLCEGIYLHTLIVVAVFAEK
QHLMWYYFLGWGFPLIPACIHAIARSLYYNDNCWISSDTHLLYIIHGPICAALLVNLFFLLNIV
RVLITKLKVTHQAESNLYMKAVRATLILVPLLGIEFVLIPWRPEGKIAEEVYDYIMHILMHFQ
GLLVSTIFCFFNGEVQAILRRNWNQYKIQFGNSFSNSEALRSASYTVSTISDGPGYSHDCPSEH
LNGKSIHDIENVLLKPENLYN (SEQ ID NO:1080)
>gi|5031627|ref|NP_0054991| C-C chemokine receptor type 4
{Homosapiens}
MNPTDIADTTLDESIYSNYYLYESIPKPCTKEGIKAFGELFLPPLYSLVFVFGLLGNSVVVLVL
FKYKRLRSMTDVYLLNLAISDLLFVFSLPFVVGYYAADQWVFGLGLCKMISWMYLVGFYSGI
FFVMLMSIDRYLAIVHAVFSLRARTLTYGVITSLATWSVAVFASLPGFLFSTCYTERNHTYCK
TKYSLNSTTVVKVLSSLEINILGLVIPLGIMLFCYSMIIRTLQHCKNEKKNKAVKMIFAVVVLFL
GFVVTPYNIVLFLETLVELEVLQDCTFERYLDYAIQATETLAFVHCCLNPHYFFLGEKFRKYIL
QLFKTCRGLFVLCQYCGLLQIYSADTPSSSYTQSTMDHDLHDAL (SEQ ID NO:1081)
>gi|5174535|ref|NP_0059041| melanocortin 5 receptor
{Homosapiens}
MNSSFHLHFLDLNLNATEGNLSGPNVKNKSSPCEDMGIAVEVFLTLGVISLLENILVIGAIVKN
KNLHSPMYFFVCSLAVADMLVSMSSAWETITIYLLNNKHLVIADAFVRHIDNVFDSMICISVV
ASMCSLLAIAVDRYVTIFYALRYHHIMTARRSGAIIAGIVVAFCTGCGIVFILYSESTYVILCLIS
MFFAMLFLLVSLYIHMFLLARTHVKRIAALPGASSARQRTSMQGAVTVTMLLGVFTVCWAP
FFLHLTLMLSCPQNLYCSRFMSHFNMYLILIMCNSVMDPLIYAFRSQEMRKTFKEIICCRGFRI
ACSFPRRD (SEQ ID NO:1082) >gi|5174593|ref|NP_0059491| melatonin
receptor 1 A {Homosapiens}
MQGNGSALPNASQPVLRGDGARPSWLASALACVLIFTIVVDILGNLLVILSVYRNKKLRNAG
NIFVVSLAVADLVVAIYPYPLVLMSIFNNGWNLGYLHCQVSGFLMGLSVIGSIFNITGIAINRY
CYICHSLKYDKLYSSKNSLCYVLLIVVLLTLAAVLPNLRAGTLQYDPRIYSCTFAQSVSSAYTI
AVVVFHFLVPMIIVIFCYLRIVVILVLQVRQRVKPDRKPKLKPQDFRNFVTMFVVFVLFAICWA
PLNFIGLAVASDPASMVPRIPEWLFVASYYMAYFNSCLNAIIYGLLNQNFRKEYRRIIVSLCTA
RVFFVDSSNDVADRVKWKPSPLMTNNNVVKVDSV (SEQ ID NO:1083)
>gi|5174595|ref|NP_0059501| melatonin receptor 1B {Homosapiens}
MSENGSFANCCEAGGWAVRPGWSGAGSARPSRTPRPPWVAPALSAVLIVTTAVDVVGNLL
VILSVLRNRKLRNAGNLFLVSLALADLVVAFYPYPLILVAIFYDGWALGEEHCKASAFVMGL
SVIGSVFNITAIAINRYCYICHSMAYHRIYRRWHTPLHICLIWLLTVVALLPNFFVGSLEYDPRI
YSCTFIQTASTQYTAAVVVIHFLLPIAVVSFCYLRIWVLVLQARRKAKPESRLCLKPSDLRSFL
TMFVVFVIFAICWAPLNCIGLAVAINPQEMAPQIPEGLFVTSYLLAYFNSCLNAIVYGLLNQNF
RREYKRILLALWNPRHCIQDASKGSHAEGLQSPAPPIIGVQHQADAL (SEQ ID NO:1084)
>gi|5453666|ref|NP_0061341| probable G-protein coupled receptor
19 {Homosapiens}
MVFAHRMDNSKPHLIIPTLLVPLQNRSCTETATPLPSQYLMELSEEHSWMSNQTDLHYVLKP
GEVATASIFFGILWLFSIFGNSLVCLVIHRSRRTQSTTNYFVVSMACADLLISVASTPFVLLQFT
TGRWTLGSATCKVVRYFQYLTPGVQIYVLLSICIDRFYTIVYPLSFKVSREKAKKMIAASWIF
DAGFVTPVLFFYGSNWDSHCNYFLPSSWEGTAYTVIHFLVGFVIPSVLIILFYQKVIKYIVVRIG
TDGRTVRRTMNIVPRTKVKTIKMFLILNLLFLLSWLPFHVAQLWHPHEQDYKKSSLVFTAIT
WISFSSSASKPTLYSIYNANFRRGMKETFCMSSMKCYRSNAYTITTSSRMAKKNYVGISEIPS
MAKTITKDSIYDSFDREAKEKKLAWPINSNPPNTFV (SEQ ID NO:1085)
>gi|5453796|ref|NP_0061651| neuropeptide Y receptor Y5
{Homosapiens}
MDLELDEYYNKTLATENNTAATRNSDFPVVVDDYKSSVDDLQYFLIGLYTFVSLLGFMGNLL
ILMALMKKRNQKTTVNFLIGNLAFSDILVVLFCSPFTLTSVLLDQWMFGKVMCHIMPFLQCV
SVLVSTLILISIAIVRYHMIKHPISNNLTANHGYFLIATVWTLGFAICSPLPVFHSLVELQETFGS
ALLSSRYLCVESWPSDSYRIAFTISLLLVQYILPLVCLTVSHTSVCRSISCGLSNKENRLEENEM
INLTLHPSKKSGPQVKLSGSHKWSYSFIKKHRRRYSKKTACVLPAPERPSQENHSRILPENFGS
VRSQLSSSSKFIPGVPTCFEIKPEENSDVHELRVKRSVTRIKKRSRSVFYRLTILILVFAVSWMP
LHLFHVVTDFNDNLISNRHFKLVYCICHLLGMMSCCLNPILYGFLNNGIKADLVSLIHCLHM (SEQ
ID NO:1086) >gi|5729798|ref|NP_0066301| cysteinyl leukotriene
receptor 1 {Homosapiens}
MDETGNLTVSSATCHDTIDDFRNQVYSTLYSMISVVGFFGNGFVLYVLIKTYHKKSAFQVYM
INLAVADLLCVCTLPLRVVYYVHKGIVVLFGDFLCRLSTYALYVNLYCSIFFMTAMSFFRCIAI
VFPVQNINLVTQKKARFVCVGIVVIFVILTSSPFLMAKPQKDEKNNTKCFEPPQDNQTKNHVL
VLHYVSLFVGFIIPFVIIIVCYTMIILTLLKKSMKKNLSSHKKAIGMIMVVTAAFLVSFMPYHIQ
RTIHLHFLHNETKPCDSVLRMQKSVVITLSLAASNCCFDPLLYFFSGGNFRKRLSTFRKHSLSS
VTYVPRKKASLPEKGEEICKV (SEQ ID NO:1087)
>gi|5730106|ref|NP_0065551| C-X-C chemokine receptor type 6
{Homosapiens}
MAEHDYHEDYGFSSFNDSSQEEHQDFLQFSKVFLPCMYLVVFVCGLVGNSLVLVISIFYHKL
QSLTDVFLVNLPLADLVFVCTLPFWAYAGIHEWVFGQVMCKSLLGIYTINFYTSMLILTCITV
DRFIVVVKATKAYNQQAKRMTWGKVTSLLIVVVISLLVSLPQIIYGNVFNLDKLICGYHDEAIS
TVVLATQMTLGFFLPLLTMIVCYSVIIKTLLHAGGFQKHRSLKIIFLVMAVFLLTQMPFNLMK
FIRSTHWEYYAMTSFHYTIMVTEAIAYLRACLNPVLYAFVSLKFRKNFWKLVKDIGCLPYLG
VSHQWKSSEDNSKTFSASHNVEATSMFQL (SEQ ID NO:1088)
>gi|5803025|ref|NP_0067851| probable G-protein coupled receptor
75 {Homosapiens}
MNSTGHLQDAPNATSLHVPHSQEGNSTSLQEGLQDLIHTATLVTCTFLLAVIFCLGSYGNFIV
FLSFFDPAFRKFRTNFDFMILNLSFCDLFICGVTAPMFTFVLFFSSASSIPDAFCFTFHLTSSGFII
MSLKTVAVIALHRLRMVLGKQPNRTASFPCTVLLTLLLWATSFTLATLATLKTSKSHLCLPM
SSLIAGKGKAILSLYVVDFTFCVAVVSVSYIMIAQTLRKNAQVRKCPPVITVDASRPQPFMGV
PVQGGGDPIQCAMPALYRNQNYNKLQHVQTRGYTKSPNQLVTPAASRLQLVSAINLSTAKD
SKAVVTCVIIVLSVLVCCLPLGISLVQVVLSSNGSFILYQFELFGFTLIFFKSGLNPFIYSRNSAG
LRRKVLWCLQYIGLGFFCCKQKTRLRAMGKGNLEVNRNKSSHHETNSAYMLSPKPQKKFV
DQACGPSHSKESMVSPKISAGHQHCGQSSSTPINTRIEPYYSIYNSSPSQEESSPCNLQPVNSFG
FANSYIAMHYHTTNDLVQEYDSTSAKQIPVPSV (SEQ ID NO:1089)
>gi|5921992|ref|NP_0006662| adenosine receptor A2a {Homosapiens}
MPIMGSSVYITVELAIAVLAILGNVLVCWAVWLNSNLQNVTNYFVVSLAAADIAVGVLAIPF
AITISTGFCAACHGCLFIACFVLVLTQSSIFSLLAIAIDRYIAIRIPLRYNGLVTGTRAKGIIAICW
VLSFAIGLTPMLGWNNCGQPKEGKNHSQGCGEGQVACLFEDVVPMNYMVYFNFFACVLVP
LLLMLGVYLRIFLAARRQLKQMESQPLPGERARSTLQKEVHAAKSLAHVGLFALCWLPLHII
NCFTFFCPDCSHAPLWLMYLAIVLSHTNSVVNPFIYAYRIREFRQTFRKIIRSHVLRQQEPFKA
AGTSARVLAAHGSDGEQVSLRLNGHPPGVVVANGSAPHPERRPNGYALGLVSGGSAQESQG
NTGLPDVELLSHELKGVCPEPPGLDDPLAQDGAGVS (SEQ ID NO:1090)
>gi|6005705|ref|NP_0091951| G-protein coupled receptor 182
{Homosapiens}
MSVKPSWGPGPSEGVTAVPTSDLGEIHNWTELLDLFNHTLSECHVELSQSTKRVVLFALYLA
MFVVGLVENLLVICVNWRGSGRAGLMNLYILNMAIADLGIVLSLPVWMLEVTLDYTWLWG
SFSCRFTHYFYFVNMYSSIFFLVCLSVDRYVTLTSASPSWQRYQHRVRRAMCAGIVVVLSAIIP
LPEVVHIQLVEGPEPMCLFMAPFETYSTWALAVALSTTILGFLLPFPLITVFNVLTACRLRQPG
QPKSRRHCLLLCAYVAVFVMCWLPYHVTLLLLTLHGTHISLHCHLVHLLYFFYDVIDCFSML
HCVINPILYNFLSPHFRGRLLNAVVHYLPKDQTKAGTCASSSSCSTQHSIIITKGDSQPAAAAP
HPEPSLSFQAHHLLPNTSPISPTQPLTPS (SEQ ID NO:1091)
>gi|6323236|ref|NP_0133081| Hrd3p {Saccharomyces cereyisiae}
MITLLLYLCVICNAIVLIRADSIADPWPEARHLLNTIAKSRDPMKEAAMEPNADEFVGFYVPM
DYSPRNEEKNYQSIVVQNEITDSQRHIYELLVQSSEQFNNSEATYTLSQIHLWSQYNFPHNMTL
AHKYLEKFNDLTHFTNHSAIFDLAVMYATGGCASGNDQTVIPQDSAKALLYYQRAAQLGNL
KAKQVLAYKYYSGFNVPRNFHKSLVLYRDIAEQLRKSYSRDEWDIVFPYVVESYNVRISDFES
GLLGKGLNSVPSSTVRKRTTRPDIGSPFIAQVNGVQMTLQIEPMGRFAFNGNDGNINGDEDD
EDASERRIIRIYYAALNDYKGTYSQSRNCERAKNLLELTYKEFQPHVDNLDPLQVFYYVRCL
QLLGHMYFTGEGSSKPNIHMAEEILTTSLEISRRAQGPIGRACIDLGLINQYITNNISQAISYYM
KAMKTQANNGIVEFQLSKLATSFPEEKIGDPFNLMETAYLNGFIPAIYEFAVMIESGMNSKSS
VENTAYLFKTFVDKNEAIMAPKLRTAFAALINDRSEVALWAYSQLAEQGYETAQVSAAYLM
YQLPYEFEDPPRTTDQRKTLAISYYTRAFKQGNIDAGVVAGDIYFQMQNYSKAMALYQGAA
LKYSIQAIVVNLGYMHEHGLGVNRDFHLAKRYYDQVSEHDHRFYLASKLSVLKLHLKSWLT
WITREKVNYWKPSSPLNPNEDTQHSKTSWYKQLTKILQRMRHKEDSDKAAEDSHKHRTVV
QNGANHRGDDQEEASEILGFQMEDLVTMGCILGIFLLSILMSTLAARRGWNVRFNGAQLNA
NGNRQQEQQQQQQAQGPPGWDFNVQIFAI (SEQ ID NO:1092)
>gi|6912348|ref|NP_0362841| lysophosphatidic acid receptor 3
{Homosapiens}
MNECHYDKHMDFFYNRSNTDTVDDWTGTKLVIVLCVGTFFCLFIFFSNSLVIAAVIKNRKFH
FPFYYLLANLAAADFFAGIAYVFLMFNTGPVSKTLTVNRWFLRQGLLDSSLTASLTNLLVIAV
ERHMSIMRMRVHSNLTKKRVTLLILLVWAIAIFMGAVPTLGWNCLCNISACSSLAPIYSRSYL
VFVVTVSNLMAFLIMVVVYLRIYVYVKRKTNVLSPHTSGSISRRRTPMKLMKTVMTVLGAFV
VCWTPGLVVLLLDGLNCRQCGVQHVKRWFLLLALLNSVVNPIIYSYKDEDMYGTMKKMIC
CFSQENPERRPSRIPSTVLSRSDTGSQYIEDSISQGAVCNKSTS (SEQ ID NO:1093)
>gi|6912464 |ref|NP_0364341| latrophilin-2 precursor
{Homosapiens} MVSS
GCRMRSLWFIIVISFLPNTEGFSRAALPFGLVRRELSCEGYSIDLRCPGSDVIMIESANYG
RTDDKICDADPFQMENTDCYLPDAFKIMTQRCNNRTQCIVVTGSDVFPDPCPGTYKYLEVQY
ECVPYIFVCPGTLKAIVDSPCIYEAEQKAGAWCKDPLQAADKIYFMPWTPYRTDTLIEYASLE
DFQNSRQTTTYKLPNRVDGTGFVVYDGAVFFNKERTRNIVKFDLRTRIKSGEAIINYANYHD
TSPYRWGGKTDIDLAVDENGLWVIYATEQNNGMIVISQLNPYTLRFEATWETVYDKRAASN
AFMICGVLYVVRSVYQDNESETGKNSIDYIYNTRLNRGEYVDVPFPNQYQYIAAVDYNPRD
NQLYVWNNNFILRYSLEFGPPDPAQVPTTAVTITSSAELFKTIISTTSTTSQKGPMSTTVAGSQ
EGSKGTKPPPAVSTTKIPPITNIFPLPERFCEALDSKGIKWPQTQRGMMVERPCPKGTRGTASY
LCMISTGTWNPKGPDLSNCTSHWVNQLAQKIRSGENAASLANELAKHTKGPVFAGDVSSSV
RLMEQLVDILDAQLQELKPSEKDSAGRSYNKAIVDTVDNLLRPEALESWKHMNSSEQAHTA
TMLLDTLEEGAFVLADNLLEPTRVSMPTENIVLEVAVLSTEGQIQDFKFPLGIKGAGSSIQLSA
NTVKQNSRNGLAKLVFIIYRSLGQFLSTENATIKLGADFIGRNSTIAVNSHVISVSINKESSRVY
LTDPVLFTLPHIDPDNYFNANCSFWNYSERTMMGYWSTQGCKLVDTNKTRTTCACSHLTNF
AILMAHREIAYKDGVHELLLTVITWVGIVISLVCLAICIFTFCFFRGLQSDRNTIHKNLCINLFIA
EFIFLIGIDKTKYAIACPIFAGLLHFFFLAAFAWMCLEGVQLYLMLVEVFESEYSRKKYYYVA
GYLFPATVVGVSAAIDYKSYGTEKACWLHVDNYFIVVSFIGPVTFIILLNIIFLVITLCKMVKHS
NTLKPDSSRLENIKSWVLGAFALLCLLGLTWSFGLLFINEETIVMAYLFTIFNAFQGVFIFIFHC
ALQKKVRKEYGKCFRHSYCCGGLPTESPHSSVKASTTRTSARYSSGTQSRIRRMWNDTVRK
QSESSFISGDINSTSTLNQGHSLNNARDTSAMDTLPLNGNFNNSYSLHKGDYNDSVQVVDCG
LSLNDTAFEKMIISELVHNNLRGSSKTHNLELTLPVKPVIGGSSSEDDAIVADASSLMHSDNPG
LELHHKELEAPLIPQRTHSLLYQPQKKVKSEGTDSYVSQLTAEAEDHLQSPNRDSLYTSMPNL
RDSPYPESSPDMEEDLSPSRRSENEDIYYKSMPNLGAGHQLQMCYQISRGNSDGYIIPINKEGC
IPEGDVREGQMQLVTSL (SEQ ID NO:1094) >gi|6912538|ref|NP_0364761|
neurotensin receptor type 2 {Homosapiens}
METSSPRPPRPSSNPGLSLDARLGVDTRLWAKVLFTALYALIWALGAAGNALSVHVVLKAR
AGRAGRLRHHVLSLALAGLLLLLVGVPVELYSFVWFHYPWVFGDLGCRGYYFVHELCAYA
TVLSVAGLSAERCLAVCQPLRARSLLTPRRTRWLVALSWAASLGLALPMAVIMGQKHELET
ADGEPEPASRVCTVLVSRTALQVFIQVNVLVSFVLPLALTAFLNGVTVSHLLALCSQVPSTST
PGSSTPSRLELLSEEGLLSFIVVVKKTFIQGGQVSLVRHKDVRRIRSLQRSVQVLRAIVVMYVIC
WLPYHARRLMYCYVPDDAWTDPLYNFYHYFYMVTNTLFYVSSAVTPLLYNAVSSSFRKLFL
EAVSSLCGEHHPMKRLPPKPQSPTLMDTASGFGDPPETRT (SEQ ID NO:1095)
>gi|7019387|ref|NP_0374771| probable G-protein coupled receptor
132 {Homosapiens}
MCPMLLKNGYNGNATPVTTTAPWASLGLSAKTCNNVSFEESRIVLVVVYSAVCTLGVPANC
LTAWLALLQVLQGNVLAVYLLCLALCELLYTGTLPLWVIYIRNQHRWTLGLLACKVTAYIFF
CNIYVSILFLCCISCDRFVAVVYALESRGRRRRRTAILISACIFILVGIVHYPVFQTEDKETCFD
MLQMDSRIAGYYYARFTVGFAIPLSIIAFTNHRIFRSIKQSMGLSAAQKAKVKHSAIAVVVIFL
VCFAPYHLVLLVKAAAFSYYRGDRNAMCGLEERLYTASVVFLCLSTVNGVADPIIYVLATD
HSRQEVSRIHKGWKEWSMKTDVTRLTHSRDTEELQSPVALADHYTFSRPVHPPGSPCPAKRL
IEESC (SEQ ID NO:1096) >gi|7108336|ref|NP_0362571| cholinergic
receptor, muscarinic 5 {Homosapiens}
MEGDSYHNATTVNGTPVNHQPLERHRLWEVITIAAVTAVVSLITIVGNVLVMISFKVNSQLK
TVNNYYLLSLACADLIIGIFSMNLYTTYILMGRWALGSLACDLWLALDYVASNASVMNLLVI
SFDRYFSITRPLTYRAKRTPKRAGIMIGLAWLISFILWAPAILCWQYLVGKRTVPLDECQIQFL
SEPTITFGTAIAAFYIPVSVMTILYCRIYRETEKRTKDLADLQGSDSVTKAEKRKPAHRALFRS
CLRCPRPTLAQRERNQASWSSSRRSTSTTGKPSQATGPSANVVAKAEQLTTCSSYPSSEDEDKP
ATDPVLQVVYKSQGKESPGEEFSAEETEETFVKAETEKSDYDTPNYLLSPAAAHRPKSQKCV
AYKFRLVVKADGNQETNNGCHKVKIMPCPFPVAKEPSTKGLNPNPSHQMTKRKRVVLVKE
RKAAQTLSAILLAFIITWTPYNIMVLVSTFCDKCVPVTLWHLGYVVLCYVNSTVNPICYALCN
RTFRKTFKMLLLCRWKKKKVEEKLYWQGNSKLP (SEQ ID NO:1097)
>gi|7305013|ref|NP_0047112| lysophosphatidic acid receptor 2
{Homosapiens}
MVIMGQCYYNETIGFFYNNSGKELSSHWRPKDVVVVALGLTVSVLVLLTNLLVIAAIASNRR
FHQPIYYLLGNLAAADLFAGVAYLFLMFHTGPRTARLSLEGWFLRQGLLDTSLTASVATLLA
IAVERHRSVMAVQLHSRLPRGRVVMLIVGVWVAALGLGLLPAHSWHCLCALDRCSRMAPL
LSRSYLAVWALSSLLVFLLMVAVYTRIFFYVRRRVQRMAEHVSCHPRYRETTLSLVKTVVIIL
GAFVVCWTPGQVVLLLDGLGCESCNVLAVEKYFLLLAEANSLVNAAVYSCRDAEMRRTFR
RLLCCACLRQSTRESVHYTSSAQGGASTRIMLPENGHPLMDSTL (SEQ ID NO:1098)
>gi|7657136|ref|NP_0551881| probable G-protein coupled receptor
160 {Homosapiens}
MTALSSENCSFQYQLRQTNQPLDVNYLLFLIILGKILLNILTLGMRRKNTCQNFMEYFCISLAF
VDLLLLVNISIILYFRDFVLLSIRFTKYHICLFTQIISFTYGFLHYPVFLTACIDYCLNFSKTTKLS
FKCQKLFYFFTVILIVVISVLAYVLGDPAIYQSLKAQNAYSRHCPFYVSIQSYVVLSFFMVMILFV
AFITCWEEVTTLVQAIRITSYMNETILYFPFSSHSSYTVRSKKIFLSKLIVCFLSTWLPFVLLQVI
IVLLKVQIPAYIEMNIPWLYFVNSFLIATVYWFNCHKLNLKDIGLPLDPFVNWKCCFIPLTIPN
LEQIEKPISIMIC (SEQ ID NO:1099) >gi|7669548|ref|NP_0010501|
tachykinin receptor 3 {Homosapiens}
MATLPAAETWIDGGGGVGADAVNLTASLAAGAATGAVETGWLQLLDQAGNLSSSPSALGL
PVASPAPSQPWANLTNQFVQPSWRIALWSLAYGVVVAVAVLGNLIVIWIILAHKRMRTVTN
YFLVNLAFSDASMAAFNTLVNFIYALHSEWYFGANYCRFQNFFPITAVFASIYSMTAIAVDRY
MAIIDPLKPRLSATATKIVIGSIVVILAFLLAFPQCLYSKTKVMPGRTLCFVQWPEGPKQHFTYH
IIVIILVYCFPLLIMGITYTIVGITLWGGEIPGDTCDKYHEQLKAKRKVVKMMIIVVMTFAICW
LPYHIYFILTAIYQQLNRWKYIQQVYLASFWLAMSSTMYNPIIYCCLNKRFRAGFKRAFRWC
PFIKVSSYDELELKTTRFHPNRQSSMYTVTRMESMTVVFDPNDADTTRSSRKKRATPRDPSFN
GCSRRNSKSASATSSFISSPYTSVDEYS (SEQ ID NO:1100)
>gi|7706103|ref|NP_0576521| relaxin/insulin-like family peptide
receptor 3 {Homosapiens}
MQMADAATIATMNKAAGGDKLAELFSLVPDLLEAANTSGNASLQLPDLWWELGLELPDGA
PPGHPPGSGGAESADTEARVRILISVVYWVVCALGLAGNLLVLYLMKSMQGWRKSSINLFV
TNLALTDFQFVLTLPFVVAVENALDFKWPFGKAMCKIVSMVTSMNMYASVFFLTAMSVTRY
HSVASALKSHRTRGHGRGDCCGRSLGDSCCFSAKALCVWIVVALAALASLPSAIFSTTVKVM
GEELCLVRFPDKLLGRDRQFVVLGLYHSQKVLLGFVLPLGIIILCYLLLVRFIADRRAAGTKGG
AAVAGGRPTGASARRLSKVTKSVTIVVLSFFLCWLPNQALTTWSILIKFNAVPFSQEYFLCQV
YAFPVSVCLAHSNSCLNPVLYCLVRREFRKALKS LLWRIASPSITSMRPFTATTKPEHEDQGL
QAPAPPHAAAEPDLLYYPPGVVVYSGGRYDLLPSSSAY (SEQ ID NO:1101)
>gi|7706451|ref|NP_0573191| G-protein coupled receptor family C
group 5 member B precursor {Homosapiens}
MFVASERKMRAHQVLTFLLLFVITSVASENASTSRGCGLDLLPQYVSLCDLDAIWGIVVEAV
AGAGALITLLLMLILLVRLPFIKEKEKKSPVGLHFLFLLGTLGLFGLTFAFIIQEDETICSVRRFL
WGVLFALCFSCLLSQAWRVRRLVRHGTGPAGWQLVGLALCLMLVQVIIAVEWLVLTVLRD
TRPACAYEPMDFVMALIYDMVLLVVTLGLALFTLCGKFKRWKLNGAFLLITAFLSVLIVVVA
WMTMYLFGNVKLQQGDAWNDPTLAITLAASGWVFVIFHAIPEIHCTLLPALQENTPNYFDTS
QPRMRETAFEEDVQLPRAYMENKAFSMDEHNAALRTAGFPNGSLGKRPSGSLGKRPSAPFR
SNVYQPTEMAVVLNGGTIPTAPPSHTGRHLW (SEQ ID NO:1102)
>gi|8923705|ref|NP_0611241| G-protein coupled receptor family C
group 5 member D {Homosapiens}
MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTILLLLAFLFLMRKIQDCSQWNVLPTQL
LFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVLFALCFSCLLAHASNLVKLVRGCVSFSWTT
ILCIAIGCSLLQIIIATEYVTLIMTRGMMFVNMTPCQLNVDFVVLLVYVLFLMALTFFVSKATF
CGPCENWKQHGRLIFITVLFSIIIVVVVWISMLLRGNPQFQRQPQWDDPVVCIALVTNAWVFLL
LYIVPELCILYRSCRQECPLQGNACPVTAYQHSFQVENQELSRARDSDGAEEDVALTSYGTPI
QPQTVDPTQECFIPQAKLSPQQDAGGV (SEQ ID NO:1103)
>gi|8923873|ref|NP_0609551| G protein-coupled receptor 77
{Homosapiens}
MGNDSVSYEYGDYSDLSDRPVDCLDGACLAIDPLRVAPLPLYAAIFLVGVPGNAMVAWVA
GKVARRRVGATWLLHLAVADLLCCLSLPILAVPIARGGHWPYGAVGCRALPSIILLTMYASV
LLLAALSADLCFLALGPAWWSTVQRACGVQVACGAAWTLALLLTVPSAIYRRLHQEHFPAR
LQCVVDYGGSSSTENAVTAIRFLFGFLGPLVAVASCHSALLCWAARRCRPLGTAIVVGFFVC
WAPYHLLGLVLTVAAPNSALLARALRAEPLIVGLALAHSCLNPMLFLYFGRAQLRRSLPAAC
HWALRESQGQDESVDSKKSTSHDLVSEMEV (SEQ ID NO:1104)
>gi|9506745|ref|NP_0618221| urotensin 2 receptor {Homosapiens}
MALTPESPSSFPGLAATGSSVPEPPGGPNATLNSSWASPTEPSSLEDLVATGTIGTLLSAMGVV
GVVGNAYTLVVTCRSLRAVASMYVYVVNLALADLLYLLSIPFIVATYVTKEWHFGDVGCRV
LFGLDFLTMHASIFTLTVMSSERYAAVLRPLDTVQRPKGYRKLLALGTWLLALLLTLPVMLA
MRLVRRGPKSLCLPAWGPRAHRAYLTLLFATSIAGPGLLIGLLYARLARAYRRSQRASFKRA
RRPGARALRLVLGIVLLFVVACFLPFWLWQLLAQYHQAPLAPRTARIVNYLTTCLTYGNSCA
NPFLYTLLTRNYRDHLRGRVRGPGSGGGRGPVPSLQPRARFQRCSGRSLSSCSPQPTDSLVLA
PAAPARPAPEGPRAPA (SEQ ID NO:1105) >gi|9506747|ref|NP_0618441| G
protein-coupled receptor 27 {Homosapiens}
MANASEPGGSGGGEAAALGLKLATLSLLLCVSLAGNVLFALLIVRERSLHRAPYYLLLDLCL
ADGLRALACLPAVMLAARRAAAAAGAPPGALGCKLLAFLAALFCFHAAFLLLGVGVTRYL
AIAHHRFYAERLAGWPCAAMLVCAAWALALAAAFPPVLDGGGDDEDAPCALEQRPDGAPG
ALGFLLLLAVVVGATHLVYLRLLFFIHDRRKMRPARLVPAVSHDWTFHGPGATGQAAANVV
TAGFGRGPTPPALVGIRPAGPGRGARRLLVLEEFKTEKRLCKMFYAVTLLFLLLWGPYVVAS
YLRVLVRPGAVPQAYLTASVWLTFAQAGINPVVCFLFNRELRDCFRAQFPCCQSPRTTQATH
PCDLKGIGL (SEQ ID NO:1106) >gi|9507143|ref|NP_0618421| probable
G-protein coupled receptor 173 {Homosapiens}
MANTTGEPEEVSGALSPPSASAYVKLVLLGLIMCVSLAGNAILSLLVLKERALHKAPYYFLL
DLCLADGIRSAVCFPFVLASVRHGSSWTFSALSCKIVAFMAVLFCFHAAFMLFCISVTRYMAI
AHHRFYAKRMTLWTCAAVICMAWTLSVAMAFPPVFDVGTYKFIREEDQCIFEHRYFKANDT
LGFMLMLAVLMAATHAVYGKLLLFEYRHRKMKPVQMVPAISQNWTFHGPGATGQAAAN
WIAGFGRGPMPPTLLGIRQNGHAASRRLLGMDEVKGEKQLGRMFYAITLLFLLLWSPYIVAC
YWRVFVKACAVPHRYLATAVWMSFAQAAVNPIVCFLLNKDLKKCLRTHAPCWGTGGAPA
PREPYCVM (SEQ ID NO:1107) >gi|9627743|ref|NP_0540301| protein
tyrosine phosphatase {Autographa californicanucleopolyhedrovirus }
MFPARWHNYLQCGQVIKDSNLICFKTPLRPELFAYVTSEEDVWTAEQIVKQNPSIGAIIDLTN
TSKYYDGVHFLRAGLLYKKIQVPGQTLPPESIVQEFIDTVKEFTEKCPGMLVGVHCTHGINRT
GYMVCRYLMHTLGIAPQEAIDRFEKARGHKIERQNYVQDLLI (SEQ ID NO:1108)
>gi|9951913|ref|NP_0628321| probable G-protein coupled receptor
162 isoform 2 {Homosapiens}
MARGGAGAEEASLRSNALSWLACGLLALLANAWIILSISAKQQKHKPLELLLCFLAGTHILM
AAVPLTTFAVVQLRRQASSDYDWNESICKVFVSTYYTLALATCFTVASLSYHRMWMVRWP
VNYRLSNAKKQALHAVMGIVVMVSFILSTLPSIGWHNNGERYYARGCQFIVSKIGLGFGVCFS
LLLLGGIVMGLVCVAITFYQTLWARPRRARQARRVGGGGGTKAGGPGALGTRPAFEVPAIV
VEDARGKRRS SLDGSESAKTSLQVTNLVSAIVFLYDSLTGVPILVVSFFSLKSDSAPPWMVLA
VLWCSMAQTLLLPSFIVVSCERYRADVRTVWEQCVAIMSEEDGDDDGGCDDYAEGRVCKVR
FDANGATGPGSRDPAQVKLLPGRHMLFPPLERVHYLQVPLSRRLSHDETNIFSTPREPGSFLH
KWSSSDDIRVLPAQSRALGGPPEYLGQRHRLEDEEDEEEAEGGGLASLRQFLESGVLGSGGG
PPRGPGFFREEITTFIDETPLPSPTASPGHS PRRPRPLGLSPRRLSLGSPESRAVGLPLGLSAGRR
CSLTGGEESARAWGGSWGPGNPIFPQLTL (SEQ ID NO:1109)
>gi|9966839|ref|NP_0651031| G protein-coupled receptor 84
{Homosapiens}
MWNSSDANFSCYHESVLGYRYVAVSWGVVVAVTGTVGNVLTLLALAIQPKLRTRFNLLIAN
LTLADLLYCTLLQPFSVDTYLHLHWRTGATFCRVFGLLLFASNSVSILTLCLIALGRYLLIAHP
KLFPQVFSAKGIVLALVSTWVVGVASFAPLWPIYILVPVVCTCSFDRIRGRPYTTILMGIYFVL
GLSSVGIFYCLIHRQVKRAAQALDQYKLRQASIHSNHVARTDEAMPGRFQELDSRLASGGPS
EGISSEPVSAATTQTLEGDSSEVGDQINSKRAKQMAEKSPPEASAKAQPIKGARRAPDSSSEF
GKVTRMCFAVFLCFALSYIPFLLLNILDARVQAPRVVHMLAANLTWLNGCINPVLYAAMNR
QFRQAYGSILKRGPRSFHRLH (SEQ ID NO:1110)
>gi|9966851|ref|NP_0651101| cysteinyl leukotriene receptor 2
{Homosapiens}
MERKFMSLQPSISVSEMEPNGTFSNNNSRNCTIENFKREFFPIVYLIIFFWGVLGNGLSIYVFLQ
PYKKSTSVNVFMLNLAISDLLFISTLPFRADYYLRGSNWIFGDLACRIMSYSLYVNMYSSIYFL
TVLSVVRFLAMVHPFRLLHVTSIRSAWILCGIIVVILIMASSIMLLDSGSEQNGSVTSCLELNLY
KIAKLQTMNYIALVVGCLLPFFTLSICYLLIIRVLLKVEVPESGLRVSHRKALTTIIITLIIFFLCF
LPYHTLRTVHLTTWKVGLCKDRLHKALVITLALAAANACFNPLLYYFAGENFKDRLKSALR
KGHPQKAKTKCVFPVSVWLRKETRV (SEQ ID NO:1111)
>gi|9966879|ref|NP_0651331| lysophosphatidic acid receptor 5
{Homosapiens}
MLANSSSTNSSVLPCPDYRPTHRLHLVVYSLVLAAGLPLNALALWVFLRALRVHSVVSVYM
CNLAASDLLFTLSLPVRLSYYALHHWPFPDLLCQTTGAIFQMNMYGSCIFLMLINVDRYAAI
VHPLRLRHLRRPRVARLLCLGVWALILVFAVPAARVHRPSRCRYRDLEVRLCFESFSDELWK
GRLLPLVLLAEALGFLLPLAAVVYSSGRVFWTLARPDATQSQRRRKTVRLLLANLVIFLLCF
VPYNSTLAVYGLLRSKLVAASVPARDRVRGVLMVMVLLAGANCVLDPLVYYFSAEGFRNT
LRGLGTPHRARTSATNGTRAALAQSERSAVTTDATRPDAASQGLLRPSDSHSLSSFTQCPQDS AL
(SEQ ID NO:1112) >gi|10092633|ref|NP_0553141| putative P2Y
purinoceptor 10 {Homosapiens}
MANLDKYTETFKMGSNSTSTAEIYCNVTNVKFQYSLYATTYILIFIPGLLANSAALWVLCRFI
SKKNKAIIFMINLSVADLAHVLSLPLRIYYYISHHWPFQRALCLLCFYLKYLNMYASICFLTCI
SLQRCFFLLKPFRARDWKRRYDVGISAAIWIVVGTACLPFPILRSTDLNNNKSCFADLGYKQ
MNAVALVGMITVAELAGFVIPVIIIAWCTWKTTISLRQPPMAFQGISERQKALRMVFMCAAV
FFICFTPYHINFIFYTMVKETIISSCPVVRIALYFHPFCLCLASLCCLLDPILYYFMASEFRDQLS
RHGSSVTRSRLMSKESGSSMIG (SEQ ID NO:1113)
>gi|10835015|ref|NP_0014611| gamma-aminobutyric acid (GABA) B
receptor 1 isoform a precursor {Homosapiens}
MLLLLLLAPLFLRPPGAGGAQTPNATSEGCQIIHPPWEGGIRYRGLTRDQVKAINFLPVDYEIE
YVCRGEREVVGPKVRKCLANGSWTDMDTPSRCVRICSKSYLTLENGKVFLTGGDLPALDGA
RVDFRCDPDFHLVGSSRSICSQGQWSTPKPHCQVNRTPHSERRAVYIGALFPMSGGWPGGQA
CQPAVEMALEDVNSRRDILPDYELKLIHHDSKCDPGQATKYLYELLYNDPIKIILMPGCSSVS
TLVAEAARMWNLIVLSYGSSSPALSNRQRFPTFFRTHPSATLHNPTRVKLFEKWGWKKIATI
QQTTEVFTSTLDDLEERVKEAGIEITFRQSFFSDPAVPVKNLKRQDARIIVGLFYETEARKVFC
EVYKERLFGKKYVWFLIGWYADNWFKIYDPSINCTVDEMTEAVEGHITTEIVMLNPANTRSI
SNMTSQEFVEKLTKRLKRHPEETGGFQEAPLAYDAIWALALALNKTSGGGGRSGVRLEDFN
YNNQTITDQIYRAMNSSSFEGVSGHVVFDASGSRMAWTLIEQLQGGSYKKIGYYDSTKDDLS
WSKTDKWIGGSPPADQTLVIKTFRFLSQKLFISVSVLSSLGIVLAVVCLSFNIYNSHVRYIQNS
QPNLNNLTAVGCSLALAAVFPLGLDGYHIGRNQFPFVCQARLWLLGLGFSLGYGSMFTKIVV
WVHTVFTKKEEKKEWRKTLEPWKLYATVGLLVGMDVLTLAIWQIVDPLHRTIETFAKEEPK
EDIDVSILPQLEHCSSRKMNTWLGIFYGYKGLLLLLGIFLAYETKSVSTEKINDHRAVGMAIY
NVAVLCLITAPVTMILSSQQDAAFAFASLAIVFSSYITLVVLFVPKMRRLITRGEWQSEAQDT
MKTGSSTNNNEEEKSRLLEKENRELEKIIAEKEERVSELRHQLQSRQQLRSRRHPPTPPEPSGG
LPRGPPEPPDRLSCDGSRVHLLYK (SEQ ID NO:1114)
>gi|10835175|ref|NP_0006121| 5-hydroxytryptamine receptor 2A
isoform 1 {Homosapiens}
MDILCEENTSLSSTTNSLMQLNDDTRLYSNDFNSGEANTSDAFNWTVDSENRTNLSCEGCLS
PSCLSLLHLQEKNWSALLTAVVIILTIAGNILVIMAVSLEKKLQNATNYFLMSLAIADMLLGF
LVMPVSMLTILYGYRWPLPSKLCAVWIYLDVLFSTASIMHLCAISLDRYVAIQNPIHHSRFNS
RTKAFLKIIAVWTISVGISMPIPVFGLQDDSKVFKEGSCLLADDNFVLIGSFVSFFIPLTIMVITY
FLTIKSLQKEATLCVSDLGTRAKLASFSFLPQSSLSSEKLFQRSIHREPGSYTGRRTMQSISNEQ
KACKVLGIVFFLFVVMWCPFFITNIMAVICKESCNEDVIGALLNVFVWIGYLSSAVNPLVYTL
FNKTYRSAFSRYIQCQYKENKKPLQLILVNTIPALAYKSSQLQMGQKKNSKQDAKTTDNDCS
MVALGKQHSEEASKDNSDGVNEKVSCV (SEQ ID NO:1115) >gi|10835197
|ref|NP_0008571| 5-hydroxytryptamine receptor 1F {Homosapiens}
MDFLNSSDQNLTSEELLNRMPSKILVSLTLSGLALMTTTINSLVIAAIIVTRKLHHPANYLICSL
AVTDFLVAVLVMPFSIVYIVRESWIMGQVVCDIWLSVDITCCTCSILHLSAIALDRYRAITDAV
EYARKRTPKHAGIMITIVWIISVFISMPPLFVVRHQGTSRDDECIIKHDHIVSTIYSTFGAFYIPLA
LILILYYKIYRAAKTLYHKRQASRIAKEEVNGQVLLESGEKSTKSVSTSYVLEKSLSDPS TDFD
KIHSTVRSLRSEFKHEKSWRRQKISGTRERKAATTLGLILGAFVICWLPFFVKELVVNVCDKC
KISEEMSNFLAWLGYLNSLINPLIYTIFNEDFKKAFQKLVRCRC (SEQ ID NO:1116)
>gi|11321563|ref|NP_0008611| 5-hydroxytryptamine receptor 4
isoform b {Homosapiens}
MDKLDANVSSEEGFGSVEKVVLLTFLSTVILMAILGNLLVMVAVCWDRQLRKIKTNYFIVSL
AFADLLVSVLVMPFGAIELVQDIVVIYGEVFCLVRTSLDVLLTTASIFHLCCISLDRYYAICCQP
LVYRNKMTPLRIALMLGGCWVIPTFISFLPIMQGWNNIGIIDLIEKRKFNQNSNSTYCVFMVN
KPYAITCSVVAFYIPFLLMVLAYYRIYVTAKEHAHQIQMLQRAGASSESRPQSADQHSTHRM
RTETKAAKTLCIIMGCFCLCWAPFFVTNIVDPFIDYTVPGQVWTAFLWLGYINSGLNPFLYAF
LNKSFRRAFLIILCCDDERYRRPSILGQTVPCSTTTINGSTHVLRDAVECGGQWESQCHPPATS
PLVAAQPSDT (SEQ ID NO:1117) >gi|11545887 |ref|NP_0714291|
neuropeptide FF receptor 1 {Homosapiens}
MEGEPSQPPNSSWPLSQNGTNTEATPATNLTFSSYYQHTSPVAAMFIVAYALIFLLCMVGNTL
VCFIVLKNRHMHTVTNMFILNLAVSDLLVGIFCMPTTLVDNLITGWPFDNATCKMSGLVQG
MSVSASVFTLVAIAVERFRCIVHPFREKLTLRKALVTIAVIVVALALLIMCPSAVTLTVTREEHH
FMVDARNRSYPLYSCWEAWPEKGMRRVYTTVLFSHIYLAPLALIVVMYARIARKLCQAPGP
APGGEEAADPRASRRRARVVHMLVMVALFFTLSWLPLWALLLLIDYGQLSAPQLHLVTVYA
FPFAHWLAFFNSSANPIIYGYFNENFRRGFQAAFRARLCPRPSGSHKEAYSERPGGLLHRRVF
VVVRPSDSGLPSESGPSSGAPRPGRLPLRNGRVAHHGLPREGPGCSHLPLTIPAWDI (SEQ ID
NO:1118) >gi|12232483|ref|NP_0736251| P2Y purinoceptor 12
{Homosapiens}
MQAVDNLTSAPGNTSLCTRDYKITQVLFPLLYTVLFFVGLITNGLAMRIFFQIRSKSNFIIFLKN
TVISDLLMILTFPFKILSDAKLGTGPLRTFVCQVTSVIFYFTMYISISFLGLITIDRYQKTTRPFKT
SNPKNLLGAKILSVVIVVAFMFLLSLPNMILTNRQPRDKNVKKCSFLKSEFGLVWHEIVNYICQ
VIFVVINFLIVIVCYTLITKELYRSYVRTRGVGKVPRKKVNVKVFIIIAVFFICFVPFHFARIPYTL
SQTRDVFDCTAENTLFYVKESTLWLTSLNACLDPFIYFFLCKSFRNSLISMLKCPNSATSLSQD
NRKKEQDGGDPNEETPM (SEQ ID NO:1119) >gi|13027636|ref|NP_0013912|
sphingosine 1-phosphate receptor 1 {Homosapiens}
MGPTSVPLVKAHRSSVSDYVNYDIIVRHYNYTGKLNISADKENSIKLTSVVFILICCFIILENIF
VLLTIVVKTKKFHRPMYYFIGNLALSDLLAGVAYTANLLLSGATTYKLTPAQWFLREGSMFV
ALSASVFSLLAIAIERYITMLKMKLHNGSNNFRLFLLISACWVISLILGGLPIMGWNCISALSSC
STVLPLYHKHYILFCTTVFTLLLLSIVILYCRIYSLVRTRSRRLTFRKNISKASRSSEKSLALLKT
VIIVLSVFIACWAPLFILLLLDVGCKVKTCDILFRAEYFLVLAVLNSGTNPIIYTLTNKEMRRAF
IRIMSCCKCPSGDSAGKFKRPIIAGMEFSRSKSDNSSHPQKDEGDNPETIMSSGNVNSSS (SEQ
ID NO:1120) >gi|13236497|ref|NP_0769171| 5-hydroxytryptamine
receptor 5A {Homosapiens }
MDLPVNLTSFSLSTPSPLETNHSLGKDDLRPSSPLLSVFGVLILTLLGFLVAATFAWNLLVLAT
ILRVRTFHRVPHNLVASMAVSDVLVAALVMPLSLVHELSGRRWQLGRRLCQLWIACDVLCC
TASIVVNVTAIALDRYWSITRHMEYTLRTRKCVSNVMIALTWALSAVISLAPLLFGWGETYSE
GSEECQVSREPSYAVFSTVGAFYLPLCVVLFVYVVKIYKAAKFRVGSRKTNSVSPISEAVEVK
DSAKQPQMVFTVRHATVTFQPEGDTWREQKEQRAALMVGILIGVFVLCWIPFFLTELISPLCS
CDIPAIWKSIFLWLGYSNSFFNPLIYTAFNKNYNSAFKNFFSRQH (SEQ ID NO:1121)
>gi|13325064|ref|NP_0013991| cadherin EGF LAG seven-pass G-type
receptor 2 precursor {Homosapiens }
MRSPATGVPLPTPPPPLLLLLLLLLPPPLLGDQVGPCRSLGSRGRGSSGACAPMGWLCPSSAS
NLWLYTSRCRDAGTELTGHLVPHHDGLRVWCPESEAHIPLPPAPEGCPWSCRLLGIGGHLSP
QGKLTLPEEHPCLKAPRLRCQSCKLAQAPGLRAGERSPEESLGGRRKRNVNTAPQFQPPSYQ
ATVPENQPAGTPVASLRAIDPDEGEAGRLEYTMDALFDSRSNQFFSLDPVTGAVTTAEELDR
ETKSTHVFRVTAQDHGMPRRSALATLTILVTDTNDHDPVFEQQEYKESLRENLEVGYEVLTV
RATDGDAPPNANILYRLLEGSGGSPSEVFEIDPRSGVIRTRGPVDREEVESYQLTVEASDQGR
DPGPRSTTAAVFLSVEDDNDNAPQFSEKRYVVQVREDVTPGAPVLRVTASDRDKGSNAVVH
YSIMSGNARGQFYLDAQTGALDVVSPLDYETTKEYTLRVRAQDGGRPPLSNVSGLVTVQVL
DINDNAPIFVSTPFQATVLESVPLGYLVLHVQAIDADAGDNARLEYRLAGVGHDFPFTINNGT
GWISVAAELDREEVDFYSFGVEARDHGTPALTASASVSVTVLDVNDNNPTFTQPEYTVRLNE
DAAVGTSVVTVSAVDRDAHSVITYQITSGNTRNRFSITSQSGGGLVSLALPLDYKLERQYVL
AVTASDGTRQDTAQIVVNVTDANTHRPVFQSSHYTVNVNEDRPAGTTVVLISATDEDTGEN
ARITYFMEDSIPQFRIDADTGAVTTQAELDYEDQVSYTLAITARDNGIPQKSDTTYLEILVNDV
NDNAPQFLRDSYQGSVYEDVPPFTSVLQISATDRDSGLNGRVFYTFQGGDDGDGDFIVESTS
GIVRTLRRLDRENVAQYVLRAYAVDKGMPPARTPMEVTVTVLDVNDNPPVFEQDEFDVFVE
ENSPIGLAVARVTATDPDEGTNAQIMYQIVEGNIPEVFQLDIFSGELTALVDLDYEDRPEYVL
VIQATSAPLVSRATVHVRLLDRNDNPPVLGNFEILFNNYVTNRSSSFPGGAIGRVPAHDPDISD
SLTYSFERGNELSLVLLNASTGELKLSRALDNNRPLEAIMSVLVSDGVHSVTAQCALRVTIIT
DEMLTHSITLRLEDMSPERFLSPLLGLFIQAVAATLATPPDHVVVFNVQRDTDAPGGHILNVS
LSVGQPPGPGGGPPFLPSEDLQERLYLNRSLLTAISAQRVLPFDDNICLREPCENYMRCVSVLR
FDSSAPFIASSSVLFRPIHPVGGLRCRCPPGFTGDYCETEVDLCYSRPCGPHGRCRSREGGYTC
LCRDGYTGEHCEVSARSGRCTPGVCKNGGTCVNLLVGGFKCDCPSGDFEKPYCQVTTRSFP
AHSFITFRGLRQRFHFTLALSFATKERDGLLLYNGRFNEKHDFVALEVIQEQVQLTFSAGEST
TTVSPFVPGGVSDGQWHTVQLKYYNKPLLGQTGLPQGPSEQKVAVVTVDGCDTGVALRFG
SVLGNYSCAAQGTQGGSKKSLDLTGPLLLGGVPDLPESFPVRMRQFVGCMRNLQVDSRHID
MADFIANNGTVPGCPAKKNVCDSNTCHNGGTCVNQWDAFSCECPLGFGGKSCAQEMANPQ
HFLGSSLVAWHGLSLPISQPWYLSLMFRTRQADGVLLQAITRGRSTITLQLREGHVMLSVEG
TGLQASSLRLEPGRANDGDWHHAQLALGASGGPGHAILSFDYGQQRAEGNLGPRLHGLHLS
NITVGGIPGPAGGVARGFRGCLQGVRVSDTPEGVNSLDPSHGESINVEQGCSLPDPCDSNPCP
ANSYCSNDWDSYSCSCDPGYYGDNCTNVCDLNPCEHQSVCTRKPSAPHGYTCECPPNYLGP
YCETRIDQPCPRGWWGHPTCGPCNCDVSKGFDPDCNKTSGECHCKENHYRPPGSPTCLLCD
CYPTGSLSRVCDPEDGQCPCKPGVIGRQCDRCDNPFAEVTTNGCEVNYDSCPRAIEAGIVVWP
RTRFGLPAAAPCPKGSFGTAVRHCDEHRGWLPPNLFNCTSITFSELKGFAERLQRNESGLDSG
RSQQLALLLRNATQHTAGYFGSDVKVAYQLATRLLAHESTQRGFGLSATQDVHFTENLLRV
GSALLDTANKRHWELIQQTEGGTAWLLQHYEAYASALAQNMRHTYLSPFTIVTPNIVISVVR
LDKGNFAGAKLPRYEALRGEQPPDLETTVILPESVFRETPPVVRPAGPGEAQEPEELARRQRR
HPELSQGEAVASVIIYRTLAGLLPHNYDPDKRSLRVPKRPIINTPVVSISVHDDEELLPRALDK
PVTVQFRLLETEERTKPICVFVVNHSILVSGTGGWSARGCEVVFRNESHVSCQCNHMTSFAVL
MDVSRRENGEILPLKTLTYVALGVTLAALLLTFFFLTLLRILRSNQHGIRRNLTAALGLAQLV
FLLGINQADLPFACTVIAILLHFLYLCTFSWALLEALHLYRALTEVRDVNTGPMRFYYMLGW
GVPAFITGLAVGLDPEGYGNPDFCWLSIYDTLIVVSFAGPVAFAVSMSVFLYILAARASCAAQ
RQGFEKKGPVSGLQPSFAVLLLLSATWLLALLSVNSDTLLFHYLFATCNCIQGPFIFLSYVVLS
KEVRKALKLACSRKPSPDPALTTKSTLTSSYNCPSPYADGRLYQPYGDSAGSLHSSRSGKSQ
PSYIPFLLREESALNPGQGPPGLGDPGSLFLEGQDQQHDPDTDSDSDLSLEDDQSGSYASTHSS
DSEEEEEEEEEEAAFPGEQGWDSLLGPGAERLPLHSTPKDGGPGPGKAPWPGDFGTTAKESS
GNGAPEERLRENGDALSREGSLGPLPGSSAQPHKGILKKKCLPTISEKSSLLRLPLEQCTGSSR
GSSASEGSRGGPPPRPPPRQSLQEQLNGVMPIAMSIKAGTVDEDSSGSEFLFFNFLH (SEQ ID
NO:1122) >gi|13435405|ref|NP_0716401| histamine H2 receptor
isoform 2 {Homosapiens}
MAPNGTASSFCLDSTACKITITVVLAVLILITVAGNVVVCLAVGLNRRLRNLTNCFIVSLAITD
LLLGLLVLPFSAIYQLSCKWSFGKVFCNIYTSLDVMLCTASILNLFMISLDRYCAVMDPLRYP
VLVTPVRVAIS LVLIWVISITLSFLSIHLGWNSRNETSKGNHTTSKCKVQVNEVYGLVDGLVT
FYLPLLIMCITYYRIFKVARDQAKRINHISSWKAATIREHKATVTLAAVMGAFIICWFPYFTAF
VYRGLRGDDAINEVLEAIVLWLGYANSALNPILYAALNRDFRTGYQQLFCCRLANRNSHKTS
LRSNASQLSRTQSREPRQQEEKPLKLQVVVSGTEVTAPQGATDR (SEQ ID NO:1123)
>gi|13540517|ref|NP_1103871| endothelial differentiation,
sphingolipid G- protein-coupled receptor,8 {Homosapiens}
MESGLLRPAPVSEVIVLHYNYTGKLRGARYQPGAGLRADAVVCLAVCAFIVLENLAVLLVL
GRHPRFHAPMFLLLGSLTLSDLLAGAAYAANILLSGPLTLKLSPALWFAREGGVFVALTASV
LSLLAIALERSLTMARRGPAPVSSRGRTLAMAAAAWGVSLLLGLLPALGWNCLGRLDACST
VLPLYAKAYVLFCVLAFVGILAAICALYARIYCQVRANARRLPARPGTAGTTSTRARRKPRS
LALLRTLSVVLLAFVACWGPLFLLLLLDVACPARTCPVLLQADPFLGLAMANSLLNPIIYTLT
NRDLRHALLRLVCCGRHSCGRDPSGSQQSASAAEASGGLRRCLPPGLDGSFSGSERSSPQRD
GLDTSGSTGSPGAPTAARTLVSEPAAD (SEQ ID NO:1124)
>gi|13540557|ref|NP_1104111| probable G-protein coupled receptor
63 {Homosapiens}
MVFSAVLTAFHTGTSNTTFVVYENTYMNITLPPPFQHPDLSPLLRYSFETMAPTGLSSLTVNS
TAVPTTPAAFKSLNLPLQITLSAIMIFILFVSFLGNLVVCLMVYQKAAMRSAINILLASLAFAD
MLLAVLNMPFALVTILTTRWIFGKFFCRVSAMFFVVLFVIEGVAILLIISIDRFLIIVQRQDKLNP
YRAKVLIAVSWATSFCVAFPLAVGNPDLQIPSRAPQCVFGYTTNPGYQAYVILISLISFFIPFLV
ILYSFMGILNTLRHNALRIHSYPEGICLSQASKLGLMSLQRPFQMSIDMGFKTRAFTTILILFAV
FIVCWAPFTTYSLVATFSKHFYYQHNFFEISTWLLWLCYLKSALNPLIYYWRIKKFHDACLD
MMPKSFKFLPQLPGHTKRRIRPSAVYVCGEHRTVV (SEQ ID NO:1125)
>gi|13929467|ref|NP_0012872| chemokine-binding protein 2
{Homosapiens}
MAATASPQPLATEDADSENSSFYYYDYLDEVAFMLCRKDAVVSFGKVFLPVFYSLIFVLGLS
GNLLLLMVLLRYVPRRRMVEIYLLNLAISNLLFLVTLPFVVGISVAWHWVFGSFLCKMVSTLY
TINFYSGIFFISCMSLDKYLEIVHAQPYHRLRTRAKSLLLATIVWAVSLAVSIPDMVFVQTHEN
PKGVWNCHADFGGHGTIVVKLFLRFQQNLLGFLLPLLAMIFFYSRIGCVLVRLRPAGQGRALK
IAAALVVAFFVLWFPYNLTLFLHTLLDLQVFGNCEVSQHLDYALQVTESIAFLHCCFSPILYA
FSSHRFRQYLKAFLAAVLGWHLAPGTAQASLSSCSESSILTAQEEMTGMNDLGERQSENYPN
KEDVGNKSA (SEQ ID NO:1126) >gi|14043044|ref|NP_0066322| C-C
chemokine receptor type 9 isoform B {Homosapiens}
MADDYGSESTSSMEDYVNFNFTDFYCEKNNVRQFASHFLPPLYWLVFIVGALGNSLVILVY
WYCTRVKTMTDMFLLNLAIADLLFLVTLPFVVAIAAADQWKFQTFMCKVVNSMYKMNFYS
CVLLIMCISVDRYIAIAQAMRAHTWREKRLLYSKMVCFTIVVVLAAALCIPEILYSQIKEESGIA
ICTMVYPSDES TKLKSAVLTLKVILGFFLPFVVMACCYTIIIHTLIQAKKSSKHKALKVTITVLT
VFVLSQFPYNCILLVQTIDAYAMFISNCAVSTNIDICFQVTQTIAFFHSCLNPVLYVFVGERFRR
DLVKTLKNLGCISQAQWVSFTRREGSLKLSSMLLETTSGALSL (SEQ ID NO:1127)
>gi|14211849|ref|NP_1159421| probable G-protein coupled receptor
174 {Homosapiens}
MPANYTCTRPDGDNTDFRYFIYAVTYTVILVPGLIGNILALWVFYGYMKETKRAVIFMINLAI
ADLLQVLSLPLRIFYYLNHDWPFGPGLCMFCFYLKYVNMYASIYFLVCISVRRFVVFLMYPFR
FHDCKQKYDLYISIAGWLIICLACVLFPLLRTSDDTSGNRTKCFVDLPTRNVNLAQSVVMMTI
GELIGFVTPLLIVLYCTWKTVLSLQDKYPMAQDLGEKQKALKMILTCAGVFLICFAPYHFSFP
LDFLVKSNEIKSCLARRVILIFHSVALCLASLNSCLDPVIYYFSTNEFRRRLSRQDLHDSIQLHA
KSFVSNHTASTMTPELC (SEQ ID NO:1128) >gi|1421185 1
|ref|NP_1159431| G-protein coupled receptor 81 {Homosapiens}
MYNGSCCRIEGDTISQVMPPLLIVAFVLGALGNGVALCGFCFHMKTWKPSTVYLFNLAVAD
FLLMICLPFRTDYYLRRRHWAFGDIPCRVGLFTLAMNRAGSIVFLTVVAADRYFKVVHPHHA
VNTISTRVAAGIVCTLWALVILGTVYLLLENHLCVQETAVSCESFIMESANGWHDIMFQLEFF
MPLGIILFCSFKIVWSLRRRQQLARQARMKKATRFIMVVAIVFITCYLPSVSARLYFLWTVPSS
ACDPSVHGALHITLSFTYMNSMLDPLVYYFSSPSFPKFYNKLKICSLKPKQPGHSKTQRPEEM
PISNLGRRSCISVANSFQSQSDGQWDPHIVEWH (SEQ ID NO:1129)
>gi|14251205|ref|NP_0676372| histamine H4 receptor isoform 1
{Homosapiens}
MPDTNSTINLSLSTRVTLAFFMSLVAFAIMLGNALVILAFVVDKNLRHRSSYFFLNLAISDFFV
GVISIPLYIPHTLFEWDFGKEICVFVVLTTDYLLCTASVYNIVLISYDRYLSVSNAVSYRTQHTG
VLKIVTLMVAVWVLAFLVNGPMILVSESWKDEGSECEPGFFSEWYILAITSFLEFVIPVILVAY
FNMNIYWSLWKRDHLSRCQSHPGLTAVSSNICGHSFRGRLSSRRSLSASTEVPASFHSERQRR
KSSLMFSSRTKMNSNTIASKMGSFSQSDSVALHQREHVELLRARRLAKSLAILLGVFAVCWA
PYSLFTIVLSFYSSATGPKSVWYRIAFWLQWFNSFVNPLLYPLCHKRFQKAFLKIFCIKKQPLP
SQHSRSVSS (SEQ ID NO:1130) >gi|14589869|ref|NP_1167431| Burkitt
lymphoma receptor 1 isoform 2 {Homosapiens}
MASFKAVFVPVAYSLIFLLGVIGNVLVLVILERHRQTRSSTETFLFHLAVADLLLVFILPFAVA
EGSVGWVLGTFLCKTVIALHKVNFYCSSLLLACIAVDRYLAIVHAVHAYRHRRLLSIHITCGT
IVVLVGFLLALPEILFAKVSQGHHNNSLPRCTFSQENQAETHAWFTSRFLYHVAGFLLPMLVM
GWCYVGVVHRLRQAQRRPQRQKAVRVAILVTSIFFLCWSPYHIVIFLDTLARLKAVDNTCKL
NGSLPVAITMCEFLGLAHCCLNPMLYTFAGVKFRSDLSRLLTKLGCTGPASLCQLFPSWRRSS
LSESENATSLTTF (SEQ ID NO:1131) >gi|15029528|ref|NP_0052831|
N-arachidonyl glycine receptor {Homosapiens}
MITLNNQDQPVPFNSSHPDEYKIAALVFYSCIFIIGLFVNITALWVFSCTTKKRTTVTIYMMNV
ALVDLIFIMTLPFRMFYYAKDEWPFGEYFCQILGALTVFYPSIALWLLAFISADRYMAIVQPK
YAKELKNTCKAVLACVGVWIMTLTTTTPLLLLYKDPDKDSTPATCLKISDIIYLKAVNVLNL
TRLTFFFLIPLFIMIGCYLVIIHNLLHGRTSKLKPKVKEKSIRIIITLLVQVLVCFMPFHICFAFLM
LGTGENSYNPWGAFTTFLMNLSTCLDVILYYIVSKQFQARVISVMLYRNYLRSMRRKSFRSG
SLRSLSNINSEML (SEQ ID NO:1132) >gi|15619006|ref|NP_0046152|
vasoactive intestinal polypeptide receptor 1 precursor
{Homosapiens}
MRPPSPLPARWLCVLAGALAWALGPAGGQAARLQEECDYVQMIEVQHKQCLEEAQLENETI
GCSKMWDNLTCWPATPRGQVVVLACPLIFKLFSSIQGRNVS RSCTDEGWTHLEPGPYPIACG
LDDKAASLDEQQTMFYGSVKTGYTIGYGLSLATLLVATAILSLFRKLHCTRNYIHMHLFISFIL
RAAAVFIKDLALFDSGESDQCSEGSVGCKAAMVFFQYCVMANFFVVLLVEGLYLYTLLAVSF
FSERKYFVVGYILIGWGVPSTFTMVWTIARIHFEDYGCWDTINSSLWWIIKGPILTSILVNFILFI
CIIRILLQKLRPPDIRKSDSSPYSRLARSTLLLIPLFGVHYIMFAFFPDNFKPEVKMVFELVVGSF
QGFVVAILYCFLNGEVQAELRRKWRRWHLQGVLGWNPKYRHPSGGSNGATCSTQVSMLTR
VSPGARRSSSFQAEVSLV (SEQ ID NO:1133) >gi|16418463|ref|NP_4431991|
MAS1 oncogene-like {Homosapiens}
MVWGKICWFSQRAGWTVFAESQISLSCSLCLHSGDQEAQNPNLVSQLCGVFLQNETNETIH
MQMSMAVGQQALPLNIIAPKAVLVSLCGVLLNGTVFWLLCCGATNPYMVYILHLVAADVIY
LCCSAVGFLQVTLLTYHGVVFFIPDFLAILSPFSFEVCLCLLVAISTERCVCVLFPIVVYRCHRPK
YTSNVVCTLIVVGLPFCINIVKSLFLTYWKHVKACVIFLKLSGLFHAILSLVMCVSSLTLLIRFL
CCSQQQKATRVYAVVQISAPMFLLWALPLSVAPLITDFKMFVTTSYLISLFLIINSSANPIIYFF
VGSLRKKRLKESLRVILQRALADKPEVGRNKKAAGIDPMEQPHSTQHVENLLPREHRVDVET (SEQ
ID NO:1134) >gi|16751917|ref|NP_4445081| trace amine associated
receptor 8 {Homosapiens}
MTSNFSQPVVQLCYEDVNGSCIETPYSPGSRVILYTAFSFGSLLAVFGNLLVMTSVLHFKQLH
SPTNFLIASLACADFLVGVTVMLFSMVRTVESCWYFGAKFCTLHSCCDVAFCYSSVLHLCFIC
IDRYIVVTDPLVYATKFTVSVSGICISVSWILPLTYSGAVFYTGVNDDGLEELVSALNCVGGC
QIIVSQGWVLIDFLLFFIPTLVMIILYSKIFLIAKQQAIKIETTSSKVESSSESYKIRVAKRERKAA
KTLGVTVLAFVISWLPYTVDILIDAFMGFLTPAYIYEICCWSAYYNSAMNPLIYALFYPWFRK
AIKLILSGDVLKASSSTISLFLE (SEQ ID NO:1135)
>gi|16876435|ref|NP_4733621| probable G-protein coupled receptor
101 {Homosapiens}
MTSTCTNSTRESNSSHTCMPLSKMPISLAHGIIRSTVLVIFLAASFVGNIVLALVLQRKPQLLQ
VTNRFIFNLLVTDLLQISLVAPWVVATSVPLFVVPLNSHFCTALVSLTHLFAFASVNTIVVVSV
DRYLSIIHPLSYPSKMTQRRGYLLLYGTWIVAILQSTPPLYGWGQAAFDERNALCSMIVVGASP
SYTILSVVSFIVIPLIVMIACYSVVFCAARRQHALLYNVKRHSLEVRVKDCVENEDEEGAEKK
EEFQDESEFRRQHEGEVKAKEGRMEAKDGSLKAKEGSTGTSESSVEARGSEEVRESSTVASD
GSMEGKEGSTKVEENSMKADKGRTEVNQCSIDLGEDDMEFGEDDINFSEDDVEAVNIPESLP
PSRRNSNSNPPLPRCYQCKAAKVIFIIIFSYVLSLGPYCFLAVLAVWVDVETQVPQWVITIIIVVL
FFLQCCIHPYVYGYMHKTIKKEIQDMLKKFFCKEKPPKEDSHPDLPGTEGGTEGKIVPSYDSA TFP
(SEQ ID NO:1136) >gi|16950636|ref|NP_0013922| lysophosphatidic
acid receptor 1 {Homosapiens}
MAAISTSIPVISQPQFTAMNEPQCFYNESIAFFYNRSGKHLATEWNTVSKLVMGLGITVCIFIM
LANLLVMVAIYVNRRFHFPIYYLMANLAAADFFAGLAYFYLMFNTGPNTRRLTVSTWLLRQ
GLIDTSLTASVANLLAIAIERHITVFRMQLHTRMSNRRVVVVIVVIVVTMAIVMGAIPSVGWNC
ICDIENCSNMAPLYS DSYLVFVVAIFNLVTFVVMVVLYAHIFGYVRQRTMRMSRHSSGPRRNR
DTMMSLLKTVVIVLGAFIICWTPGLVLLLLDVCCPQCDVLAYEKFFLLLAEFNSAMNPIIYSY
RDKEMSATFRQILCCQRSENPTGPTEGSDRSASSLNHTILAGVHSNDHSVV (SEQ ID
NO:1137) >gi|17978491|ref|NP_5109661| CD97 antigen isoform 1
precursor {Homosapiens}
MGGRVFLAFCVWLTLPGAETQDSRGCARWCPQNSSCVNATACRCNPGFSSFSEIITTPTETCD
DINECATPSKVSCGKFSDCWNTEGSYDCVCSPGYEPVSGAKTFKNESENTCQDVDECQQNPR
LCKSYGTCVNTLGSYTCQCLPGFKFIPEDPKVCTDVNECTSGQNPCHSSTHCLNNVGSYQCR
CRPGWQPIPGSPNGPNNTVCEDVDECSSGQHQCDSSTVCFNTVGSYSCRCRPGWKPRHGIPN
NQKDTVCEDMTFSTWTPPPGVHSQTLSRFFDKVQDLGRDSKTSSAEVTIQNVIKLVDELMEA
PGDVEALAPPVRHLIATQLLSNLEDIMRILAKSLPKGPFTYISPSNTELTLMIQERGDKNVTMG
QSSARMKLNWAVAAGAEDPGPAVAGILSIQNMTTLLANASLNLHSKKQAELEEIYESSIRGV
QLRRLSAVNSIFLSHNNTKELNSPILFAFSHLESSDGEAGRDPPAKDVMPGPRQELLCAFWKS
DSDRGGHWATEGCQVLGSKNGSTTCQCSHLSSFAILMAHYDVEDWKLTLITRVGLALSLFC
LLLCILTFLLVRPIQGSRTTIHLHLCICLFVGSTIFLAGIENEGGQVGLRCRLVAGLLHYCFLAA
FCWMSLEGLELYFLVVRVFQGQGLSTRWLCLIGYGVPLLIVGVSAAIYSKGYGRPRYCWLDF
EQGFLWSFLGPVTFIILCNAVIFVTTVWKLTQKFSEINPDMKKLKKARALTITAIAQLFLLGCT
WVFGLFIFDDRSLVLTYVFTILNCLQGAFLYLLHCLLNKKVREEYRKWACLVAGGSKYSEFT
STTSGTGHNQTRALRASESGI
(SEQ ID NO:1138) >gi|18201870|ref|NP_5430071| probable G-protein
coupled receptor 82 {Homosapiens}
MNNNTTCIQPSMISSMALPIIYILLCIVGVFGNTLSQWIFLTKIGKKTSTHIYLSHLVTANLLVC
SAMPFMSIYFLKGFQWEYQSAQCRVVNFLGTLSMHASMFVSLLILSWIAISRYATLMQKDSS
QETTSCYEKIFYGHLLKKFRQPNFARKLCIYIWGVVLGIIIPVTVYYSVIEATEGEESLCYNRQ
MELGAMISQIAGLIGTTFIGFSFLVVLTSYYSFVSHLRKIRTCTSIMEKDLTYSSVKRHLLVIQIL
LIVCFLPYSIFKPIFYVLHQRDNCQQLNYLIETKNILTCLASARSSTDPIIFLLLDKTFKKTLYNL
FTKSNSAHMQSYG (SEQ ID NO:1139) >gi|18677729|ref|NP_5707181|
relaxin receptor 2 isoform 1 {Homosapiens}
MIVFLVFKHLFSLRLITMFFLLHFIVLINVKDFALTQGSMITPSCQKGYFPCGNLTKCLPRAFH
CDGKDDCGNGADEENCGDTSGWATIFGTVHGNANSVALTQECFLKQYPQCCDCKETELEC
VNGDLKSVPMISNNVTLLSLKKNKIHSLPDKVFIKYTKLKKIFLQHNCIRHISRKAFFGLCNLQ
ILYLNHNCITTLRPGIFKDLHQLTWLILDDNPITRISQRLFTGLNSLFFLSMVNNYLEALPKQM
CAQMPQLNWVDLEGNRIKYLTNSTFLSCDSLTVLFLPRNQIGFVPEKTFSSLKNLGELDLSSN
TITELSPHLFKDLKLLQKLNLSSNPLMYLHKNQFESLKQLQSLDLERIEIPNINTRMFQPMKNL
SHIYFKNFRYCSYAPHVRICMPLTDGISSFEDLLANNILRIFVWVIAFITCFGNLFVIGMRSFIKA
ENTTHAMSIKILCCADCLMGVYLFFVGIFDIKYRGQYQKYALLWMESVQCRLMGFLAMLST
EVSVLLLTYLTLEKFLVIVFPFSNIRPGKRQTSVILICIWMAGFLIAVIPFWNKDYFGNFYGKN
GVCFPLYYDQTEDIGSKGYSLGIFLGVNLLAFLIIVFSYITMFCSIQKTALQTTEVRNCFGREV
AVANRFFFIVFSDAICWIPVFVVKILSLFRVEIPDTMTSWIVIFFLPVNSALNPILYTLTTNFFKD
KLKQLLHKHQRKSIFKIKKKSLSTSIVVVIEDSSSLKLGVLNKITLGDSIMKPVS (SEQ ID
NO:1140) >gi|19923245|ref|NP_0043732| corticotropin-releasing
factor receptor 1 isoform 2 {Homosapiens}
MGGHPQLRLVKALLLLGLNPVSASLQDQHCESLSLASNISGLQCNASVDLIGTCWPRSPAGQ
LVVRPCPAFFYGVRYNTTNNGYRECLANGSWAARVNYSECQEILNEEKKSKVHYHVAVIIN
YLGHCISLVALLVAFVLFLRLRSIRCLRNIIHWNLISAFILRNATWFVVQLTMSPEVHQSNVG
WCRLVTAAYNYFHVTNFFVVMFGEGCYLHTAIVLTYSTDRLRKWMFICIGWGVPFPIIVAWAI
GKLYYDNEKCWFGKRPGVYTDYIYQGPMILVLLINFIFLFNIVRILMTKLRASTTSETIQYRKA
VKATLVLLPLLGITYMLFFVNPGEDEVSRVVFIYFNSFLESFQGFFVSVFYCFLNSEVRSAIRK
RWHRWQDKHSIRARVARAMSIPTSPTRVSFHSIKQSTAV (SEQ ID NO:1141)
>gi|19923975 |ref|NP_612454 1| G protein-coupled receptor 146
{Homosapiens}
MWSCSWFNGTGLVEELPACQDLQLGLSLLSLLGLVVGVPVGLCYNALLVLANLHSKASMT
MPDVYFVNMAVAGLVLSALAPVHLLGPPSSRWALWSVGGEVHVALQIPFNVSSLVAMYST
ALLSLDHYIERALPRTYMASVYNTRHVCGFVWGGALLTSFSSLLFYICSHVSTRALECAKMQ
NAEAADATLVFIGYVVPALATLYALVLLSRVRREDTPLDRDTGRLEPSAHRLLVATVCTQFG
LWTPHYLILLGHTVIISRGKPVDAHYLGLLHFVKDFSKLLAFSSSFVTPLLYRYMNQSFPSKL
QRLMKKLPCGDRHCSPDHMGVQQVLA (SEQ ID NO:1142)
>gi|20373179|ref|NP_6204141| G protein-coupled receptor 73
{Homosapiens}
METTMGFMDDNATNTSTSFLSVLNPHGAHATSFPFNFSYSDYDMPLDEDEDVTNSRTFFAA
KIVIGMALVGIMLVCGIGNFIFIAALVRYKKLRNLTNLLIANLAISDFLVAIVCCPFEMDYYVV
RQLSWEHGHVLCTSVNYLRTVSLYVSTNALLAIAIDRYLAIVHPLRPRMKCQTATGLIALVW
TVSILIAIPSAYFTTETVLVIVKSQEKIFCGQIVVPVDQQLYYKSYFLFIFGIEFVGPVVTMTLCY
ARISRELWFKAVPGFQTEQIRKRLRCRRKTVLVLMCILTAYVLCWAPFYGFTIVRDFFPTVFV
KEKHYLTAFYIVECIAMSNSMINTLCFVTVKNDTVKYFKKIMLLHWKASYNGGKSSADLDL
KTIGMPATEEVDCIRLK (SEQ ID NO:1143) >gi|20544172 |ref|NP_000701
2| B1 bradykinin receptor {Homosapiens}
MASSWPPLELQSSNQSQLFPQNATACDNAPEAWDLLHRVLPTFIISICFFGLLGNLFVLLVFLL
PRRQLNVAEIYLANLAASDLVFVLGLPFWAENIWNQFNWPFGALLCRVINGVIKANLFISIFL
VVAISQDRYRVLVHPMASRRQQRRRQARVTCVLIVVVVGGLLSIPTFLLRSIQAVPDLNITACI
LLLPHEAWHFARIVELNILGFLLPLAAIVFFNYHILASLRTREEVSRTRCGGRKDSKTTALILTL
VVAFLVCWAPYHFFAFLEFLFQVQAVRGCFVVEDFIDLGLQLANFFAFTNSSLNPVIYVFVGR
LFRTKVVVELYKQCTPKSLAPISSSHRKEIFQLFVVRN (SEQ ID NO:1144)
>gi|21264324|ref|NP_6122001| trace amine associated receptor 1
{Homosapiens}
MMPFCHNIINISCVKNNWSNDVRASLYSLMVLIILTTLVGNLIVIVSISHFKQLHTPTNWLIHS
MATVDFLLGCLVMPYSMVRSAEHCWYFGEVFCKIHTSTDIMLSSASIFHLSFISIDRYYAVCD
PLRYKAKMNILVICVMIFISWSVPAVFAFGMIFLELNFKGAEEIYYKHVHCRGGCSVFFSKISG
VLTFMTSFYIPGSIMLCVYYRIYLIAKEQARLISDANQKLQIGLEMKNGISQSKERKAVKTLGI
VMGVFLICWCPFFICTVMDPFLHYIIPPTLNDVLIVVFGYLNSTFNPMVYAFFYPWFRKALKM
MLFGKIFQKDSSRCKLFLELSS (SEQ ID NO:1145) >gi|21361557
|ref|NP_0033732| vasoactive intestinal polypeptide receptor 2
{Homosapiens}
MRTLLPPALLTCWLLAPVNSIHPECRFHLEIQEEETKCAELLRSQTEKHKACSGVWDNITCW
RPANVGETVTVPCPKVFSNFYSKAGNISKNCTSDGWSETFPDFVDACGYSDPEDESKITFYIL
VKAIYTLGYSVSLMSLATGSIILCLFRKLHCTRNYIHLNLFLSFILRAISVLVKDDVLYSSSGTL
HCPDQPSSWVGCKLSLVFLQYCIMANFFVVLLVEGLYLHTLLVAMLPPRRCFLAYLLIGWGLP
TVCIGAWTAARLYLEDTGCWDTNDHSVPWWVIRIPILISIIVNFVLFISIIRILLQKLTSPDVGG
NDQSQYKRLAKSTLLLIPLFGVHYMVFAVFPISISSKYQILFELCLGSFQGLVVAVLYCFLNSE
VQCELKRKWRSRCPTPSASRDYRVCGSSFSRNGSEGALQFHRGSRAQSFLQTETSVI (SEQ ID
NO:1146) >gi|21426829|ref|NP_6589861| prokineticin receptor 2
{Homosapiens}
MAAQNGNTSFTPNFNPPQDHASSLSFNFSYGDYDLPMDEDEDMTKTRTFFAAKIVIGIALAGI
MLVCGIGNFVFIAALTRYKKLRNLTNLLIANLAISDFLVAIICCPFEMDYYVVRQLSWEHGHV
LCASVNYLRTVSLYVSTNALLAIAIDRYLAIVHPLKPRMNYQTASFLIALVWMVSILIAIPSAY
FATETVLFIVKSQEKIFCGQIVVPVDQQLYYKSYFLFIFGVEFVGPVVTMTLCYARISRELWFK
AVPGFQTEQIRKRLRCRRKTVLVLMCILTAYVLCWAPFYGFTIVRDFFPTVFVKEKHYLTAF
YVVECIAMSNSMINTVCFVTVKNNTMKYFKKMMLLHWRPSQRGSKSSADLDLRTNGVPTT
EEVDCIRLK (SEQ ID NO:1147) >gi|22507376 |ref|NP_6837651|
oxoeicosanoid receptor 1 {Homosapiens}
MLCHRGGQLIVPIIPLCPEHSCRGRRLQNLLSGPWPKQPMELHNLSSPSPSLSSSVLPPSFSPSP
SSAPSAFTTVGGSSGGPCHPTSSSLVSAFLAPILALEFVLGLVGNSLALFIFCIHTRPWTSNTVF
LVSLVAADFLLISNLPLRVDYYLLHETWRFGAAACKVNLFMLSTNRTASVVFLTAIALNRYL
KVVQPHHVLSRASVGAAARVAGGLWVGILLLNGHLLLSTFSGPSCLSYRVGTKPSASLRWH
QALYLLEFFLPLALILFAIVSIGLTIRNRGLGGQAGPQRAMRVLAMVVAVYTICFLPSIIFGMA
SMVAFWLSACRSLDLCTQLFHGSLAFTYLNSVLDPVLYCFSSPNFLHQSRALLGLTRGRQGP
VSDESSYQPSRQWRYREASRKAEAIGKLKVQGEVSLEKEGSSQG (SEQ ID NO:1148)
>gi|23238240|ref|NP_0006772| type-2 angiotensin II receptor
{Homosapiens}
MKGNSTLATTSKNITSGLHFGLVNISGNNESTLNCSQKPSDKHLDAIPILYYIIFVIGFLVNIVV
VTLFCCQKGPKKVSSIYIFNLAVADLLLLATLPLWATYYSYRYDWLFGPVMCKVFGSFLTLN
MFASIFFITCMSVDRYQSVIYPFLSQRRNPWQASYIVPLVWCMACLSSLPTFYFRDVRTIEYLG
VNACIMAFPPEKYAQWSAGIALMKNILGFIIPLIFIATCYFGIRKHLLKTNSYGKNRITRDQVL
KMAAAVVLAFIICWLPFHVLTFLDALAWMGVINSCEVIAVIDLALPFAILLGFTNSCVNPFLY
CFVGNRFQQKLRSVFRVPITWLQGKRESMSCRKSSSLREMETFVS (SEQ ID NO:1149)
>gi|2339768 1 |ref|NP_0384752| EGF-like module-containing
mucin-like hormone receptor-like 2 isoform a {Homosapiens}
MGGRVFLVFLAFCVWLTLPGAETQDSRGCARWCPQDSSCVNATACRCNPGFSSFSEIITTPM
ETCDDINECATLSKVSCGKFSDCWNTEGSYDCVCSPGYEPVSGAKTFKNESENTCQDVDECQ
QNPRLCKSYGTCVNTLGSYTCQCLPGFKLKPEDPKLCTDVNECTSGQNPCHSSTHCLNNVGS
YQCRCRPGWQPIPGSPNGPNNTVCEDVDECSSGQHQCDSSTVCFNTVGSYSCRCRPGWKPR
HGIPNNQKDTVCEDMTFSTWTPPPGVHSQTLSRFFDKVQDLGRDYKPGLANNTIQSILQALD
ELLEAPGDLETLPRLQQHCVASHLLDGLEDVLRGLSKNLSNGLLNFSYPAGTELSLEVQKQV
DRSVTLRQNQAVMQLDWNQAQKSGDPGPSVVGLVSIPGMGKLLAEAPLVLEPEKQMLLHE
THQGLLQDGSPILLSDVISAFLSNNDTQNLSSPVTFTFSHRSVIPRQKVLCVFWEHGQNGCGH
WATTGCSTIGTRDTSTICRCTHLSSFAVLMAHYDVQEEDPVLTVITYMGLSVSLLCLLLAALT
FLLCKAIQNTSTSLHLQLSLCLFLAHLLFLVAIDQTGHKVLCSIIAGTLHYLYLATLTWMLLEA
LYLFLTARNLTVVNYSSINRFMKKLMFPVGYGVPAVTVAISAASRPHLYGTPSRCWLQPEKG
FIVVGFLGPVCAIFSVNLVLFLVTLWILKNRLSSLNSEVSTLRNTRMLAFKATAQLFILGCTWC
LGILQVGPAARVMAYLFTIINSLQGVFIFLVYCLLSQQVREQYGKWSKGIRKLKTESEMHTLS
SSAKADTSKPSTVN (SEQ ID NO:1150) >gi|23463303|ref|NP_0025572|
purinergic receptor P2Y11 {Homosapiens}
MAANVSGAKSCPANFLAAADDKLSGFQGDFLWPILVVEFLVAVASNGLALYRFSIRKQRPW
HPAVVFSVQLAVSDLLCALTLPPLAAYLYPPKHWRYGEAACRLERFLFTCNLLGSVIFITCISL
NRYLGIVHPFFARSHLRPKHAWAVSAAGWVLAALLAMPTLSFSHLKRPQQGAGNCSVARPE
ACIKCLGTADHGLAAYRAYSLVLAGLGCGLPLLLTLAAYGALGRAVLRSPGMTVAEKLRVA
ALVASGVALYASSYVPYHIMRVLNVDARRRWSTRCPSFADIAQATAALELGPYVGYQVMR
GLMPLAFCVHPLLYMAAVPSLGCCCRHCPGYRDSWNPEDAKSTGQALPLNATAAPKPSEPQ
SRELSQ (SEQ ID NO:1151) >gi|23592220|ref|NP_7031431| G-protein
coupled receptor 26 {Homosapiens}
MNSWDAGLAGLLVGTMGVSLLSNALVLLCLLHSADIRRQAPALFTLNLTCGNLLCTVVNMP
LTLAGVVAQRQPAGDRLCRLAAFLDTFLAANSMLSMAALSIDRWVAVVFPLSYRAKMRLR
DAALMVAYTWLHALTFPAAALALSWLGFHQLYASCTLCSRRPDERLRFAVFTGAFHALSFL
LSFVVLCCTYLKVLKVARFHCKRIDVITMQTLVLLVDLHPSVRERCLEEQKRRRQRATKKIST
FIGTFLVCFAPYVITRLVELFSTVPIGSHWGVLSKCLAYSKAASDPFVYSLLRHQYRKSCKEIL
NRLLHRRSIHSSGLTGDSHSQNILPVSE (SEQ ID NO:1152)
>gi|24475871|ref|NP_7225791| G protein-coupled receptor 114
precursor {Homosapiens}
MDHCGALFLCLCLLTLQNATTETWEELLSYMENMQVSRGRSSVFSSRQLHQLEQMLLNTSF
PGYNLTLQTPTIQSLAFKLSCDFSGLSLTSATLKRVPQAGGQHARGQHAMQFPAELTRDACK
TRPRELRLICIYFSNTHFFKDENNSSLLNNYVLGAQLSHGHVNNLRDPVNISFVVHNQSLEGYT
LTCVFVVKEGARKQPWGGWSPEGCRTEQPSHSQVLCRCNHLTYFAVLMQLSPALVPAELLAP
LTYISLVGCSISIVASLITVLLHFHFRKQSDSLTRIHMNLHASVLLLNIAFLLSPAFAMSPVPGS
ACTALAAALHYALLSCLTWMAIEGFNLYLLLGRVYNIYIRRYVFKLGVLGWGAPALLVLLS
LSVKSSVYGPCTIPVFDSWENGTGFQNMSICWVRSPVVHSVLVMGYGGLTSLFNLVVLAWA
LWTLRRLRERADAPSVRACHDTVTVLGLTVLLGTTWALAFFSFGVFLLPQLFLFTILNSLYGF
FLFLWFCSQRCRSEAEAKAQIEAFSSSQTTQ (SEQ ID NO:1153)
>gi|24476016|ref|NP_7225611| G protein-coupled receptor 161
isoform 2 {Homosapiens}
MSLNSSLSCRKELSNLTEEEGGEGGVIITQFIAIIVITIFVCLGNLVIVVTLYKKSYLLTLSNKFV
FSLTLSNFLLSVLVLPFVVTSSIRREWIFGVVWCNFSALLYLLISSASMLTLGVIAIDRYYAVL
YPMVYPMKITGNRAVMALVYIVVLHSLIGCLPPLFGWSSVEFDEFKWMCVAAWHREPGYTA
FVVQIVVCALFPFLVMLVCYGFIFRVARVKARKVHCGTVVIVEEDAQRTGRKNSSTSTSSSGSR
RNAFQGVVYSANQCKALITILVVLGAFMVTWGPYMVVIASEALWGKSSVSPSLETWATWLS
FASAVCHPLIYGLWNKTVRKELLGMCFGDRYYREPFVQRQRTSRLFSISNRITDLGLSPHLTA
LMAGGQPLGHSSSTGDTGFSCSQDSGTDMMLLEDYTSDDNPPSHCTCPPKRRSSVTFEDEVE
QIKEAAKNSILHVKAEVHKSLDSYAASLAKAIEAEAKINLFGEEALPGVLVTARTVPGGGFG
GRRGSRTLVSQRLQLQSIEEGDVLAAEQR (SEQ ID NO:1154)
>gi|28173558|ref|NP_7782371| trace amine-associated receptor 6
{Homosapiens}
MSSNSSLLVAVQLCYANVNGSCVKIPFSPGSRVILYIVFGFGAVLAVFGNLLVMISILHFKQLH
SPTNFLVASLACADFLVGVTVMPFSMVRTVESCWYFGRSFCTFHTCCDVAFCYSSLFHLCFIS
IDRYIAVTDPLVYPTKFTVSVSGICISVSWILPLMYSGAVFYTGVYDDGLEELSDALNCIGGCQ
TVVNQNVVVLTDFLSFFIPTFIMIILYGNIFLVARRQAKKIENTGSKTESSSESYKARVARRERK
AAKTLGVTVVAFMISWLPYSIDSLIDAFMGFITPACIYEICCWCAYYNSAMNPLIYALFYPWF
RKAIKVIVTGQVLKNSSATMNLFSEHI (SEQ ID NO:1155)
>gi|28466969|ref|NP_0009441| prostaglandin D2 receptor
{Homosapiens}
MKSPFYRCQNTTSVEKGNSAVMGGVLFSTGLLGNLLALGLLARSGLGWCSRRPLRPLPSVFY
MLVCGLTVTDLLGKCLLSPVVLAAYAQNRSLRVLAPALDNSLCQAFAFFMSFFGLSSTLQLL
AMALECWLSLGHPFFYRRHITLRLGALVAPVVSAFSLAFCALPFMGFGKFVQYCPGTWCFIQ
MVHEEGSLSVLGYSVLYSSLMALLVLATVLCNLGAMRNLYAMHRRLQRHPRSCTRDCAEP
RADGREASPQPLEELDHLLLLALMTVLFTMCSLPVIYRAYYGAFKDVKEKNRTSEEAEDLRA
LRFLSVISIVDPWIFIIFRSPVFRIFFHKIFIRPLRYRSRCSNSTNMESSL (SEQ ID
NO:1156) >gi|28872720|ref|NP_0025552| P2Y purinoceptor 2
{Homosapiens}
MAADLGPWNDTINGTWDGDELGYRCRFNEDFKYVLLPVSYGVVCVPGLCLNAVALYIFLC
RLKTWNASTTYMFHLAVSDALYAASLPLLVYYYARGDHWPFSTVLCKLVRFLFYTNLYCSI
LFLTCISVHRCLGVLRPLRSLRWGRARYARRVAGAVWVLVLACQAPVLYFVTTSARGGRVT
CHDTSAPELFSRFVAYSSVMLGLLFAVPFAVILVCYVLMARRLLKPAYGTSGGLPRAKRKSV
RTIAVVLAVFALCFLPFHVTRTLYYSFRSLDLSCHTLNAINMAYKVTRPLASANSCLDPVLYF
LAGQRLVRFARDAKPPTGPSPATPARRRLGLRRSDRTDMQRIEDVLGSSEDSRRTESTPAGSE
NTKDIRL (SEQ ID NO:1157) >gi|28875799|ref|NP_7953441|
gastrinicholecystokinin type B receptor {Homosapiens}
MELLKLNRSVQGTGPGPGASLCRPGAPLLNSSSVGNLSCEPPRIRGAGTRELELAIRITLYAVI
FLMSVGGNMLIIVVLGLSRRLRTVTNAFLLSLAVSDLLLAVACMPFTLLPNLMGTFIFGTVIC
KAVSYLMGVSVSVSTLSLVAIALERYSAICRPLQARVWQTRSHAARVIVATWLLSGLLMVPY
PVYTVVQPVGPRVLQCVHRWPSARVRQTWSVLLLLLLFFIPGVVMAVAYGLISRELYLGLRF
DGDSDSDSQSRVRNQGGLPGAVHQNGRCRPETGAVGEDSDGCYVQLPRSRPALELTALTAP
GPGSGSRPTQAKLLAKKRVVRMLLVIVVLFFLCWLPVYSANTWRAFDGPGAHRALSGAPISF
IHLLSYASACVNPLVYCFMHRRFRQACLETCARCCPRPPRARPRALPDEDPPTPSIASLSRLSY
TTISTLGPG (SEQ ID NO:1158) >gi|2917131 1 |ref|NP_8082191|
G-protein coupled receptor 109A {Homosapiens}
MNRHHLQDHFLEIDKKNCCVFRDDFIVKVLPPVLGLEFIFGLLGNGLALWIFCFHLKSWKSSR
IFLFNLAVADFLLIICLPFLMDNYVRRWDWKFGDIPCRLMLFMLAMNRQGSIIFLTVVAVDR
YFRVVHPHHALNKISNRTAAIISCLLWGITIGLTVHLLKKKMPIQNGGANLCSSFSICHTFQWH
EAMFLLEFFLPLGIILFCSARIIVVSLRQRQMDRHAKIKRAITFIMVVAIVFVICFLPSVVVRIRIF
WLLHTSGTQNCEVYRSVDLAFFITLSFTYMNSMLDPVVYYFSSPSFPNFFSTLINRCLQRKMT
GEPDNNRSTSVELTGDPNKTRGAPEALMANSGEPWSPSYLGPTSP (SEQ ID NO:1159)
>gi|29171759|ref|NP_0011092| pituitary adenylate
cyclase-activating polypeptide type I receptor precursor
{Homosapiens}
MAGVVHVSLAALLLLPMAPAMHSDCIFKKEQAMCLEKIQRANELMGFNDSSPGCPGMWDN
ITCWKPAHVGEMVLVSCPELFRIFNPDQVVVETETIGESDFGDSNSLDLSDMGVVSRNCTEDG
WSEPFPHYFDACGFDEYESETGDQDYYYLSVKALYTVGYSTSLVTLTTAMVILCRFRKLHCT
RNFIHMNLFVSFMLRAISVFIKDWILYAEQDSNHCFISTVECKAVMVFFHYCVVSNYFVVLFIE
GLYLFTLLVETFFPERRYFYVVYTIIGWGTPTVCVTVWATLRLYFDDTGCWDMNDSTALWW
VIKGPVVGSIMVNFVLFIGIIVILVQKLQSPDMGGNESSIYLRLARSTLLLIPLFGIHYTVFAFSP
ENVSKRERLVFELGLGSFQGFVVAVLYCFLNGEVQAEIKRKWRSWKVNRYFAVDFKHRHPS
LASSGVNGGTQLSILSKSSSQIRMSGLPADNLAT
(SEQ ID NO:1160) >gi|30023826|ref|NP_8352301| P2Y purinoceptor 8
{Homosapiens}
MQVPNSTGPDNATLQMLRNPAIAVALPVVYSLVAAVSIPGNLFSLWVLCRRMGPRSPSVIFM
INLSVTDLMLASVLPFQIYYHCNRHHWVFGVLLCNVVTVAFYANMYSSILTMTCISVERFLG
VLYPLSSKRWRRRRYAVAACAGTWLLLLTALSPLARTDLTYPVHALGIITCFDVLKWTMLPS
VAMWAVFLFTIFILLFLIPFVITVACYTATILKLLRTEEAHGREQRRRAVGLAAVVLLAFVTCF
APNNFVLLAHIVSRLFYGKSYYHVYKLTLCLSCLNNCLDPFVYYFASREFQLRLREYLGCRR
VPRDTLDTRRESLFSARTTSVRSEAGAHPEGMEGATRPGLQRQESVF (SEQ ID NO:1161)
>gi|30425400|ref|NP_8485661| glucose-dependent insulinotropic
receptor {Homosapiens } MESSFSFGVILAVLA
LIIATNTLVAVAVLLLIHKNDGVSLCFTLNLAVADTLIGVAISGLLTD
QLSSPSRPTQKTLCSLRMAFVTSSAAASVLTVMLITFDRYLAIKQPFRYLKIMSGFVAGACIA
GLWLVSYLIGFLPLGIPMFQQTAYKGQCSFFAVFHPHFVLTLSCVGFFPAMLLFVFFYCDMLK
IASMHSQQIRKMEHAGAMAGGYRSPRTPSDFKALRTVSVLIGSFALSWTPFLITGIVQVACQE
CHLYLVLERYLWLLGVGNSLLNPLIYAYWQKEVRLQLYHMALGVKKVLTSFLLFLSARNCG
PERPRESSCHIVTISSSEFDG (SEQ ID NO:1162)
>gi|30581164|ref|NP_0052772| neuropeptides B/W receptor type 2
{Homosapiens}
MQAAGHPEPLDSRGSFSLPTMGANVSQDNGTGHNATFSEPLPFLYVLLPAVYSGICAVGLTG
NTAVILVILRAPKMKTVTNVFILNLAVADGLFTLVLPVNIAEHLLQYWPFGELLCKLVLAVD
HYNIFSSIYFLAVMSVDRYLVVLATVRSRHMPWRTYRGAKVASLCVWLGVTVLVLPFFSFA
GVYSNELQVPSCGLSFPWPEQVVVFKASRVYTLVLGFVLPVCTICVLYTDLLRRLRAVRLRSG
AKALGKARRKVTVLVLVVLAVCLLCWTPFHLASVVALTTDLPQTPLVISMSYVITSLSYANS
CLNPFLYAFLDDNFRKNFRSILRC (SEQ ID NO:1163)
>gi|30795217|ref|NP_8485401| chemokine (C-C motif) receptor-like
1 {Homosapiens}
MALEQNQSTDYYYEENEMNGTYDYSQYELICIKEDVREFAKVFLPVFLTIVFVIGLAGNSMV
VAIYAYYKKQRTKTDVYILNLAVADLLLLFTLPFWAVNAVHGWVLGKIMCKITSALYTLNF
VSGMQFLACISIDRYVAVTKVPSQSGVGKPCWIICFCVVVMAAILLSIPQLVFYTVNDNARCIPI
FPRYLGTSMKALIQMLEICIGFVVPFLIMGVCYFITARTLMKMPNIKISRPLKVLLTVVIVFIVT
QLPYNIVKFCRAIDIIYSLITSCNMSKRMDIAIQVTESIALFHSCLNPILYVFMGASFKNYVMKV
AKKYGSWRRQRQSVEEFPFDSEGPTEPTSTFSI (SEQ ID NO:1164) >gi|31083315
|ref|NP_0091583| probable G-protein coupled receptor 45
{Homosapiens } MACNSTSLEAYTYLLLNTS
NASDSGSTQLPAPLRISLAIVMLLMTVVGFLGNTVVCIIVYQRP
AMRSAINLLLATLAFSDIMLSLCCMPFTAVTLITVRWHFGDHFCRLSATLYWFFVLEGVAILL
IISVDRFLIIVQRQDKLNPRRAKVIIAVSWVLSFCIAGPSLTGWTLVEVPARAPQCVLGYTELP
ADRAYVVTLVVAVFFAPFGVMLCAYMCILNTVRKNAVRVHNQSDSLDLRQLTRAGLRRLQ
RQQQVSVDLSFKTKAFTTILILFVGFSLCWLPHSVYSLLSVFSQRFYCGSSFYATSTCVLWLSY
LKSVFNPIVYCWRIKKFREACIELLPQTFQILPKVPERIRRRIQPSTVYVCNENQSAV (SEQ ID
NO:1165) >gi|31083344|ref|NP_0647071| C-X-C chemokine receptor
type 7 {Homosapiens}
MDLHLFDYSEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMIANSV
VVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVTHLIFS
INLFGSIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVVVLLAFCVSLPDTYYLKTVTSA
SNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAISASSDQEKHSSRKIIF
SYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVTQCLSLVHCCVNPVLYSFIN
RNYRYELMKAFIFKYSAKTGLTKLIDASRVSETEYSALEQSTK (SEQ ID NO:1166)
>gi|31657138|ref|NP_0001362| follicle-stimulating hormone
receptor isoform 1 precursor {Homosapiens }
MALLLVSLLAFLSLGSGCHHRICHCSNRVFLCQESKVTEIPSDLPRNAIELRFVLTKLRVIQKG
AFSGFGDLEKIEISQNDVLEVIEADVFSNLPKLHEIRIEKANNLLYINPEAFQNLPNLQYLLISN
TGIKHLPDVHKIHSLQKVLLDIQDNINIHTIERNSFVGLSFESVILWLNKNGIQEIHNCAFNGTQ
LDELNLSDNNNLEELPNDVFHGASGPVILDISRTRIHSLPSYGLENLKKLRARSTYNLKKLPTL
EKLVALMEASLTYPSHCCAFANVVRRQISELHPICNKS ILRQEVDYMTQARGQRSSLAEDNES
SYSRGFDMTYTEFDYDLCNEVVDVTCSPKPDAFNPCEDIMGYNILRVLIWFISILAITGNIIVLV
ILTTSQYKLTVPRFLMCNLAFADLCIGIYLLLIASVDIHTKSQYHNYAIDWQTGAGCDAAGFF
TVFASELSVYTLTAITLERWHTITHAMQLDCKVQLRHAASVMVMGWIFAFAAALFPIFGISSY
MKVSICLPMDIDSPLSQLYVMSLLVLNVLAFVVICGCYIHIYLTVRNPNIVSSSSDTRIAKRMA
MLIFTDFLCMAPISFFAISASLKVPLITVSKAKILLVLFHPINSCANPFLYAIFTKNFRRDFFILLS
KCGCYEMQAQIYRTETSSTVHNTHPRNGHCSSAPRVTSGSTYILVPLSHLAQN (SEQ ID
NO:1167) >gi|31881630|ref|NP_0009472| prostaglandin E2 receptor
EP2 subtype {Homosapiens}
MGNASNDSQSEDCETRQWLPPGESPAISSVMFSAGVLGNLIALALLARRWRGDVGCSAGRR
SSLSLFHVLVTELVFTDLLGTCLISPVVLASYARNQTLVALAPESRACTYFAFAMTFFSLATM
LMLFAMALERYLSIGHPYFYQRRVSRSGGLAVLPVIYAVSLLFCSLPLLDYGQYVQYCPGTW
CFIRHGRTAYLQLYATLLLLLIVSVLACNFSVILNLIRMHRRSRRSRCGPSLGSGRGGPGARRR
GERVSMAEETDHLILLAIMTITFAVCSLPFTIFAYMNETSSRKEKWDLQALRFLSINSIIDPWVF
AILRPPVLRLMRSVLCCRISLRTQDATQTSCSTQSDASKQADL (SEQ ID NO:1168)
>gi|31881792|ref|NP_8580431| leukotriene B4 receptor 1
{Homosapiens}
MNTTSSAAPPSLGVEFISLLAIILLSVALAVGLPGNSFVVWSILKRMQKRSVTALMVLNLALA
DLAVLLTAPFFLHFLAQGTWSFGLAGCRLCHYVCGVSMYASVLLITAMSLDRSLAVARPFVS
QKLRTKAMARRVLAGIVVVLSFLLATPVLAYRTVVPWKTNMSLCFPRYPSEGHRAFHLIFEA
VTGFLLPFLAVVASYSDIGRRLQARRFRRSRRTGRLVVLIILTFAAFWLPYHVVNLAEAGRAL
AGQAAGLGLVGKRLSLARNVLIALAFLSSSVNPVLYACAGGGLLRSAGVGFVAKLLEGTGS
EASSTRRGGSLGQTARSGPAALEPGPSESLTASSPLKLNELN (SEQ ID NO:1169)
>gi|32261309|ref|NP_0720932| probable G-protein coupled receptor
135 {Homosapiens}
MEEPQPPRPPASMALLGSQHSGAPSAAGPPGGTSSAATAAVLSFSTVATAALGNLSDASGGG
TAAAPGGGGLGGSGAAREAGAAVRRPLGPEAAPLLSHGAAVAAQALVLLLIFLLSSLGNCA
VMGVIVKHRQLRTVTNAFILSLSLSDLLTALLCLPAAFLDLFTPPGGSAPAAAAGPWRGFCA
ASRFFSSCFGIVSTLSVALISLDRYCAIVRPPREKIGRRRALQLLAGAWLTALGFSLPWELLGA
PRELAAAQSFHGCLYRTSPDPAQLGAAFSVGLVVACYLLPFLLMCFCHYHICKTVRLSDVRV
RPVNTYARVLRFFSEVRTATTVLIMIVFVICCWGPYCFLVLLAAARQAQTMQAPSLLSVVAV
WLTVVANGAINPVIYAIRNPNISMLLGRNREEGYRTRNVDAFLPSQGPGLQARSRSRLRNRYA
NRLGACNRMSSSNPASGVAGDVAMWARKNPVVLFCREGPPEPVTAVTKQPKSEAGDTSL (SEQ ID
NO:1170) >gi|32307152|ref|NP_0009072| oxytocin receptor
{Homosapiens}
MEGALAANVVSAEAANASAAPPGAEGNRTAGPPRRNEALARVEVAVLCLILLLALSGNACVL
LALRTTRQKHSRLFFFMKHLSIADLVVAVFQVLPQLLWDITFRFYGPDLLCRLVKYLQVVGM
FASTYLLLLMSLDRCLAICQPLRSLRRRTDRLAVLATWLGCLVASAPQVHIFSLREVADGVF
DCWAVFIQPWGPKAYITWITLAVYIVPVIVLAACYGLISFKIVVQNLRLKTAAAAAAEAPEGA
AAGDGGRVALARVSSVKLISKAKIRTVKMTFIIVLAFIVCWTPFFFVQMWSVWDANAPKEAS
AFIIVMLLASLNSCCNPWIYMLFTGHLFHELVQRFLCCSASYLKGRRLGETSASKKSNSSSFV
LSHRSSSQRSCSQPSTA (SEQ ID NO:1171) >gi|32307159|ref|NP_0018742|
corticotropin-releasing factor receptor 2 precursor {Homosapiens}
MDAALLHSLLEANCSLALAEELLLDGWGPPLDPEGPYSYCNTTLDQIGTCWPRSAAGALVE
RPCPEYFNGVKYNTTRNAYRECLENGTWASKINYSQCEPILDDKQRKYDLHYRIALVVNYL
GHCVSVAALVAAFLLFLALRSIRCLRNVIHWNLITTFILRNVMWFLLQLVDHEVHESNEVVVC
RCITTIFNYFVVTNFFWMFVEGCYLHTAIVMTYSTERLRKCLFLFIGWCIPFPIIVAWAIGKLY
YENEQCWFGKEPGDLVDYIYQGPIILVLLINFVFLFNIVRILMTKLRASTTSETIQYRKAVKAT
LVLLPLLGITYMLFFVNPGEDDLSQIMFIYFNSFLQSFQGFFVSVFYCFFNGEVRSAVRKRWH
RWQDHHSLRVPMARAMSIPTSPTRISFHSIKQTAAV (SEQ ID NO:1172)
>gi|32401433|ref|NP_8614551| G protein-coupled receptor 142
{Homosapiens}
MSIMMLPMEQKIQWVPTSLQDITAVLGTEAYTEEDKSMVSHAQKSQHSCLSHSRWLRSPQV
TGGSWDLR1RPSKDSSSFRQAQCLRKDPGANNHLESQGVRGTAGDADRELRGPSEKATAGQ
PRVTLLPTPHVSGLSQEFESHWPEIAERSPCVAGVIPVIYYSVLLGLGLPVSLLTAVALARLAT
RTRRPSYYYLLALTASDIIIQVVIVFAGFLLQGAVLARQVPQAVVRTANILEFAANHASVWIAI
LLTVDRYTALCHPLHHRAASSPGRTRRAIAAVLSAALLTGIPFYWWLDMWRDTDSPRTLDE
VLKWAHCLTVYFIPCGVFLVTNSAIIHRLRRRGRSGLQPRVGKSTAILLGITTLFTLLWAPRVF
VMLYHMYVAPVHRDWRVHLALDVANMVAMLHTAANFGLYCFVSKTFRATVRQVIHDAY
LPCTLASQPEGMAAKPVMEPPGLPTGAEV (SEQ ID NO:1173)
>gi|32401435|ref|NP_8614561| G protein-coupled receptor 141
{Homosapiens}
MPGHNTSRNSSCDPIVTPHLISLYFIVLIGGLVGVISILFLLVKMNTRSVTTMAVINLVVVHSVF
LLTVPFRLTYLIKKTVVMFGLPFCKFVSAMLHIHMYLTFLFYVVILVTRYLIFFKCKDKVEFYR
KLHAVAASAGMWTLVIVIVVPLVVSRYGIHEEYNEEHCFKFHKELAYTYVKIINYMIVIFVIA
VAVILLVFQVFIIMLMVQKLRHSLLSHQEFVVAQLKNLFFIGVILVCFLPYQFFRIYYLNVVTHS
NACNSKVAFYNEIFLSVTAISCYDLLLFVFGGSHWFKQKIIGLWNCVLCR (SEQ ID NO:1174)
>gi|32483397 |ref|NP_000788 2| d(4) dopamine receptor
{Homosapiens}
MGNRSTADADGLLAGRGPAAGASAGASAGLAGQGAAALVGGVLLIGAVLAGNSLVCVSVA
TERALQTPTNSFIVSLAAADLLLALLVLPLFVYS EVQGGAWLLSPRLCDALMAMDVMLCTA
SIFNLCAISVDRFVAVAVPLRYNRQGGSRRQLLLIGATWLLSAAVAAPVLCGLNDVRGRDPA
VCRLEDRDYVVYSSVCS FFLPCPLMLLLYWATFRGLQRWEVARRAKLHGRAPRRPSGPGPP
SPTPPAPRLPQDPCGPDCAPPAPGLPRGPCGPDCAPAAPSLPQDPCGPDCAPPAPGLPPDPCGS
NCAPPDAVRAAALPPQTPPQTRRRRRAKITGRERKAMRVLPVVVGAFLLCWTPFFVVHITQA
LCPACSVPPRLVSAVTWLGYVNSALNPVIYTVFNAEFRNVFRKALRACC (SEQ ID NO:1175)
>gi|32490567|ref|NP_8710011| relaxin-3 receptor 2 {Homosapiens}
MPTLNTSASPPTFFVVANASGGSVLSADDAPMPVKFLALRLMVALAYGLVGAIGLLGNLAVL
WVLSNCARRAPGPPSDTFVFNLALADLGLALTLPFVVAAESALDFHWPFGGALCKMVLTATV
LNVYASIFLITALSVARYWVVAMAAGPGTHLSLFVVARIATLAVWAAAALVTVPTAVFGVEG
EVCGVRLCLLRFPSRYVVLGAYQLQRVVLAFMVPLGVITTSYLLLLAFLQRRQRRRQDSRVV
ARSVRILVASFFLCWFPNHVVTLWGVLVKFDLVPWNSTFYTIQTYVFPVTTCLAHSNSCLNP
VLYCLLRREPRQALAGTFRDLRLRLWPQGGGWVQQVALKQVGRRWVASNPRESRPSTLLT
NLDRGTPG (SEQ ID NO:1176) >gi|33598960|ref|NP_0006732| alpha-2B
adrenergic receptor {Homosapiens}
MDHQDPYSVQATAAIAAAITFLILFTIFGNALVILAVLTSRSLRAPQNLFLVSLAAADILVATLI
IPFSLANELLGYWYFRRTVVCEVYLALDVLFCTSSIVHLCAISLDRYWAVSRALEYNSKRTPRR
IKCIILTVWLIAAVISLPPLIYKGDQGPQPRGRPQCKLNQEAWYILASSIGSFFAPCLIMILVYLR
IYLIAKRSNRRGPRAKGGPGQGESKQPRPDHGGALASAKLPALASVASAREVNGHSKSTGEK
EEGETPEDTGTRALPPSWAALPNSGQGQKEGVCGASPEDEAEEEEEEEEEEEECEPQAVPVSP
ASACSPPLQQPQGSRVLATLRGQVLLGRGVGAIGGQWWRRRAQLTREKRFTFVLAVVIGVF
VLCWFPFFFSYSLGAICPKHCKVPHGLFQFFFWIGYCNSSLNPVIYTIFNQDFRRAFRRILCRP
WTQTAW (SEQ ID NO:1177) >gi|33695097|ref|NP_0052922| G
protein-coupled receptor 35 {Homosapiens}
MNGTYNTCGSSDLTWPPAIKLGFYAYLGVLLVLGLLLNSLALWVFCCRMQQWTETRIYMT
NLAVADLCLLCTLPFVLHSLRDTSDTPLCQLSQGIYLTNRYMSISLVTAIAVDRYVAVRHPLR
ARGLRSPRQAAAVCAVLWVLVIGSLVARWLLGIQEGGFCFRSTRHNFNSMAFPLLGFYLPLA
VVVFCSLKVVTALAQRPPTDVGQAEATRKAARMVWANLLVFVVCFLPLHVGLTVRLAVG
WNACALLETIRRALYITSKLSDANCCLDAICYYYMAKEFQEASALAVAPSAKAHKSQDSLCV TLA
(SEQ ID NO:1178) >gi|33695104|ref|NP_0035992| G protein-coupled
receptor 65 {Homosapiens}
MNSTCIEEQHDLDHYLFPIVYIFVIIVSIPANIGSLCVSFLQAKKESELGIYLFSLSLSDLLYALT
LPLWIDYTWNKDNWTFSPALCKGSAFLMYMNFYSSTAFLTCIAVDRYLAVVYPLKFFFLRTR
RFALMVSLSIVVILETIFNAVMLWEDETVVEYCDAEKSNFTLCYDKYPLEKWQINLNLFRTCT
GYAIPLVTILICNRKVYQAVRHNKATENKEKKRIIKLLVSITVTFVLCFTPFHVMLLIRCILEHA
VNFEDHSNSGKRTYTMYRITVALTSLNCVADPILYCFVTETGRYDMWNILKFCTGRCNTSQR
QRKRILSVSTKDTMELEVLE (SEQ ID NO:1179)
>gi|33695107|ref|NP_0056742| G-protein coupled receptor 55
{Homosapiens}
MSQQNTSGDCLFDGVNELMKTLQFAVHIPTFVLGLLLNLLAIHGFSTFLKNRWPDYAATSIY
MINLAVFDLLLVLSLPFKMVLSQVQSPFPSLCTLVECLYFVSMYGSVFTICFISMDRFLAIRYP
LLVSHLRSPRKIFGICCTIVVVLVVVTGSIPIYSFHGKVEKYMCFHNMSDDTWSAKVFFPLEVFG
FLLPMGIMGFCCSRSIHILLGRRDHTQDWVQQKACIYSIAASLAVFVVSFLPVHLGFFLQFLV
RNSFIVECRAKQSISFFLQLSMCFSNVNCCLDVFCYYFVIKEFRMNIRAHRPSRVQLVLQDTTI
SRG (SEQ ID NO:1180) >gi|33695113|ref|NP_0057582| G-protein
coupled purinergic receptor P2Y5 {Homosapiens}
MVSVNSSHCFYNDSFKYTLYGCMFSMVFVLGLISNCVAIYIFICVLKVRNETTTYMINLAMS
DLLFVFTLPFRIFYFTTRNWPFGDLLCKISVMLFYTNMYGSILFLTCISVDRFLAIVYPFKSKTL
RTKRNAKIVCTGVWLTVIGGSAPAVFVQSTHSQGNNASEACFENFPEATWKTYLSRIVIFIEIV
GFFIPLILNVTCSSMVLKTLTKPVTLSRSKINKTKVLKMIFVHLIIFCFCFVPYNINLILYSLVRT
QTFVNCSVVAAVRTMYPITLCIAVSNCCFDPIVYYFTSDTIQNSIKMKNWSVRRSDFRFSEVH
GAENFIQHNLQTLKSKIFDNESAA (SEQ ID NO:1181)
>gi|34577052|ref|NP_0052333| proteinase-activated receptor 2
precursor {Homosapiens}
MRSPSAAWLLGAAILLAASLSCSGTIQGTNRSSKGRSLIGKVDGTSHVTGKGVTVETVFSVDE
FSASVLTGKLTTVFLPIVYTIVFVVGLPSNGMALWVFLFRTKKKHPAVIYMANLALADLLSVI
WFPLKIAYHIHGNNWIYGEALCNVLIGFFYGNMYCSILFMTCLSVQRYWVIVNPMGHSRKK
ANIAIGISLAIWLLILLVTIPLYVVKQTIFIPALNITTCHDVLPEQLLVGDMFNYFLSLAIGVFLF
PAFLTASAYVLMIRMLRSSAMDENSEKKRKRAIKLIVTVLAMYLICFTPSNLLLVVHYFLIKS
QGQSHVYALYIVALCLSTLNSCIDPFVYYFVSHDFRDHAKNALLCRSVRTVKQMQVSLTSKK
HSRKSSSYSSSSTTVKTSY (SEQ ID NO:1182)
>gi|36951012|ref|NP_0052702| probable G-protein coupled receptor
1 {Homosapiens}
MEDLEETLFEEFENYSYDLDYYSLESDLEEKVQLGVVHWVSLVLYCLAFVLGIPGNAIVIVVF
TGFKWKKTVTTLWFLNLAIADFIFLLFLPLYISYVAMNFHWPFGIVVLCKANSFTAQLNMFAS
VFFLTVISLDHYIHLIHPVLSHRHRTLKNSLIVIIFIVVLLASLIGGPALYFRDTVEFNNHTLCYNN
FQKHDPDLTLIRHHVLTWVKFIIGYLFPLLTMSICYLCLIFKVKKRSILISSRHFWTILVVVVAF
VVCWTPYHLFSIVVELTIHHNSYSHHVMQAGIPLSTGLAFLNSCLNPILYVLISKKFQARFRSSV
AEILKYTLWEVSCSGTVSEQLRNSETKNLCLLETAQ (SEQ ID NO:1183)
>gi|36951034|ref|NP_5430092| G-protein coupled receptor 78
{Homosapiens}
MGPGEALLAGLLVMVLAVALLSNALVLLCCAYSAELRTRASGVLLVNLSLGHLLLAALDMP
FTLLGVMRGRTPSAPGACQVIGFLDTFLASNAALSVAALSADQWLAVGFPLRYAGRLRPRY
AGLLLGCAWGQSLAFSGAALGCSWLGYSSAFASCSLRLPPEPERPRFAAFTATLHAVGFVLP
LAVLCLTSLQVHRVARRHCQRMDTVTMKALALLADLHPSVRQRCLIQQKRRRHRATRKIGI
AIATFLICFAPYVMTRLAELVPFVTVNAQWGILSKCLTYSKAVADPFTYSLLRRPFRQVLAG
MVHRLLKRTPRPASTHDSSLDVAGMVHQLLKRTPRPASTHNGSVDTENDSCLQQTH (SEQ ID
NO:1184) >gi|37187860|ref|NP_0043582| C-C chemokine receptor
type 6 {Homosapiens}
MSGESMNFSDVFDSSEDYFVSVNTSYYSVDSEMLLCSLQEVRQFSRLFVPIAYSLICVFGLLG
NILVVITFAFYKKARSMTDVYLLNMAIADILFVLTLPFVVAVSHATGAWVFSNATCKLLKGIY
AINFNCGMLLLTCISMDRYIAIVQATKSFRLRSRTLPRSKIICLVVVVGLSVHSSSTFVFNQKYN
TQGSDVCEPKYQTVSEPIRWKLLMLGLELLFGFFIPLMFMIFCYTFIVKTLVQAQNSKRHKAI
RVIIAVVLVFLACQIPHNMVLLVTAANLGKMNRSCQSEKLIGYTKTVTEVLAFLHCCLNPVL
YAFIGQKFRNYFLKILKDLWCVRRKYKSSGFSCAGRYSENISRQTSETADNDNASSFTM (SEQ ID
NO:1185) >gi|37577159|ref|NP_0003792| calcium-sensing receptor
precursor {Homosapiens}
MAFYSCCWVLLALTWHTSAYGPDQRAQKKGDIILGGLFPIHFGVAAKDQDLKSRPESVECIR
YNFRGFRWLQAMIFAIEEINSSPALLPNLTLGYRIFDTCNTVSKALEATLSFVAQNKIDSLNLD
EFCNCSEHIPSTIAVVGATGSGVSTAVANLLGLFYIPQVSYASSSRLLSNKNQFKSFLRTIPNDE
HQATAMADHEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFSELISQYSDEEEIQHV
VEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIVVLASEAWASSSLIAMPQYFHVVGGTIGF
ALKAGQIPGFREFLKKVHPRKSVHNGFAKEFVVEETFNCHLQEGAKGPLPVDTFLRGHEESGD
RFSNSSTAFRPLCTGDENISSVETPYIDYTHLRISYNVYLAVYSIAHALQDIYTCLPGRGLFTNG
SCADIKKVEAWQVLKHLRHLNFTNNMGEQVTFDECGDLVGNYSIINWHLSPEDGSIVFKEV
GYYNVYAKKGERLFINEEKILWSGFSREVPFSNCSRDCLAGTRKGIIEGEPTCCFECVECPDGE
YSDETDASACNKCPDDFWSNENHTSCIAKEIEFLSWTEPFGIALTLFAVLGIFLTAFVLGVFIK
FRNTPIVKATNRELSYLLLFSLLCCFSSSLFFIGEPQDWTCRLRQPAFGISFVLCISCILVKTNRV
LLVFEAKIPTSFHRKWWGLNLQFLLVFLCTFMQIVICVIVVLYTAPPSSYRNQELEDEIIFITCHE
GSLMALGFLIGYTCLLAAICFFFAFKSRKLPENFNEAKFITFSMLIFFIVWISFIPAYASTYGKFV
SAVEVIAILAASFGLLACIFFNKIYIILFKPSRNTIEEVRCSTAAHAFKVAARATLRRSNVSRKR
SSSLGGSTGSTPSSSISSKSNSEDPFPQPERQKQQQPLALTQQEQQQQPLTLPQQQRSQQQPRC
KQKVIFGSGTVTFSLSFDEPQKNAMAHRNSTHQNSLEAQKSSDTLTRHQPLLPLQCGETDLD
LTVQETGLQGPVGGDQRPEVEDPEELSPALVVSSSQSFVISGGGSTVTENVVNS (SEQ ID
NO:1186) >gi|37622910|ref|NP_0007292| cholinergic receptor,
muscarinic 1 {Homosapiens}
MNTSAPPAVSPNITVLAPGKGPWQVAFIGITTGLLSLATVTGNLLVLISFKVNTELKTVNNYF
LLSLACADLIIGTFSMNLYTTYLLMGHWALGTLACDLWLALDYVASNASVMNLLLISFDRYF
SVTRPLSYRAKRTPRRAALMIGLAWLVSFVLWAPAILFWQYLVGERTVLAGQCYIQFLSQPII
TFGTAMAAFYLPVTVMCTLYWRIYRETENRARELAALQGSETPGKGGGSSSSSERSQPGAEG
SPETPPGRCCRCCRAPRLLQAYSWKEEEEEDEGSMESLTSSEGEEPGSEVVIKMPMVDPEAQ
APTKQPPRSSPNTVKRPTKKGRDRAGKGQKPRGKEQLAKRKTFSLVKEKKAARTLSAILLAF
ILTWTPYNIMVLVSTFCKDCVPETLWELGYWLCYVNSTINPMCYALCNKAFRDTFRLLLLCR
WDKRRWRKIPKRPGSVHRTPSRQC (SEQ ID NO:1187)
>gi|38194224|ref|NP_0052892| G protein-coupled receptor 25
{Homosapiens}
MAPTEPWSPSPGSAPWDYSGLDGLEELELCPAGDLPYGYVYIPALYLAAFAVGLLGNAFVV
WLLAGRRGPRRLVDTFVLHLAAADLGFVLTLPLWAAAAALGGRWPFGDGLCKLSSFALAG
TRCAGALLLAGMSVDRYLAVVKLLEARPLRTPRCALASCCGVWAVALLAGLPSLVYRGLQP
LPGGQDSQCGEEPSHAFQGLSLLLLLLTFVLPLVVTLFCYCRISRRLRRPPHVGRARRNSLRIIF
AIESTFVGSWLPFSALRAVFHLARLGALPLPCPLLLALRWGLTIATCLAFVNSCANPLIYLLLD
RSFRARALDGACGRTGRLARRISSASSLSRDDSSVFRCRAQAANTASASW (SEQ ID NO:1188)
>gi|38455410|ref|NP_9407991| growth hormone secretagogue
receptor type 1 isoform 1a {Homosapiens}
MWNATPSEEPGFNLTLADLDWDASPGNDSLGDELLQLFPAPLLAGVTATCVALFVVGIAGN
LLTMLVVSRFRELRTTTNLYLSSMAFSDLLIFLCMPLDLVRLWQYRPWNFGDLLCKLFQFVS
ESCTYATVLTITALSVERYFAICFPLRAKVVVTKGRVKLVIFVIVVAVAFCSAGPIFVLVGVEHE
NGTDPWDTNECRPTEFAVRSGLLTVMVWVSSIFFFLPVFCLTVLYSLIGRKLWRRRRGDAVV
GASLRDQNHKQTVKMLAVVVFAFILCWLPFHVGRYLFSKSFEPGSLEIAQISQYCNLVSFVLF
YLSAAINPILYNIMSKKYRVAVFRLLGFEPFSQRKLSTLKDESSRAWTESSINT (SEQ ID
NO:1189) >gi|38455413|ref|NP_0020213| N-formyl peptide receptor
3 {Homosapiens}
METNFSIPLNETEEVLPEPAGHTVLWIFSLLVHGVTFVFGVLGNGLVIVVVAGFRMTRTVNTIC
YLNLALADFSFSAILPFRMVSVAMREKWPFGSFLCKLVHVMIDINLFVSVYLITIIALDRCICV
LHPAWAQNHRTMSLAKRVMTGLWIFTIVLTLPNFIFVVTTISTTNGDTYCIFNFAFWGDTAVE
RLNVFITMAKVFLILHFIIGFSVPMSIITVCYGIIAAKIHRNHMIKSSRPLRVFAAVVASFFICWF
PYELIGILMAVWLKEMLLNGKYKIILVLINPTSSLAFFNSCLNPILYVFMGRNFQERLIRSLPTS
LERALTEVPDSAQTSNTDTTSASPPEETELQAM (SEQ ID NO:1190)
>gi|38505172|ref|NP_0009482| prostaglandin E receptor 3, subtype
EP3 isoform 1 {Homosapiens}
MKETRGYGGDAPFCTRLNHSYTGMWAPERSAEARGNLTRPPGSGEDCGSVSVAFPITMLLT
GFVGNALAMLLVSRSYRRRESKRKKSFLLCIGWLALTDLVGQLLTTPVVIVVYLSKQRWEHI
DPSGRLCTFFGLTMTVFGLSSLFIASAMAVERALAIRAPHWYASHMKTRATRAVLLGVWLA
VLAFALLPVLGVGQYTVQWPGTWCFISTGRGGNGTSSSHNVVGNLFFASAFAFLGLLALTVTF
SCNLATIKALVSRCRAKATASQSSAQWGRITTETAIQLMGIMCVLSVCWSPLLIMMLKMIFN
QTSVEHCKTHTEKQKECNFFLIAVRLASLNQILDPWVYLLLRKILLRKFCQMRKRRLREQAP
LLPTSTVIDPSRFCAQPFRWFLDLSFPAMSSSHPQLPLTLASFKLLREPCSVQLS (SEQ ID
NO:1191) >gi|38505194|ref|NP_0009462| prostaglandin E2 receptor
EP1 subtype {Homosapiens}
MSPCGPLNLSLAGEATTCAAPWVPNTSAVPPSGASPALPIFSMTLGAVSNLLALALLAQAAG
RLRRRRSAATFLLFVASLLATDLAGHVIPGALVLRLYTAGRAPAGGACHFLGGCMVFFGLCP
LLLGCGMAVERCVGVTRPLLHAARVSVARARLALAAVAAVALAVALLPLARVGRYELQYP
GTWCFIGLGPPGGWRQALLAGLFASLGLVALLAALVCNTLSGLALLRARWRRRSRRPPPAS
GPDSRRRWGAHGPRSASASSASSIASASTFFGGSRSSGSARRARAHDVEMVGQLVGIMVVSC
ICWSPMLVLVALAVGGWSSTSLQRPLFLAVRLASWNQILDPWVYILLRQAVLRQLLRLLPPR
AGAKGGPAGLGLTPSAWEASSLRSSRHSGLSHF (SEQ ID NO:1192)
>gi|38678524|ref|NP_8595281| opsin 5 isoform 1 {Homosapiens}
MALNHTALPQDERLPHYLRDGDPFASKLSWEADLVAGFYLTIIGILSTFGNGYVLYMSSRRK
KKLRPAEIMTINLAVCDLGISVVGKPFTIISCFCHRWVFGWIGCRWYGWAGFFFGCGSLITMT
AVSLDRYLKICYLSYGVWLKRKHAYICLAAIVVAYASFVVTTMPLVGLGDYVPEPFGTSCTLD
WWLAQASVGGQVFILNILFFCLLLPTAVIVFSYVKIIAKVKSSSKEVAHFDSRIHSSHVLEMKL
TKVAMLICAGFLIAWIPYAVVSVWSAFGRPDSIPIQLSVVPTLLAKSAAMYNPIIYQVIDYKFA
CCQTGGLKATKKKSLEGFRLHTVTTVRKSSAVLEIHEEWE (SEQ ID NO:1193)
>gi|38683844|ref|NP_0571672| cannabinoid receptor 1 isoform a
{Homosapiens}
MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTSFRGSPFQEKMT
AGDNPQLVPADQVNITEFYNKSLSSFKENEENIQCGENFMDIECFMVLNPSQQLAIAVLSLTL
GTFTVLENLLVLCVILHSRSLRCRPSYHFIGSLAVADLLGSVIFVYSFIDFHVFHRKDSRNVFLF
KLGGVTASFTASVGSLFLTAIDRYISIHRPLAYKRIVTRPKAVVAFCLMWTIAIVIAVLPLLGW
NCEKLQSVCSDIFPHIDETYLMFVVIGVTSVLLLFIVYAYMYILWKAHSHAVRMIQRGTQKSIII
HTSEDGKVQVTRPDQARMDIRLAKTLVLILVVLIICWGPLLAIMVYDVFGKMNKLIKTVFAF
CSMLCLLNSTVNPIIYALRSKDLRHAFRSMFPSCEGTAQPLDNSMGDSDCLHKHANNAASVH
RAAESCIKSTVKIAKVTMSVSTDTSAEAL (SEQ ID NO:1194)
>gi|38788193|ref|NP_0052172| sphingosine-1-phosphate receptor 3
{Homosapiens}
MATALPPRLQPVRGNETLREHYQYVGKLAGRLKEASEGSTLTTVLFLVICSFIVLENLMVLIA
IVVKNNKFHNRMYFFIGNLALCDLLAGIAYKVNILMSGKKTFSLSPTVWFLREGSMFVALGAS
TCSLLAIAIERHLTMIKMRPYDANKRHRVFLLIGMCWLIAFTLGALPILGWNCLHNLPDCSTIL
PLYSKKYIAFCISIFTAILVTIVILYARIYFLVKSSSRKVANHNNSERSMALLRTVVIVVSVFIAC
WSPLFILFLIDVACRVQACPILFKAQWFIVLAVLNSAMNPVIYTLASKEMRRAFFRLVCNCLV
RGRGARASPIQPALDPSRSKSSSSNNSSHSPKVKEDLPHTAPSSCIMDKNAALQNGIFCN (SEQ
ID NO:1195) >gi|39725940|ref|NP_0009032| kappa-type opioid
receptor {Homosapiens}
MDSPIQIFRGEPGPTCAPSACLPPNSSAWFPGWAEPDSNGSAGSEDAQLEPAHISPAIPVIITAV
YSVVFVVGLVGNSLVMFVIIRYTKMKTATNIYIFNLALADALVTTTMPFQSTVYLMNSWPFG
DVLCKIVISIDYYNMFTSIFTLTMMSVDRYIAVCHPVKALDFRTPLKAKIINICIVVLLSSSVGIS
AIVLGGTKVREDVDVIECSLQFPDDDYSWWDLFMKICVFIFAFVIPVLIIIVCYTLMILRLKSV
RLLSGSREKDRNLRRITRLVLVVVAVFVVCWTPIHIFILVEALGSTSHSTAALSSYYFCIALGY
TNSSLNPILYAFLDENFKRCFRDFCFPLKMRMERQSTSRVRNTVQDPAYLRDIDGMNKPV (SEQ
ID NO:1196) >gi|40217829|ref|NP_0034762| ovarian cancer
G-protein coupled receptor 1 {Homosapiens}
MRSVAPSGPKMGNITADNSSMSCTIDHTIHQTLAPVVYVTVLVVGFPANCLSLYFGYLQIKA
RNELGVYLCNLTVADLFYICSLPFVVLQYVLQHDNWSHGDLSCQVCGILLYENIYISVGFLCCI
SVDRYLAVAHPFRFHQFRTLKAAVGVSVVIWAKELLTSIYFLMHEEVIEDENQHRVCFEHYPI
QAWQRAINYYRFLVGFLFPICLLLASYQGILRAVRRSHGTQKSRKDQIQRLVLSTVVIFLACF
LPYHVLLLVRSVVVEASCDFAKGVFNAYHFSLLLTSFNCVADPVLYCFVSETTHRDLARLRGA
CLAFLTCSRTGRAREAYPLGAPEASGKSGAQGEEPELLTKLHPAFQTPNSPGSGGFPTGRLA (SEQ
ID NO:1197) >gi|40217833|ref|NP_0611233| G-protein coupled
receptor family C group 5 member C isoform b {Homosapiens}
MGTQPEPGLGARMAIHKALVMCLGLPLFLFPGAWAQGHVPPGCSQGLNPLYYNLCDRSGA
WGIVLEAVAGAGIVTTFVLTIILVASLPFVQDTKKRSLLGTQVFFLLGTLGLFCLVFACVVKP
DFSTCASRRFLFGVLFAICFSCLAAHVFALNFLARKNHGPRGWVIFTVALLLTLVEVIINTEWL
IITLVRGSGEGGPQGNSSAGWAVASPCAIANMDFVMALIYVMLLLLGAFLGAWPALCGRYK
RWRKHGVFVLLTTATSVAIWVVWIVMYTYGNKQHNSPTWDDPTLAIALAANAWAFVLFYV
IPEVSQVTKSSPEQSYQGDMYPTRGVGYETILKEQKGQSMFVENKAFSMDEPVAAKRPVSPY
SGYNGQLLTSVYQPTEMALMHKVPSEGAYDIILPRATANSQVMGSANSTLRAEDMYSAQSH
QAATPPKDGKNSQVFRNPYVVVD (SEQ ID NO:1198)
>gi|40255245|ref|NP_0054495| gamma-aminobutyric acid type B
receptor subunit 2 precursor {Homosapiens}
MASPRSSGQPGPPPPPPPPPARLLLLLLLPLLLPLAPGAWGWARGAPRPPPSSPPLSIMGLMPL
TKEVAKGSIGRGVLPAVELAIEQIRNESLLRPYFLDLRLYDTECDNAKGLKAFYDAIKYGPNH
LMVFGGVCPSVTSHAESLQGWNLVQLSFAATTPVLADKKKYPYFFRTVPSDNAVNPAILKLL
KHYQWKRVGTLTQDVQRFSEVRNDLTGVLYGEDIEISDTESFSNDPCTSVKKLKGNDVRIIL
GQFDQNMAAKVFCCAYEENMYGSKYQWIIPGWYEPSWWEQVHTEANSSRCLRKNLLAAM
EGYIGVDFEPLSSKQIKTISGKTPQQYEREYNNKRSGVGPSKFHGYAYDGIVVVIAKTLQRAM
ETLHASSRHQRIQDFNYTDHTLGRIILNAMNETNFFGVTGQVVFRNGERMGTIKFTQFQDSRE
VKVGEYNAVADTLEIINDTIRFQGSEPPKDKTIILEQLRKISLPLYSILSALTILGMIMASAFLFF
NIKNRNQKLIKMSSPYMNNLIILGGMLSYASIFLFGLDGSFVSEKTFETLCTVRTVVILTVGYTT
AFGAMFAKTWRVHAIFKNVKMKKKIIKDQKLLVIVGGMLLIDLCILICWQAVDPLRRTVEKY
SMEPDPAGRDISIRPLLEHCENTHMTIVVLGIVYAYKGLLMLFGCFLAWETRNVSIPALNDSKY
IGMSVYNVGIMCIIGAAVSFLTRDQPNVQFCIVALVIIFCSTITLCLVFVPKLITLRTNPDAATQ
NRRFQFTQNQKKEDSKTSTSVTSVNQASTSRLEGLQSENHRLRMKITELDKDLEEVTMQLQD
TPEKTTYIKQNHYQELNDILNLGNFTESTDGGKAILKNHLDQNPQLQWNTTEPSRTCKDPIED
INSPEHIQRRLSLQLPILHHAYLPSIGGVDASCVSPCVSPTASPRHRHVPPSFRVMVSGL (SEQ
ID NO:1199) >gi|40385873|ref|NP_9547131| G protein-coupled
receptor 150 {Homosapiens}
MEDLFSPSILPPAPNISVPILLGWGLNLTLGQGAPASGPPSRRVRLVFLGVILVVAVAGNTTVL
CRLCGGGGPWAGPKRRKMDFLLVQLALADLYACGGTALSQLAWELLGEPRAATGDLACRF
LQLLQASGRGASAHLVVLIALERRRAVRLPHGRPLPARALAALGWLLALLLALPPAFVVRGD
SPSPLPPPPPPTSLQPGAPPAARAWPGERRCHGIFAPLPRWHLQVYAFYEAVAGFVAPVTVLG
VACGHLLSVWWRHRPQAPAAAAPWSASPGRAPAPSALPRAKVQSLKMSLLLALLFVGCELP
YFAARLAAAWSSGPAGDWEGEGLSAALRVVAMANSALNPFVYLFFQAGDCRLRRQLRKRL
GSLCCAPQGGAEDEEGPRGHQALYRQRWPHPHYHHARREPLDEGGLRPPPPRPRPLPCSCES AF
(SEQ ID NO:1200) >gi|40807489|ref|NP_0019653| EGF-like
module-containing mucin-like hormone receptor-like 1 precursor
{Homosapiens}
MRGFNLLLFWGCCVMHSWEGHIRPTRKPNTKGNNCRDSTLCPAYATCTNTVDSYYCACKQ
GFLSSNGQNHFKDPGVRCKDIDECSQSPQPCGPNSSCKNLSGRYKCSCLDGFSSPTGNDWVP
GKPGNFSCTDINECLTSSVCPEHSDCVNSMGSYSCSCQVGFISRNSTCEDVDECADPRACPEH
ATCNNTVGNYSCFCNPGFESSSGHLSFQGLKASCEDIDECTEMCPINSTCTNTPGSYFCTCHP
GFAPSNGQLNFTDQGVECRDIDECRQDPSTCGPNSICTNALGSYSCGCIAGFHPNPEGSQKDG
NFSCQRVLFKCKEDVIPDNKQIQQCQEGTAVKPAYVSFCAQINNIFSVLDKVCENKTTVVSLK
NTTESFVPVLKQISTWTKFTKEETSSLATVFLESVESMTLASFVVKPSANITPAVRTEYLDIESK
VINKECSEENVTLDLVAKGDKMKIGCSTIEESESTETTGVAFVSFVGMESVLNERFFKDHQAP
LTTSEIKLKMNSRVVGGIMTGEKKDGFSDPIIYTLENIQPKQKFERPICVSWSTDVKGGRWTS
FGCVILEASETYTICSCNQMANLAVIMASGELTMDFSLYIISHVGIIISLVCLVLAIATFLLCRSI
RNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLACFFVVMLVEAVILFL
MVRNLKVVNYFSSRNIKMLHICAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIVVS
FLGPVCTVIVINSLLLTWTLWILRQRLSSVNAEVSTLKDTRLLTFKAFAQLFILGCSWVLGIFQI
GPVAGVMAYLFTIINSLQGAFIFLIHCLLNGQVREEYKRWITGKTKPSSQSQTSRILLSSMPSA
SKT (SEQ ID NO:1201) >gi|41281557|ref|NP_05573621| atrophilin-1
isoform 2 precursor {Homosapiens}
MARLAAVLWNLCVTAVLVTSATQGLSRAGLPFGLMRRELACEGYPIELRCPGSDVIMVENA
NYGRTDDKICDADPFQMENVQCYLPDAFKIMSQRCNNRTQCVVVAGSDAFPDPCPGTYKYL
EVQYDCVPYIFVCPGTLQKVLEPTSTHESEHQSGAWCKDPLQAGDRIYVMPWIPYRTDTLTE
YASWEDYVAARHTTTYRLPNRVDGTGFVVYDGAVFYNKERTRNIVKYDLRTRIKSGETVIN
TANYHDTSPYRWGGKTDIDLAVDENGLWVIYATEGNNGRLVVSQLNPYTLRFEGTWETGY
DKRSASNAFMVCGVLYVLRSVYVDDDSEAAGNRVDYAFNTNANREEPVSLTFPNPYQFISS
VDYNPRDNQLYVWNNYFVVRYSLEFGPPDPSAGPATSPPLSTTTTARPTPLTSTASPAATTPL
RRAPLTTHPVGAINQLGPDLPPATAPVPSTRRPPAPNLHVSPELFCEPREVRRVQWPATQQGM
LVERPCPKGTRGIASFQCLPALGLWNPRGPDLSNCTSPWVNQVAQKIKSGENAANIASELAR
HTRGSIYAGDVSSSVKLMEQLLDILDAQLQALRPIERESAGKNYNKMHKRERTCKDYIKAVV
ETVDNLLRPEALESWKDMNATEQVHTATMLLDVLEEGAFLLADNVREPARFLAAKENVVL
EVTVLNTEGQVQELVFPQEEYPRKNSIQLSAKTIKQNSRNGVVKVVFILYNNLGLFLSTENAT
VKLAGEAGPGGPGGASLVVNSQVIAASINKESSRVFLMDPVIFTVAHLEDKNHFNANCSFVVN
YSERSMLGYWSTQGCRLVESNKTHTTCACSHLTNFAVLMAHREIYQGRINELLLSVITWVGI
VISLVCLAICISTFCFLRGLQTDRNTIHKNLCINLFLAELLFLVGIDKTQYEIACPIFAGLLHYFF
LAAFSWLCLEGVHLYLLLVEVFESEYSRTKYYYLGGYCFPALVVGIAAAIDYRSYGTEKAC
WLRVDNYFIVVSFIGPVSFVIVVNLVFLMVTLHKMIRSSSVLKPDSSRLDNIKSWALGAIALLF
LLGLTWAFGLLFINKESVVMAYLFTTFNAFQGVFIFVFHCALQKKVHKEYSKCLRHSYCCIRS
PPGGTHGSLKTSAMRSNTRYYTGTQSRIRRMWNDTVRKQTESSFMAGDINSTPTLNRGTMG
NHLLTNPVLQPRGGTSPYNTLIAESVGFNPSSPPVFNSPGSYREPKHPLGGREACGMDTLPLN
GNFNNSYSLRSGDFPPGDGGPEPPRGRNLADAAAFEKMIISELVHNNLRGSSSAAKGPPPPEP
PVPPVPGGGGEEEAGGPGGADRAEIELLYKALEEPLLLPRAQSVLYQSDLDESESCTAEDGAT
SRPLSSPPGRDSLYASGANLRDSPSYPDSSPEGPSEALPPPPPAPPGPPEIYYTSRPPALVARNPL
QGYYQVRRPSHEGYLAAPGLEGPGPDGDGQMQLVTSL (SEQ ID NO:1202)
>gi|41584200|ref|NP_0056733| G-protein coupled receptor 56
isoform a precursor {Homosapiens }
MTPQSLLQTTLFLLSLLFLVQGAHGRGHREDFRFCSQRNQTHRSSLHYKPTPDLRISIENSEEA
LTVHAPFPAAHPASRSFPDPRGLYHFCLYWNRHAGRLHLLYGKRDFLLSDKASSLLCFQHQE
ESLAQGPPLLATSVTSWWSPQNISLPSAASFTFSFHSPPHTAAHNASVDMCELKRDLQLLSQF
LKHPQKASRRPSAAPASQQLQSLESKLTSVRFMGDMVSFEEDRINATVWKLQPTAGLQDLHI
HSRQEEEQSEIMEYSVLLPRTLFQRTKGRSGEAEKRLLLVDFSSQALFQDKNSSQVLGEKVLG
IVVQNTKVANLTEPVVLTFQHQLQPKNVTLQCVFVVVEDPTLSSPGHWSSAGCETVRRETQTS
CFCNHLTYFAVLMVSSVEVDAVHKHYLSLLSYVGCVVSALACLVTIAAYLCSRVPLPCRRKP
RDYTIKVHMNLLLAVFLLDTSFLLSEPVALTGSEAGCRASAIFLHFSLLTCLSWMGLEGYNLY
RLVVEVFGTYVPGYLLKLSAMGWGFPIFLVTLVALVDVDNYGPIILAVHRTPEGVIYPSMCW
IRDSLVSYITNLGLFSLVFLFNMAMLATMVVQILRLRPHTQKWSHVLTLLGLSLVLGLPWALI
FFSFASGTFQLVVLYLFSIITSFQGFLIFIVVYVVSMRLQARGGPSPLKSNSDSARLPISSGSTSSSR
I (SEQ ID NO:1203) >gi|42794265|ref|NP_9446052| mas-related
G-protein coupled receptor member D {Homosapiens}
MNQTLNSSGTVESALNYSRGSTVHTAYLVLSSLAMFTCLCGMAGNSMVIVVLLGFRMHRNPF
CIYILNLAAADLLFLFSMASTLSLETQPLVNTTDKVHELMKRLMYFAYTVGLSLLTAISTQRC
LSVLFPIVVFKCHRPRHLSAWVCGLLWTLCLLMNGLTSSFCSKFLKFNEDRCFRVDMVQAALI
MGVLTPVMTLSSLTLFVWVRRSSQQWRRQPTRLFVVVLASVLVFLICSLPLSIYWFVLYWLS
LPPEMQVLCFSLSRLSSSVSSSANPVIYFLVGSRRSHRLPTRSLGTVLQQALREEPELEGGETPT
VGTNEMGA (SEQ ID NO:1204) >gi|42822887|ref|NP_0020272| Duffy
blood group antigen isoform b {Homosapiens}
MGNCLHRAELSPSTENSSQLDFEDVWNSSYGVNDSFPDGDYGANLEAAAPCHSCNLLDDSA
LPFFILTSVLGILASSTVLFMLFRPLFRWQLCPGWPVLAQLAVGSALFSIVVPVLAPGLGSTRS
SALCSLGYCVWYGSAFAQALLLGCHASLGHRLGAGQVPGLTLGLTVGIVVGVAALLTLPVTL
ASGASGGLCTLIYSTELKALQATHTVACLAIFVLLPLGLFGAKGLKKALGMGPGPWMNILW
AWFIFVVWPHGVVLGLDFLVRSKLLLLSTCLAQQALDLLLNLAEALAILHCVATPLLLALFCH
QATRTLLPSLPLPEGWSSHLDTLGSKS (SEQ ID NO:1205)
>gi|45433552|ref|NP_9421222| probable G-protein coupled receptor
133 precursor {Homosapiens}
MEKLLRLCCWYSWLLLFYYNFQVRGVYSRSQDHPGFQVLASASHYWPLENVDGIHELQDT
TGDIVEGKVNKGIYLKEEKGVTLLYYGRYNSSCISKPEQCGPEGVTFSFFWKTQGEQSRPIPS
AYGGQVISNGFKVCSSGGRGSVELYTRDNSMTWEASFSPPGPYVVTHVLFTVVKSKEGLKVYV
NGTLSTSDPSGKVSRDYGESNVNLVIGSEQDQAKCYENGAFDEFIIVVERALTPDEIAMYFTAA
IGKHALLSSTLPSLFMTSTASPVMPTDAYHPIITNLTEERKTFQSPGVILSYLQNVSLSLPSKSLS
EQTALNLTKTFLKAVGEILLLPGWIALSEDSAVVLSLIDTIDTVMGHVSSNLHGSTPQVTVEG
SSAMAEFSVAKILPKTVNSSHYRFPAHGQSFIQIPHEAFHRHAWSTVVGLLYHSMHYYLNNI
WPAHTKIAEAMHHQDCLLFATSHLISLEVSPPPTLSQNLSGSPLITVHLKHRLTRKQHSEATNS
SNRVFVYCAFLDFSSGEGVVVSNHGCALTRGNLTYSVCRCTHLTNFAILMQVVPLELARGHQ
VALSSISYVGCSLSVLCLVATLVTFAVLSSVSTIRNQRYHIHANLSFAVLVAQVLLLISFRLEP
GTTPCQVMAVLLHYFFLSAFAWMLVEGLHLYSMVIKVFGS EDSKHRYYYGMGWGFPLLICI
ISLSFAMDSYGTSNNCWLSLASGAIWAFVAPALFVIVVNIGILIAVTRVISQISADNYKIHGDPS
AFKLTAKAVAVLLPILGTSWVFGVLAVNGCAVVFQYMFATLNSLQGLFIFLFHCLLNSEVRA
AFKHKTKVWSLTSSSARTSNAKPFHSDLMNGTRPGMASTKLSPWDKSSHSAHRVDLSAV (SEQ ID
NO:1206) >gi|4624367 1 |ref|NP_9968801| G protein-coupled
receptor 152 {Homosapiens }
MDTTMEADLGATGHRPRTELDDEDSYPQGGWDTVFLVALLLLGLPANGLMAWLAGSQAR
HGAGTRLALLLLSLALSDFLFLAAAAFQILEIRHGGHWPLGTAACRFYYFLWGVSYSSGLFLL
AALSLDRCLLALCPHWYPGHRPVRLPLWVCAGVWVLATLFSVPWLVFPEAAVWWYDLVIC
LDFWDSEELSLRMLEVLGGFLPFLLLLVCHVLTQATACRTCHRQQQPAACRGFARVARTILS
AYVVLRLPYQLAQLLYLAFLWDVYSGYLLWEALVYSDYLILLNSCLSPFLCLMASADLRTLL
RSVLSSFAAALCEERPGSFTPTEPQTQLDSEGPTLPEPMAEAQSQMDPVAQPQVNPTLQPRSD
PTAQPQLNPTAQPQSDPTAQPQLNLMAQPQSDSVAQPQADTNVQTPAPAASSVPSPCDEASP
TPSSHPTPGALEDPATPPASEGESPSSTPPEAAPGAGPT (SEQ ID NO:1207)
>gi|46358417|ref|NP_0008312| metabotropic glutamate receptor 3
precursor {Homosapiens}
MKMLTRLQVLTLALFSKGFLLSLGDHNFLRREIKIEGDLVLGGLFPINEKGTGTEECGRINED
RGIQRLEAMLFAIDEINKDDYLLPGVKLGVHILDTCSRDTYALEQSLEFVRASLTKVDEAEY
MCPDGSYAIQENIPLLIAGVIGGSYSSVSIQVANLLRLFQIPQISYASTSAKLSDKSRYDYFART
VPPDFYQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFEQEARLRNICIATAEKVGRSNIR
KSYDSVIRELLQKPNARVVVLFMRSDDSRELIAAASRANASFTWVASDGWGAQESIIKGSEH
VAYGAITLELASQPVRQFDRYFQSLNPYNNHRNPWFRDFWEQKFQCSLQNKRNHRRVCDK
HLAIDSSNYEQESKIMFVVNAVYAMAHALHKMQRTLCPNTTKLCDAMKILDGKKLYKDYL
LKINFTAPFNPNKDADSIVKFDTFGDGMGRYNVFNFQNVGGKYSYLKVGHWAETLSLDVNS
IHWSRNSVPTSQCSDPCAPNEMKNMQPGDVCCWICIPCEPYEYLADEFTCMDCGSGQWPTA
DLTGCYDLPEDYIRWEDAWAIGPVTIACLGFMCTCMVVTVFIKHNNTPLVKASGRELCYILL
FGVGLSYCMTFFFIAKPSPVICALRRLGLGSSFAICYSALLTKTNCIARIFDGVKNGAQRPKFIS
PSSQVFICLGLILVQIVMVSVWLILEAPGTRRYTLAEKRETVILKCNVKDSSMLISLTYDVILVI
LCTVYAFKTRKCPENFNEAKFIGFTMYTTCIIVVLAFLPIFYVTSSDYRVQTTTMCISVSLSGFV
VLGCLFAPKVHIILFQPQKNVVTHRLHLNRFSVSGTGTTYSQSSASTYVPTVCNGREVLDSTT SSL
(SEQ ID NO:1208) >gi|46395496|ref|NP_9970551| neuropeptide S
receptor isoform A {Homosapiens}
MPANFTEGSFDSSGTGQTLDSSPVACTETVTFTEVVEGKEWGSFYYSFKTEQLITLWVLFVFT
IVGNSVVLFSTVVRRKKKSRMTFFVTQLAITDSFTGLVNILTDINWRFTGDFTAPDLVCRVVRY
LQVVLLYASTYVLVSLSIDRYHAIVYPMKFLQGEKQARVLIVIAWSLSFLFSIPTLIIFGKRTLS
NGEVQCWALWPDDSYWTPYMTIVAFLVYFIPLTIISIMYGIVIRTIVVIKSKTYETVISNCSDGK
LCSSYNRGLISKAKIKAIKYSIIIILAFICCWSPYFLFDILDNFNLLPDTQERFYASVIIQNLPALN
SAINPLIYCVFSSSISFPCREQRSQDSRMTFRERTERHEMQILSKPEFI (SEQ ID NO:1209)
>gi|47271392|ref|NP_1490392| succinate receptor 1 {Homosapiens}
MLGIMAWNATCKNWLAAEAALEKYYLSIFYGIEFVVGVLGNTIVVYGYIFSLKNWNSSNIYL
FNLSVSDLAFLCTLPMLIRSYANGNWIYGDVLCISNRYVLHANLYTSILFLTFISIDRYLIIKYPF
REHLLQKKEFAILISLAIWVLVTLELLPILPLINPVITDNGTTCNDFASSGDPNYNLIYSMCLTL
LGFLIPLFVMCFFYYKIALFLKQRNRQVATALPLEKPLNLVIMAVVIFSVLFTPYHVMRNVRI
ASRLGSWKQYQCTQVVINSFYIVTRPLAFLNSVINPVFYFLLGDHFRDMLMNQLRHNFKSLT
SFSRWAHELLLSFREK (SEQ ID NO:1210)
>gi|50897278|ref|NP_0010029111| probable G-protein coupled
receptor 139 {Homosapiens}
MEHTHAHLAANSSLSWWSPGSACGLGFVPVVYYSLLLCLGLPANILTVIILSQLVARRQKSS
YNYLLALAAADILVLFFIVFVDFLLEDFILNMQMPQVPDKIIEVLEFSSIHTSIVVITVPLTIDRYI
AVCHPLKYHTVSYPARTRKVIVSVYITCFLTSIPYYWWPNIVVTEDYISTSVHHVLIWIHCFTV
YLVPCSIFFILNSIIVYKLRRKSNFRLRGYSTGKTTAILFTITSIFATLWAPRIIMILYHLYGAPIQ
NRWLVHIMSDIANMLALLNTAINFFLYCFISKRFRTMAAATLKAFFKCQKQPVQFYTNHNFSI
TSSPWISPANSHCIKMLVYQYDKNGKPIKVSP (SEQ ID NO:1211)
>gi|52426748|ref|NP_0007322| cholinergic receptor, muscarinic 4
{Homosapiens}
MANFTPVNGSSGNQSVRLVTSSSHNRYETVEMVFIATVTGSLSLVTVVGNILVMLSIKVNRQ
LQTVNNYFLFSLACADLIIGAFSMNLYTVYIIKGYWPLGAVVCDLWLALDYVVSNASVMNL
LIISFDRYFCVTKPLTYPARRTTKMAGLMIAAAWVLSFVLWAPAILFWQFVVGKRTVPDNQC
FIQFLSNPAVTFGTAIAAFYLPVVIMTVLYIHISLASRSRVHKHRPEGPKEKKAKTLAFLKSPL
MKQSVKKPPPGEAAREELRNGKLEEAPPPALPPPPRPVADKDTSNESSSGSATQNTKERPATE
LSTTEATTPAMPAPPLQPRALNPASRWSKIQIVTKQTGNECVTAIEIVPATPAGMRPAANVAR
KFASIARNQVRKKRQMAARERKVTRTIFAILLAFILTWTPYNVMVLVNTFCQSCIPDTVWSIG
YWLCYVNSTINPACYALCNATFKKTFRHLLLCQYRNIGTAR (SEQ ID NO:1212)
>gi|52426789|ref|NP_5430083| 2-oxoglutarate receptor 1
{Homosapiens}
MNEPLDYLANASDFPDYAAAFGNCTDENIPLKMHYLPVIYGIIFLVGFPGNAVVISTYIFKMR
PWKSSTIIMLNLACTDLLYLTSLPFLIHYYASGENWIFGDFMCKFIRFSFHFNLYSSILFLTCFSI
FRYCVIIHPMSCFSIHKTRCAVVACAVVWIISLVAVIPMTFLITSTNRTNRSACLDLTSSDELNT
IKWYNLILTATTFCLPLVIVTLCYTTIIHTLTHGLQTDSCLKQKARRLTILLLLAFYVCFLPFHIL
RVIRIESRLLSISCSIENQIHEAYIVSRPLAALNTFGNLLLYVVVSDNFQQAVCSTVRCKVSGNL
EQAKKISYSNNP (SEQ ID NO:1213) >gi|53828924|ref|NP_0052762|
neuropeptides B/W receptor type 1 {Homosapiens}
MDNASFSEPWPANASGPDPALSCSNASTLAPLPAPLAVAVPVVYAVICAVGLAGNSAVLYV
LLRAPRMKTVTNLFILNLAIADELFTLVLPINIADFLLRQWPFGELMCKLIVAIDQYNTFSSLY
FLTVMSADRYLVVLATAESRRVAGRTYSAARAVSLAVWGIVTLVVLPFAVFARLDDEQGRR
QCVLVFPQPEAFWWRASRLYTLVLGFAIPVSTICVLYTTLLCRLHAMRLDSHAKALERAKKR
VTFLVVAILAVCLLCWTPYHLSTVVALTTDLPQTPLVIAISYFITSLSYANSCLNPFLYAFLDA
SFRRNLRQLITCRAAA (SEQ ID NO:1214) >gi|55953085|ref|NP_8595292|
G-protein coupled receptor 120 {Homosapiens}
MSPECARAAGDAPLRSLEQANRTRFPFFSDVKGDHRLVLAAVETTVLVLIFAVSLLGNVCAL
VLVARRRRRGATACLVLNLFCADLLFISAIPLVLAVRWTEAWLLGPVACHLLFYVMTLSGSV
TILTLAAVSLERMVCIVHLQRGVRGPGRRARAVLLALIVVGYSAVAALPLCVFFRVVPQRLPG
ADQEISICTLIVVPTIPGEISWDVSFVTLNFLVPGLVIVISYSKILQTSEHLLDARAVVTHSEITKA
SRKRLTVSLAYSESHQIRVSQQDFRLFRTLFLLMVSFFIMWSPIIITILLILIQNFKQDLVIVVPSLF
FVVVVAFTFANSALNPILYNMTLCRNEWKKIFCCFVVFPEKGAILTDTSVKRNDLSIISG (SEQ
ID NO:1215) >gi|55956923|ref|NP_0005152| 5-hydroxytryptamine
receptor 1A {Homosapiens}
MDVLSPGQGNNTTSPPAPFETGGNTTGISDVTVSYQVITSLLLGTLIFCAVLGNACVVAAIAL
ERSLQNVANYLIGSLAVTDLMVSVLVLPMAALYQVLNKWTLGQVTCDLFIALDVLCCTSSIL
HLCAIALDRYWAITDPIDYVNKRTPRRAAALISLTWLIGFLISIPPMLGWRTPEDRSDPDACTIS
KDHGYTIYSTFGAFYIPLLLMLVLYGRIFRAARFRIRKTVKKVEKTGADTRHGASPAPQPKKS
VNGESGSRNWRLGVESKAGGALCANGAVRQGDDGAALEVIEVHRVGNSKEHLPLPSEAGPT
PCAPASFERKNERNAEAKRKMALARERKTVKTLGIIMGTFILCWLPFFIVALVLPFCESSCHM
PTLLGAIINWLGYSNSLLNPVIYAYFNKDFQNAFKKIIKCKFCRQ (SEQ ID NO:1216)
>gi|57165355|ref|NP_0010087011| latrophilin-1 is oform 1
precursor {Homosapiens}
MARLAAVLWNLCVTAVLVTSATQGLSRAGLPFGLMRRELACEGYPIELRCPGSDVIMVENA
NYGRTDDKICDADPFQMENVQCYLPDAFKIMSQRCNNRTQCVVVAGSDAFPDPCPGTYKYL
EVQYDCVPYKVEQKVFVCPGTLQKVLEPTSTHESEHQSGAWCKDPLQAGDRIYVMPWIPYR
TDTLTEYASWEDYVAARHTTTYRLPNRVDGTGFVVYDGAVFYNKERTRNIVKYDLRTRIKS
GETVINTANYHDTSPYRWGGKTDIDLAVDENGLWVIYATEGNNGRLVVSQLNPYTLRFEGT
WETGYDKRSASNAFMVCGVLYVLRSVYVDDDSEAAGNRVDYAFNTNANREEPVSLTFPNP
YQFISSVDYNPRDNQLYVWNNYFVVRYSLEFGPPDPSAGPATSPPLSTTTTARPTPLTSTASPA
ATTPLRRAPLTTHPVGAINQLGPDLPPATAPVPSTRRPPAPNLHVSPELFCEPREVRRVQWPA
TQQGMLVERPCPKGTRGIASFQCLPALGLWNPRGPDLSNCTSPWVNQVAQKIKSGENAANIA
SELARHTRGSIYAGDVSSSVKLMEQLLDILDAQLQALRPIERESAGKNYNKMHKRERTCKDY
IKAVVETVDNLLRPEALESWKDMNATEQVHTATMLLDVLEEGAFLLADNVREPARFLAAKE
NVVLEVTVLNTEGQVQELVFPQEEYPRKNSIQLSAKTIKQNSRNGVVKVVFILYNNLGLFLST
ENATVKLAGEAGPGGPGGASLVVNSQVIAASINKESSRVFLMDPVIFTVAHLEDKNHFNANC
SFVVNYSERSMLGYWSTQGCRLVESNKTHTTCACSHLTNFAVLMAHREIYQGRINELLLSVIT
WVGIVISLVCLAICISTFCFLRGLQTDRNTIHKNLCINLFLAELLFLVGIDKTQYEIACPIFAGLL
HYFFLAAFSWLCLEGVHLYLLLVEVFESEYSRTKYYYLGGYCFPALVVGIAAAIDYRSYGTE
KACWLRVDNYFIWSFIGPVSFVIVVNLVFLMVTLHKMIRSSSVLKPDSSRLDNIKSWALGAIA
LLFLLGLTWAFGLLFINKESVVMAYLFTTFNAFQGVFIFVFHCALQKKVHKEYSKCLRHSYC
CIRSPPGGTHGSLKTSAMRSNTRYYTGTQSRIRRMWNDTVRKQTESSFMAGDINSTPTLNRG
TMGNHLLTNPVLQPRGGTSPYNTLIAESVGFNPSSPPVFNSPGSYREPKHPLGGREACGMDTL
PLNGNFNNSYSLRSGDFPPGDGGPEPPRGRNLADAAAFEKMIISELVHNNLRGSSSAAKGPPP
PEPPVPPVPGGGGEEEAGGPGGADRAEIELLYKALEEPLLLPRAQSVLYQSDLDESESCTAED
GATSRPLSSPPGRDSLYASGANLRDSPSYPDSSPEGPSEALPPPPPAPPGPPEIYYTSRPPALVA
RNPLQGYYQVRRPSHEGYLAAPGLEGPGPDGDGQMQLVTSL (SEQ ID NO:1217)
>gi|57165371|ref|NP_1141423| probable G-protein coupled receptor
61 {Homosapiens}
MESSPIPQSSGNSSTLGRVPQTPGPSTASGVPEVGLRDVASESVALFFMLLLDLTAVAGNAAV
MAVIAKTPALRKFVFVFHLCLVDLLAALTLMPLAMLSSSALFDHALFGEVACRLYLFLSVCF
VSLAILSVSAINVERYYYVVHPMRYEVRMTLGLVASVLVGVWVKALAMASVPVLGRVSWE
EGAPSVPPGCSLQWSHSAYCQLFVVVFAVLYFLLPLLLILVVYCSMFRVARVAAMQHGPLPT
WMETPRQRSESLSSRSTMVTSSGAPQTTPHRTFGGGKAAVVLLAVGGQFLLCWLPYFSFHLY
VALSAQPISTGQVESVVTWIGYFCFTSNPFFYGCLNRQIRGELSKQFVCFFKPAPEEELRLPSR
EGSIEENFLQFLQGTGCPSESWVSRPLPSPKQEPPAVDFRIPGQIAEETSEFLEQQLTSDIIMSDS
YLRPAASPRLES (SEQ ID NO:1218) >gi|57977305|ref|NP_9192272| G
protein-coupled receptor 151 {Homosapiens}
MLAAAFADSNSSSMNVSFAHLHFAGGYLPSDSQDWRTIIPALLVAVCLVGFVGNLCVIGILL
HNAWKGKPSMIHSLILNLSLADLSLLLFSAPIRATAYSKSVWDLGWFVCKSSDWFIHTCMAA
KSLTIVVVAKVCFMYASDPAKQVSIHNYTIWSVLVAIWTVASLLPLPEWFFSTIRHHEGVEM
CLVDVPAVAEEFMSMFGKLYPLLAFGLPLFFASFYFWRAYDQCKKRGTKTQNLRNQIRSKQ
VTVMLLSIAIISALLWLPEWVAWLWVVVHLKAAGPAPPQGFIALSQVLMFSISSANPLIFLVMS
EEFREGLKGVWKWMITKKPPTVSESQETPAGNSEGLPDKVPSPESPASIPEKEKPSSPSSGKGK
TEKAEIPILPDVEQFVVHERDTVPSVQDNDPIPWEHEDQETGEGVK (SEQ ID NO:1219)
>gi|58530851|ref|NP_0008142| growth hormone-releasing hormone
receptor isoform a precursor {Homosapiens}
MDRRMWGAHVFCVLSPLPTVLGHMHPECDFITQLREDESACLQAAEEMPNTTLGCPATWD
GLLCWPTAGSGEWVTLPCPDFFSHFSSESGAVKRDCTITGWSEPFPP YPVACPVPLELLAEEE
SYFSTVKIIYTVGHSISIVALFVAITILVALRRLHCPRNYVHTQLFTTFILKAGAVFLKDAALFH
SDDTDHCSFSTVLCKVSVAASHFATMTNFSWLLAEAVYLNCLLASTSPSSRRAFWWLVLAG
WGLPVLFTGTWVSCKLAFEDIACWDLDDTSPYVVWIIKGPIVLSVGVNFGLFLNIIRILVRKLE
PAQGSLHTQSQYWRLSKSTLFLIPLFGIHYIIFNFLPDNAGLGIRLPLELGLGSFQGFIVAILYCF
LNQEVRTEISRKWHGHDPELLPAWRTRAKWTTPSRSAAKVLTSMC (SEQ ID NO:1220)
>gi|59710093|ref|NP_7225763| probable G-protein coupled receptor
112 {Homosapiens}
MKEHIIYQKLYGLILMSSFIFLSDTLSLKGKKLDFFGRGDTYVSLIDTIPELSRFTACIDLVFMD
DNSRYWMAFSYITNNALLGREDIDLGLAGDHQQLILYRLGKTFSIRHHLASFQWHTICLIVVD
GVKGKLELFLNKERILEVTDQPHNLTPHGTLFLGHFLKNESSEVKSMMRSFPGSLYYFQLWD
HILENEEFMKCLDGNIVSWEEDVWLVNKIIPTVDRTLRCFVPENMTIQEKSTTVSQQIDMTTP
SQITGVKPQNTAHSSTLLSQSIPIFATDYTTISYSNTTSPPLETMTAQKILKTLVDETATFAVDV
LSTSSAISLPTQSISIDNTTNSMKKTKSPSSESTKTTKMVEAMATEIFQPPTPSNFLSTSRFTKNS
VVSTTSAIKSQSAVTKTTSLFSTIESTSMSTTPCLKQKSTNTGALPISTAGQEFIESTAAGTVPW
FTVEKTSPASTHVGTASSFPPEPVLISTAAPVDSVFPRNQTAFPLATTDMKIAFTVHSLTLPTRL
IETTPAPRTAETELTSTNFQDVSLPRVEDAMSTSMSKETSSKTFSFLTSFSFTGTESVQTVIDAE
ATRTALTPEITLASTVAETMLSSTITGRVYTQNTPTADGHLLTLMSTRSASTSKAPESGPTSTT
DEAAHLFSSNETIVVTSRPDQALLASMNTTTILTFVPNENFTSAFHENTTYTEYLSATTNITPLK
ASPEGKGTTANDATTARYTTAVSKLTSPWFANFSIVSGTTSITNMPEFKLTTLLLKTIPMSTKP
ANELPLTPRETVVPSVDIISTLACIQPNFSTEESASETTQTEINGAIVFGGTTTPVPKSATTQRLN
ATVTRKEATSHYLMRKSTIAAVAEVSPFSTMLEVTDESAQRVTASVTVSSFPDIEKLSTPLDN
KTATTEVRESWLLTKLVKTTPRSSYNEMTEMFNFNHTYVAHWTSETSEGISAGSPTSGSTHIF
GEPLGASTTRIS TSFSTTPTDRTATSLSDGILPPQPTAAHSSATPVPVTHMFSLPVNGSSVVAE
ETEVTMSEPSTLARAFSTSVLSDVSNLSSTTMTTALVPPLDQTASTTIVIVPTHGDLIRTTSEAT
VISVRKTSMAVPSLTETPFHSLRLSTPVTAKAETTLFSTSVDTVTPSTHTLVCSKPPPDNIPPAS
STHVISTTSTPEATQPISQVEETSTYALSFPYTFSGGGVVASLATGTTETSVVDETTPSHISANK
LTTSVNSHISSSATYRVHTPVSIQLVTSTSVLSSDKDQMTISLGKTPRTMEVTEMSPSKNSFISY
SRGTPSLEMTDTGFPETTKISSHQTHSPSEIPLGTPSDGNLASSPTSGSTQITPTLTSSNTVGVHI
PEMSTSLGKTALPSQALTITTFLCPEKESTSALPAYTPRTVEMIVNSTYVTHSVSYGQDTSFVD
TTTSSSTRISNPMDINTTFSHLHSLRTQPEVTSVASFISESTQTFPESLSLSTAGLYNDGFTVLSD
RITTAFSVPNVPTMLPRESSMATSTPIYQMSSLPVNVTAFTSKKVSDTPPIVITKSSKTMHPGC
LKSPCTATSGPMSEMSSIPVNNSAFTPATVSSDTSTRVGLFSTLLSSVTPRTTMTMQTSTLDVT
PVIYAGATSKNKMVSSAFTTEMIEAPSRITPTTFLSPTEPTLPFVKTVPTTIMAGIVTPFVGTTA
FSPLSSKSTGAISSIPKTTFSPFLSATQQSSQADEATTLGILSGITNRSLSTVNSGTGVALTDTYS
RITVPENMLSPTHADSLHTSFNIQVSPSLTSFKSASGPTKNVKTTTNCFSSNTRKMTSLLEKTS
LTNYATSLNTPVSYPPWTPSSATLPSLTSFVYSPHSTEAEISTPKTSPPPTSQMVEFPVLGTRMT
SSNTQPLLMTSWNIPTAEGSQFPISTTINVPTSNEMETETLHLVPGPLSTFTASQTGLVSKDVM
AMSSIPMSGILPNHGLSENPSLSTSLRAITSTLADVKHTFEKMTTSVTPGTTLPSILSGATSGSVI
SKSPILTVVLLSSLPSGSPPATVSNAPHVMTSSTVEVSKSTFLTSDMISAHPFTNLTTLPSATMST
ILTRTIPTPTLGGITTGFPTSLPMSINVTDDIVYISTHPEASSRTTITANPRTVSHPSSFSRKTMSP
STTDHTLSVGAMPLPSSTITSSWNRIPTASSPSTLIIPKPTLDSLLNIMTTTSTVPGASFPLISTGV
TYPFTATVSSPISSFFETTVVLDSTPSFLSTEASTSPTATKSTVSFYNVEMSFSVFVEEPRIPITSVI
NEFTENSLNSIFQNSEFSLATLETQIKSRDISEEEMVMDRAILEQREGQEMATISYVPYSCVCQ
VIIKASSSLASSELMRKIKSKIHGNFTHGNFTQDQLTLLVNCEHVAVKKLEPGNCKADETASK
YKGTYKWLLTNPTETAQTRCIKNEDGNATRFCSISINTGKSQWEKPKFKQCKLLQELPDKIV
DLANITISDENAEDVAEHILNLINESPALGKEETKIIVSKISDISQCDEISMNLTHVMLQIINVVL
EKQNNSASDLHEISNEILRIIERTGHKMEFSGQIANLTVAGLALAVLRGDHTFDGMAFSIHSYE
EGTDPEIFLGNVPVGGILASIYLPKSLTERIPLSNLQTILFNFFGQTSLFKTKNVTKALTTYVVS
ASISDDMFIQNLADPVVITLQHIGGNQNYGQVHCAFWDFENNNGLGGWNSSGCKVKETNVN
YTICQCDHLTHFGVLMDLSRSTVDSVNEQILALITYTGCGISSIFLGVAVVTYIAFHKLRKDYP
AKILINLCTALLMLNLVFLINSWLSSFQKVGVCITAAVALHYFLLVSFTVVMGLEAVHMYLAL
VKVFNIYIPNYILKFCLVGWGIPAIMVAITVSVKKDLYGTLSPTTPFCWIKDDSIFYISVVAYFC
LIFLMNLSMFCTVLVQLNSVKSQIQKTRRKMILHDLKGTMSLTFLLGLTWGFAFFAWGPMR
NFFLYLFAIFNTLQGFFIFVFHCVMKESVREQWWILCCGWLRLDNSSDGSSRCQIKVGYKQE
GLKKIFEHKLLTPSLKSTATSSTFKSLGSAQGTPSEISFPNDDFDKDPYCSSP (SEQ ID
NO:1221) >gi|59823631|ref|NP_6603332| probable G-protein coupled
receptor 125 precursor {Homosapiens}
MEPPGRRRGRAQPPLLLPLSLLALLALLGGGGGGGAAALPAGCKHDGRPRGAGRAAGAAE
GKVVCSSLELAQVLPPDTLPNRTVTLILSNNKISELKNGSFSGLSLLERLDLRNNLISSIDPGAF
WGLSSLKRLDLTNNRIGCLNADIFRGLTNLVRLNLSGNLFSSLSQGTFDYLASLRSLEFQTEY
LLCDCNILWMHRWVKEKNITVRDTRCVYPKSLQAQPVTGVKQELLTCDPPLELPSFYMTPSH
RQVVFEGDSLPFQCMASYIDQDMQVLWYQDGRIVETDESQGIFVEKNMIHNCSLIASALTISN
IQAGSTGNWGCHVQTKRGNNTRTVDIVVLESSAQYCPPERVVNNKGDFRWPRTLAGITAYL
QCTRNTHGSGIYPGNPQDERKAWRRCDRGGFVVADDDYSRCQYANDVTRVLYMFNQMPLN
LTNAVATARQLLAYTVEAANFSDKMDVIFVAEMIEKFGRFTKEEKSKELGDVMVDIASNIML
ADERVLWLAQREAKACSRIVQCLQRIATYRLAGGAHVYSTYSPNIALEAYVIKSTGFTGMTC
TVFQKVAASDRTGLSDYGRRDPEGNLDKQLSFKCNVSNTFSSLALKNTIVEASIQLPPSLFSPK
QKRELRPTDDSLYKLQLIAFRNGKLFPATGNSTNLADDGKRRTVVTPVILTKIDGVNVDTHHI
PVNVTLRRIAHGADAVAARWDFDLLNGQGGWKSDGCHILYSDENITTIQCYSLSNYAVLMD
LTGSELYTQAASLLHPVVYTTAIILLLCLLAVIVSYIYHHSLIRISLKSWHMLVNLCFHIFLTCV
VFVGGITQTRNASICQAVGIILHYSTLATVLWVGVTARNIYKQVTKKAKRCQDPDEPPPPPRP
MLRFYLIGGGIPIIVCGITAAANIKNYGSRPNAPYCWMAWEPSLGAFYGPASFITFVNCMYFL
SIFIQLKRHPERKYELKEPTEEQQRLAANENGEINHQDSMSLSLISTSALENEHTFHSQLLGAS
LTLLLYVALWMFGALAVSLYYPLDLVFSFVFGATSLSFSAFFVVHHCVNREDVRLAWIMTC
CPGRSSYSVQVNVQPPNSNGTNGEAPKCPNSSAESSCTNKSASSFKNSSQGCKLTNLQAAAA
QCHANSLPLNSTPQLDNSLTEHSMDNDIKMHVAPLEVQFRTNVHSSRHHKNRSKGHRASRL
TVLREYAYDVPTSVEGSVQNGLPKSRLGNNEGHSRSRRAYLAYRERQYNPPQQDSSDACST
LPKSSRNFEKPVSTTSKKDALRKPAVVELENQQKSYGLNLAIQNGPIKSNGQEGPLLGTDSTG
NVRTGLWKHETTV (SEQ ID NO:1222) >gi|61743940|ref|NP_7225822|
probable G-protein coupled receptor 110 isoform 1 {Homosapiens}
MKVGVLWLISFFTFTDGHGGFLGKNDGIKTKKELIVNKKKHLGPVEEYQLLLQVTYRDSKE
KRDLRNFLKLLKPPLLWSHGLIRIIRAKATTDCNSLNGVLQCTCEDSYTVVFPPSCLDPQNCYL
HTAGALPSCECHLNNLSQSVNFCERTKIVVGTFKINERFTNDLLNSSSAIYSKYANGIEIQLKKA
YERIQGFESVQVTQFRNGSIVAGYEVVGSSSASELLSAIEHVAEKAKTALHKLFPLEDGSFRV
FGKAQCNDIVFGFGSKDDEYTLPCSSGYRGNITAKCESSGWQVIRETCVLSLLEELNKNFSMI
VGNATEAAVSSFVQNLSVIIRQNPSTTVGNLASVVSILSNISSLSLASHFRVSNSTMEDVISIAD
NILNSASVTNWTVLLREEKYASSRLLETLENISTLVPPTALPLNFSRKFIDWKGIPVNKSQLKR
GYSYQIKMCPQNTSIPIRGRVLIGSDQFQRSLPETHSMASLTLGNILPVSKNGNAQVNGPVIST
VIQNYSINEVFLFFSKIESNLSQPHCVFVVDFSHLQWNDAGCHLVNETQDIVTCQCTHLTSFSIL
MSPFVPSTIFPVVKWITYVGLGISIGSLILCLIIEALFVVKQIKKSQTSHTRRICMVNIALSLLIAD
VWFIVGATVDTTVNPSGVCTAAVFFTHFFYLSLFFWMLMLGILLAYRIILVFHHMAQHLMM
AVGFCLGYGCPLIISVITIAVTQPSNTYKRKDVCWLNWSNGSKPLLAFVVPALAIVAVNFVVV
LLVLTKLWRPTVGERLSRDDKATIIRVGKSLLILTPLLGLTWGFGIGTIVDSQNLAWHVIFALL
NAFQGFFILCFGILLDSKLRQLLFNKLSALSSWKQTEKQNSSDLSAKPKFSKPFNPLQNKGHY
AFSHTGDSSDNIMLTQFVSNE (SEQ ID NO:1223)
>gi|62865887|ref|NP_1159402| kiSS-1 receptor {Homosapiens}
MHTVATSGPNASWGAPANASGCPGCGANASDGPVPSPRAVDAWLVPLFFAALMLLGLVGN
SLVIYVICRHKPMRTVTNFYIANLAATDVTFLLCCVPFTALLYPLPGWVLGDFMCKFVNYIQ
QVSVQATCATLTAMSVDRWYVTVFPLRALHRRTPRLALAVSLSIVVVGSAAVSAPVLALHRL
SPGPRAYCSEAFPSRALERAFALYNLLALYLLPLLATCACYAAMLRHLGRVAVRPAPADSAL
QGQVLAERAGAVRAKVSRLVAAVVLLFAACWGPIQLFLVLQALGPAGSWHPRSYAAYALK
TWAHCMSYSNSALNPLLYAFLGSHFRQAFRRVCPCAPRRPRRPRRPGPSDPAAPHAELLRLG
SHPAPARAQKPGSSGLAARGLCVLGEDNAPL (SEQ ID NO:1224)
>gi|62912472|ref|NP_06764921| eucine-rich repeat-containing G
protein-coupled receptor 6 isoform 2 {Homosapiens}
MGRPRLTLVCQVSIIISARDLSMNNLTELQPGLFHHLRFLEELRLSGNHLSHIPGQAFSGLYSL
KILMLQNNQLGGIPAEALWELPSLQSLRLDANLISLVPERSFEGLSSLRHLWLDDNALTEIPVR
ALNNLPALQAMTLALNRISHIPDYAFQNLTSLVVLHLHNNRIQHLGTHSFEGLHNLETLDLN
YNKLQEFPVAIRTLGRLQELGFHNNNIKAIPEKAFMGNPLLQTIHFYDNPIQFVGRSAFQYLPK
LHTLSLNGAMDIQEFPDLKGTTSLEILTLTRAGIRLLPSGMCQQLPRLRVLELSHNQIEELPSL
HRCQKLEEIGLQHNRIVVEIGADTFSQLSSLQALDLSWNAIRSIHPEAFSTLHSLVKLDLTDNQL
TTLPLAGLGGLMHLKLKGNLALSQAFSKDSFPKLRILEVPYAYQCCPYGMCASFFKASGQW
EAEDLHLDDEESSKRPLGLLARQAENHYDQDLDELQLEMEDSKPHPSVQCSPTPGPFKPCEY
LFESWGIRLAVWAIVLLSVLCNGLVLLTVFAGGPVPLPPVKFVVGAIAGANTLTGISCGLLAS
VDALTFGQFSEYGARWETGLGCRATGFLAVLGSEASVLLLTLAAVQCSVSVSCVRAYGKSP
SLGSVRAGVLGCLALAGLAAALPLASVGEYGASPLCLPYAPPEGQPAALGFTVALVMMNSF
CFLVVAGAYIKLYCDLPRGDFEAVWDCAMVRHVAWLIFADGLLYCPVAFLSFASMLGLFPV
TPEAVKSVLLVVLPLPACLNPLLYLLFNPHFRDDLRRLRPRAGDSGPLAYAAAGELEKSSCDS
TQALVAFSDVDLILEASEAGRPPGLETYGFPSVTLISCQQPGAPRLEGSHCVEPEGNHFGNPQP
SMDGELLLRAEGSTPAGGGLSGGGGFQPSGLAFASHV (SEQ ID NO:1225)
>gi|63477962|ref|NP_0009023| delta-type opioid receptor
{Homosapiens}
MEPAPSAGAELQPPLFANASDAYPSACPSAGANASGPPGARSASSLALAIAITALYSAVCAVG
LLGNVLVMFGIVRYTKMKTATNIYIFNLALADALATSTLPFQSAKYLMETWPFGELLCKAVL
SIDYYNMFTSIFTLTMMSVDRYIAVCHPVKALDFRTPAKAKLINICIVVVLASGVGVPIMVMA
VTRPRDGAVVCMLQFPSPSWYWDTVTKICVFLFAFVVPILIITVCYGLMLLRLRSVRLLSGSK
EKDRSLRRITRMVLVVVGAFVVCWAPIHIFVIVWTLVDIDRRDPLVVAALHLCIALGYANSSL
NPVLYAFLDENFKRCFRQLCRKPCGRPDPSSFSRAREATARERVTACTPSDGPGGGAAA (SEQ ID
NO:1226) >gi|64085121|ref|NP_0003602| thyroid stimulating
hormone receptor isoform 1 precursor {Homosapiens}
MRPADLLQLVLLLDLPRDLGGMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHL
RTIPSHAFSNLPNISRIYVSIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKF
LGIFNTGLKMFPDLTKVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQG
YAFNGTKLDAVYLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARN
TWTLKKLPLSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLMCNESSMQSLRQRKSVNALN
SPLHQEYEENLGDSIVGYKEKSKFQDTHNNAHYYVFFEEQEDEIIGFGQELKNPQEETLQAFD
SHYDYTICGDSEDMVCTPKSDEFNPCEDIMGYKFLRIVVWFVSLLALLGNVFVLLILLTSHYK
LNVPRFLMCNLAFADFCMGMYLLLIASVDLYTHSEYYNHAIDWQTGPGCNTAGFFTVFASE
LSVYTLTVITLERWYAITFAMRLDRKIRLRHACAIMVGGWVCCFLLALLPLVGISSYAKVSIC
LPMDTETPLALAYIVFVLTLNIVAFVIVCCCYVKIYITVRNPQYNPGDKDTKIAKRMAVLIFTD
FICMAPISFYALSAILNKPLITVSNSKILLVLFYPLNSCANPFLYAIFTKAFQRDVFILLSKFGICK
RQAQAYRGQRVPPKNSTDIQVQKVTHEMRQGLHNMEDVYELIENSHLTPKKQGQISEEYMQ TVL
(SEQ ID NO:1227 >gi|66529100|ref|NP_0008302| metabotropic
glutamate receptor 2 isoform a precursor {Homosapiens}
MGSLLALLALLLLWGAVAEGPAKKVLTLEGDLVLGGLFPVHQKGGPAEDCGPVNEHRGIQR
LEAMLFALDRINRDPHLLPGVRLGAHILDSCSKDTHALEQALDFVRASLSRGADGSRHICPDG
SYATHGDAPTAITGVIGGSYSDVSIQVANLLRLFQIPQISYASTSAKLSDKSRYDYFARTVPPD
FFQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFELEARARNICVATSEKVGRAMSRAAF
EGVVRALLQKPSARVAVLFTRSEDARELLAASQRLNASFTWVASDGWGALESVVAGSEGA
AEGAITIELASYPISDFASYFQSLDPWNNSRNPWFREFWEQRFRCSFRQRDCAAHSLRAVPFE
QESKIMFVVNAVYAMAHALHNMHRALCPNTTRLCDAMRPVNGRRLYKDFVLNVKFDAPFR
PADTHNEVRFDRFGDGIGRYNIFTYLRAGSGRYRYQKVGYWAEGLTLDTSLIPWASPSAGPL
PASRCSEPCLQNEVKSVQPGEVCCWLCIPCQPYEYRLDEFTCADCGLGYWPNASLTGCFELP
QEYIRWGDAWAVGPVTIACLGALATLFVLGVFVRHNATPVVKASGRELCYILLGGVFLCYC
MTFIFIAKPSTAVCTLRRLGLGTAFSVCYSALLTKTNRIARIFGGAREGAQRPRFISPASQVAIC
LALISGQLLIVVAWLVVEAPGTGKETAPERREVVTLRCNHRDASMLGSLAYNVLLIALCTLY
AFKTRKCPENFNEAKFIGFTMYTTCHVVLAFLPIFYVTSSDYRVQTTTMCVSVSLSGSVVLGCL
FAPKLHIILFQPQKNVVSHRAPTSRFGSAAARASSSLGQGSGSQFVPTVCNGREVVDSTTSSL
(SEQ ID NO:1228) >gi|68215224|ref|NP_0039562| C-C chemokine
receptor-like 2 isoform 1 {Homosapiens}
MANYTLAPEDEYDVLIEGELESDEAEQCDKYDAQALSAQLVPS LCSAVFVIGVLDNLLVVLI
LVKYKGLKRVENIYLLNLAVSNLCFLLTLPFWAHAGGDPMCKILIGLYFVGLYSETFFNCLLT
VQRYLVFLHKGNFFSARRRVPCGIITSVLAWVTAILATLPEFVVYKPQMEDQKYKCAFSRTPF
LPADETFWKHFLTLKMNISVLVLPLFIFTFLYVQMRKTLRFREQRYSLFKLVFAIMVVFLLM
WAPYNIAFFLSTFKEHFSLSDCKSSYNLDKSVHITKLIATTHCCINPLLYAFLDGTFSKYLCRC
FHLRSNTPLQPRGQSAQGTSREEPDHSTEV (SEQ ID NO:1229) >gi|71773208
|ref|NP_000674 2| alpha-2C adrenergic receptor {Homosapiens}
MASPALAAALAVAAAAGPNASGAGERGSGGVANASGASWGPPRGQYSAGAVAGLAAVVG
FLIVFTVVGNVLVVIAVLTSRALRAPQNLFLVSLASADILVATLVMPFSLANELMAYWYFGQ
VWCGVYLALDVLFCTSSIVHLCAISLDRYWSVTQAVEYNLKRTPRRVKATIVAVWLISAVIS
FPPLVSLYRQPDGAAYPQCGLNDETWYILSSCIGSFFAPCLIMGLVYARIYRVAKLRTRTLSE
KRAPVGPDGASPTTENGLGAAAGAGENGHCAPPPADVEPDESSAAAERRRRRGALRRGGRR
RAGAEGGAGGADGQGAGPGAAESGALTASRSPGPGGRLSRASSRSVEFFLSRRRRARSSVCR
RKVAQAREKRFTFVLAVVMGVFVLCWFPFFFSYSLYGICREACQVPGPLFKFFFVVIGYCNSS
LNPVIYTVFNQDFRRSFKHILFRRRRRGFRQ (SEQ ID NO:1230) +22gi 17199913 1
|ref|NP_0551372| opsin-3 {Homosapiens}
MYSGNRSGGHGYWDGGGAAGAEGPAPAGTLSPAPLFSPGTYERLALLLGSIGLLGVGNNLL
VLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVVVDTVGCVWDGFSGSL
FGIVSIATLTVLAYERYIRVVHARVINFSWAWRAITYIVVLYSLAWAGAPLLGWNRYILDVHG
LGCTVDWKSKDANDSSFVLFLFLGCLVVPLGVIAHCYGHILYSIRMLRCVEDLQTIQVIKILK
YEKKLAKMCFLMIFTFLVCWMPYIVICFLVVNGHGHLVTPTISIVSYLFAKSNTVYNPVIYVF
MIRKFRRSLLQLLCLRLLRCQRPAKDLPAAGSEMQIRPIVMSQKDGDRPKKKVTFNSSSIIFIIT
SDESLSVDDSDKTNGSKVDVIQVRPL (SEQ ID NO:1231)
>gi|74048357|ref|NP_0651884| G-protein coupled receptor 126
alpha 1 precursor {Homosapiens}
MMFRSDRMWSCHWKWKPSPLLFLFALYIMCVPHSVWGCANCRVVLSNPSGTFTSPCYPND
YPNSQACMWTLRAPTGYIIQITFNDFDIEEAPNCIYDSLSLDNGESQTKFCGATAKGLSFNSSA
NEMHVSFSSDFSIQKKGFNASYIRVAVSLRNQKVILPQTSDAYQVSVAKSISIPELSAFTLCFE
ATKVGHEDSDWTAFSYSNASFTQLLSFGKAKSGYFLSISDSKCLLNNALPVKEKEDIFAESFE
QLCLVWNNSLGSIGVNFKRNYETVPCDSTISKVIPGNGKLLLGSNQNEIVSLKGDIYNFRLWN
FTMNAKILSNLSCNVKGNVVDWQNDFVVNIPNLALKAESNLSCGSYLIPLPAAELASCADLGT
LCQATVNSPSTTPPTVTTNMPVTNRIDKQRNDGIIYRISVVIQNILRHPEVKVQSKVAEWLNST
FQNWNYTVYVVNISFHLSAGEDKIKVKRSLEDEPRLVLWALLVYNATNNTNLEGKIIQQKLL
KNNESLDEGLRLHTVNVRQLGHCLAMEEPKGYYWPSIQPSEYVLPCPDKPGFSASRICFYNA
TNPLVTYWGPVDISNCLKEANEVANQILNLTADGQNLTSANITNIVEQVKRIVNKEENIDITL
GSTLMNIFSNILSSSDSDLLESSSEALKTIDELAFKIDLNSTSHVNITTRNLALSVSSLLPGTNAIS
NFSIGLPSNNESYFQMDFESGQVDPLASVILPPNLLENLSPEDSVLVRRAQFTFFNKTGLFQDV
GPQRKTLVSYVMACSIGNITIQNLKDPVQIKIKHTRTQEVHHPICAFVVDLNKNKSFGGWNTS
GCVAHRDSDASETVCLCNHFTHFGVLMDLPRSASQLDARNTKVLTFISYIGCGISAIFSAATL
LTYVAFEKLRRDYPSKILMNLSTALLFLNLLFLLDGWITSFNVDGLCIAVAVLLHFFLLATFT
WMGLEAIHMYIALVKVFNTYIRRYILKFCIIGWGLPALVVSVVLASRNNNEVYGKESYGKEK
GDEFCWIQDPVIFYVTCAGYFGVMFFLNIAMFIVVMVQICGRNGKRSNRTLREEVLRNLRSV
VSLTFLLGMTWGFAFFAWGPLNIPFMYLFSIFNSLQGLFIFIFHCAMKENVQKQWRRHLCCG
RFRLADNSDWSKTATNIIKKSSDNLGKSLSSSSIGSNSTYLTSKSKSSSTTYFKRNSHTDNVSY
EHSFNKSGSLRQCFHGQVLVKTGPC) (SEQ ID NO:1232)
>gi|74275344|ref|NP_0010282521| trace amine-associated receptor
2 isoform 1 {Homosapiens}
MAVSSEQHELSHFKRTQTKKEKFNCSEYGNRSCPENERSLGVRVAMYSFMAGSIFITIFGNLA
MIISISYFKQLHTPTNFLILSMAITDFLLGFTIMPYSMIRSVENCWYFGLTFCKIYYSFDLMLSIT
SIFHLCSVAIDRFYAICYPLLYSTKITIPVIKRLLLLCWSVPGAFAFGVVFSEAYADGIEGYDIL
VACSSSCPVMFNKLWGTTLFMAGFFTPGSMMVGIYGKIFAVSRKHAHAINNLRENQNNQVK
KDKKAAKTLGIVIGVFLLCWFPCFFTILLDPFLNFSTPVVLFDALTWFGYFNSTCNPLIYGFFY
PWFRRALKYILLGKIFSSCFHNTILCMQKESE (SEQ ID NO:1233)
>gi|84662753|ref|NP_0010337941| G protein-coupled receptor 149
{Homosapiens}
MSLFLSNLSTNDSSLWKENHNSTDLLNPPGTLNIYLFCLTCLMTFAALVGSIYSLISLLKMQN
RTVVSMLVASWSVDDLMSVLSVTIFMFLQWPNEVPGYFQFLCTTSALMYLCQGLSSNLKAT
LLVSYNFYTMHRGVGSQTASRRSGQVLGVVLTVVVAASLLLSALPLCGWGAFVRTPWGCLV
DCSSSYVLFLSIVYALAFGLLVGLSVPLTHRLLCSEEPPRLHSNYQEISRGASIPGTPPTAGRVV
SLSPEDAPGPSLRRSGGCSPSSDTVFGPGAPAAAGAEACRRENRGTLYGTRSFTVSVAQKRFA
LILALTKVVLWLPMMMHMVVQNVVGFQSLPLETFSFLLTLLATTVTPVFVLSKRWTHLPCG
CIINCRQNAYAVASDGKKIKRKGFEFNLSFQKSYGIYKIAHEDYYDDDENSIFYHNLMNSECE
TTKDPQRDNRNIFNAIKVEISTTPSLDSSTQRGINKCTNTDITEAKQDSNNKKDAFSDKTGGDI
NYEETTFSEGPERRLSHEESQKPDLSDWEWCRSKSERTPRQRSGYALAIPLCAFQGTVSLHAP
TGKTLSLSTYEVSAEGQKITPASKKIEVYRSKSVGHEPNSEDSSSTFVDTSVKIHLEVLEICDNE
EALDTVSIISNISQSSTQVRSPSLRYSRKENRFVSCDLGETASYSLFLPTSNPDGDINISIPDTVE
AHRQNSKRQHQERDGYQEEIQLLNKAYRKREEESKGS (SEQ ID NO:1234)
>gi|85986587|ref|NP_0010342541| mas-related G-protein coupled
receptor member E {Homosapiens}
MEPREAGQHVGAANGAQEDVAFNLIILSLTEGLGLGGLLGNGAVLWLLSS NVYRNPFAIYLL
DVACADLIFLGCHMVAIVPDLLQGRLDFPGFVQTSLATLRFFCYIVGLSLLAAVSVEQCLAAL
FPAWYSCRRPRHLTTCVCALTWALCLLLHLLLSGACTQFFGEPSRHLCRTLWLVAAVLLALL
CCTMCGASLMLLLRVERGPQRPPPRGFPGLILLTVLLFLFCGLPFGIYVVLSRNLLWYIPHYFY
HFSFLMAAVHCAAKPVVYFCLGSAQGRRLPLRLVLQRALGDEAELGAVRETSRRGLVDIAA (SEQ
ID NO:1235) >gi|85986601|ref|NP_0676472| relaxin/insulin-like
family peptide receptor 1 {Homosapiens}
MTSGSVFFYILIFGKYFSHGGGQDVKCSLGYFPCGNITKCLPQLLHCNGVDDCGNQADEDNC
GDNNGWSLQFDKYFASYYKMTSQYPFEAETPECLVGSVPVQCLCQGLELDCDETNLRAVPS
VSSNVTAMSLQWNLIRKLPPDCFKNYHDLQKLYLQNNKITSISIYAFRGLNSLTKLYLSHNRI
TFLKPGVFEDLHRLEWLIIEDNHLSRISPPTFYGLNSLILLVLMNNVLTRLPDKPLCQHMPRLH
WLDLEGNHIHNLRNLTFISCSNLTVLVMRKNKINHLNENTFAPLQKLDELDLGSNKIENLPPLI
FKDLKELSQLNLSYNPIQKIQANQFDYLVKLKSLSLEGIEISNIQQRMFRPLMNLSHIYFKKFQ
YCGYAPHVRSCKPNTDGISSLENLLASIIQRVFVWVVSAVTCFGNIFVICMRPYIRSENKLYA
MSIISLCCADCLMGIYLFVIGGFDLKFRGEYNKHAQLWMESTHCQLVGSLAILSTEVSVLLLT
FLTLEKYICIVYPFRCVRPGKCRTITVLILIVVITGFIVAFIPLSNKEFFKNYYGTNGVCFPLHSED
TESIGAQIYSVAIFLGINLAAFIIIVFSYGSMFYSVHQSAITATEIRNQVKKEMILAKRFFFIVFTD
ALCWIPIFVVKFLSLLQVEIPGTITSWVVIFILPINSALNPILYTLTTRPFKEMIHRFWYNYRQRK
SMDSKGQKTYAPSFIVVVEMWPLQEMPPELMKPDLFTYPCEMSLISQSTRLNSY (SEQ ID
NO:1236) >gi|88758590|ref|NP_0052883| melanin-concentrating
hormone receptor 1 {Homosapiens}
MSVGAMKKGVGRAVGLGGGSGCQATEEDPLPNCGACAPGQGGRRWRLPQPAWVEGSSAR
LWEQATGTGWMDLEASLLPTGPNASNTSDGPDNLTSAGSPPRTGSISYINIIMPSVFGTICLLG
IIGNSTVIFAVVKKSKLHWCNNVPDIFIINLSVVDLLFLLGMPFMIHQLMGNGVWHFGETMCT
LITAMDANSQFTSTYILTAMAIDRYLATVHPISSTKFRKPSVATLVICLLWALSFISITPVVVLYA
RLIPFPGGAVGCGIRLPNPDTDLYWFTLYQFFLAFALPFVVITAAYVRILQRMTSSVAPASQRS
IRLRTKRVTRTAIAICLVFFVCWAPYYVLQLTQLSISRPTLTFVYLYNAAISLGYANSCLNPFV
YIVLCETFRKRLVLSVKPAAQGQLRAVSNAQTADEERTESKGT (SEQ ID NO:1237)
>gi|89191861|ref|NP_0007872| d(3) dopamine receptor isoform a
{Homosapiens} MASLSQLSGHLNYTCGAENS
TGASQARPHAYYALSYCAULAIVFGNGLVCMAVLKERALQ
TTTNYLVVSLAVADLLVATLVMPWVVYLEVTGGVWNFSRICCDVFVTLDVMMCTASILNL
CAISIDRYTAVVMPVHYQHGTGQSSCRRVALMITAVWVLAFAVSCPLLFGFNTTGDPTVCSI
SNPDFVIYSSVVSFYLPFGVTVLVYARIYVVLKQRRRKRILTRQNSQCNSVRPGFPQQTLSPDP
AHLELKRYYSICQDTALGGPGFQERGGELKREEKTRNSLSPTIAPKLSLEVRKLSNGRLSTSL
KLGPLQPRGVPLREKKATQMVAIVLGAFIVCWLPFFLTHVLNTHCQTCHVSPELYSATTWLG
YVNSALNPVIYTTFNIEFRKAFLKILSC (SEQ ID NO:1238)
>gi|89257346|ref|NP_0052842| G-protein coupled receptor 20
{Homosapiens}
MPSVSPAGPSAGAVPNATAVTTVRTNASGLEVPLFHLFARLDEELHGTFPGLWLALMAVHG
AIFLAGLVLNGLALYVFCCRTRAKTPSVIYTINLVVTDLLVGLSLPTRFAVYYGARGCLRCAF
PHVLGYFLNMHCSILFLTCICVDRYLAIVRPEGSRRCRQPACARAVCAFVWLAAGAVTLSVL
GVTGSRPCCRVFALTVLEFLLPLLVISVFTGRIMCALSRPGLLHQGRQRRVRAMQLLLTVLIIF
LVCFTPFHARQVAVALWPDMPHHTSLVVYHVAVTLSSLNSCMDPIVYCFVTSGFQATVRGL
FGQHGEREPSSGDVVSMHRSSKGSGRHHILSAGPHALTQALANGPEA (SEQ ID NO:1239)
>gi|89353783|ref|NP_0039412| proteinase-activated receptor 4
precursor {Homosapiens}
MWGRLLLWPLVLGFSLSGGTQTPSVYDESGSTGGGDDSTPSILPAPRGYPGQVCANDSDTLE
LPDSSRALLLGWVPTRLVPALYGLVLVVGLPANGLALWVLATQAPRLPSTMLLMNLAAADL
LLALALPPRIAYHLRGQRWPFGEAACRLATAALYGHMYGSVLLLAAVSLDRYLALVHPLRA
RALRGRRLALGLCMAAWLMAAALALPLTLQRQTFRLARSDRVLCHDALPLDAQASHWQPA
FTCLALLGCFLPLLAMLLCYGATLHTLAASGRRYGHALRLTAVVLASAVAFFVPSNLLLLLH
YSDPSPSAWGNLYGAYVPSLALSTLNSCVDPFIYYYVSAEFRDKVRAGLFQRSPGDTVASKA
SAEGGSRGMGTHSSLLQ (SEQ ID NO:1240) >gi|91106202|ref|NP_0052862|
probable G-protein coupled receptor 22 {Homosapiens}
MCFSPILEINMQSESNITVRDDIDDINTNMYQPLSYPLSFQVSLTGFLMLEIVLGLGSNLTVLV
LYCMKSNLINSVSNIITMNLHVLDVIICVGCIPLTIVILLLSLESNTALICCFHEACVSFASVSTAI
NVFAITLDRYDISVKPANRILTMGRAVMLMISIVVIFSFFSFLIPFIEVNFFSLQSGNTWENKTLL
CVSTNEYYTELGMYYHLLVQIPIFFFTVVVMLITYTKILQALNIRIGTRFSTGQKKKARKKKTI
SLTTQHEATDMSQSSGGRNVVFGVRTSVSVIIALRRAVKRHRERRERQKRVFRMSLLIISTFL
LCWTPISVLNTTILCLGPSDLLVKLRLCFLVMAYGTTIFHPLLYAFTRQKFQKVLKSKMKKRV
VSIVEADPLPNNAVIHNSWIDPKRNKKITFEDSEIREKCLVPQVVTD (SEQ ID NO:1241)
>gi|93204867|ref|NP_0658032| probable G-protein coupled receptor
158 precursor {Homosapiens}
MGAMAYPLLLCLLLAQLGLGAVGASRDPQGRPDSPRERTPKGKPHAQQPGRASASDSSAPW
SRSTDGTILAQKLAEEVPMDVASYLYTGDSHQLKRANCSGRYELAGLPGKWPALASAHPSL
HRALDTLTHATNFLNVMLQSNKSREQNLQDDLDWYQALVWSLLEGEPSISRAAITFSTDSLS
APAPQVFLQATREESRILLQDLSSSAPHLANATLETEWFHGLRRKWRPHLHRRGPNQGPRGL
GHSWRRKDGLGGDKSHFKWSPPYLECENGSYKPGWLVTLSSAIYGLQPNLVPEFRGVMKV
DINLQKVDIDQCSSDGWFSGTHKCHLNNSECMPIKGLGFVLGAYECICKAGFYHPGVLPVNN
FRRRGPDQHISGSTKDVSEEAYVCLPCREGCPFCADDSPCFVQEDKYLRLAIISFQALCMLLD
FVSMLVVYHFRKAKSIRASGLILLETILFGSLLLYFPVVILYFEPSTFRCILLRWARLLGFATVY
GTVTLKLHRVLKVFLSRTAQRIPYMTGGRVMRMLAVILLVVFVVFLIGWTSSVCQNLEKQISL
IGQGKTSDHLIFNMCLIDRWDYMTAVAEFLFLLWGVYLCYAVRTVPSAFHEPRYMAVAVH
NELIISAIFHTIRFVLASRLQSDWMLMLYFAHTHLTVTVTIGLLLIPKFSHSSNNPRDDIATEAY
EDELDMGRSGSYLNSSINSAWSEHSLDPEDIRDELKKLYAQLEIYKRKKMITNNPHLQKKRC
SKKGLGRSIMRRITEIPETVSRQCSKEDKEGADHGTAKGTALIRKNPPESSGNTGKSKEETLK
NRVFSLKKSHSTYDHVRDQTEESSSLPTESQEEETTENSTLESLSGKKLTQKLKEDSEAESTES
VPLVCKSASAHNLSSEKKTGHPRTSMLQKSLSVIASAKEKTLGLAGKTQTAGVEERTKSQKP
LPKDKETNRNHSNSDNTETKDPAPQNSNPAEEPRKPQKSGIMKQQRVNPTTANSDLNPGTTQ
MKDNFDIGEVCPWEVYDLTPGPVPSESKVQKHVSIVASEMEKNPTFSLKEKSHHKPKAAEVC
QQSNQKRIDKAEVCLWESQGQSILEDEKLLISKTPVLPERAKEENGGQPRAANVCAGQSEEL
PPKAVASKTENENLNQIGHQEKKTSSSEENVRGSYNSSNNFQQPLTSRAEVCPWEFETPAQPN
AGRSVALPASSALSANKIAGPRKEEIVVDSFKV (SEQ ID NO:1242)
>gi|93204873|ref|NP_0792564| probable G-protein coupled receptor
157 {Homosapiens}
MQPSPPPTELVPSERAVVLLSCALSALGSGLLVATHALWPDLRSRARRLLLFLSLADLLSAAS
YFYGVLQNFAGPSWDCVLQGALSTFANTSSFFWTVAIALYLYLSIVRAARGPRTDRLLWAFH
VVSWGVPLVITVAAVALKKIGYDASDVSVGWCWIDLEAKDHVLWMLLTGKLWEMLAYVL
LPLLYLLVRKHINRAHTALSEYRPILSQEHRLLRHSSMADKKLVLIPLIFIGLRVWSTVRFVLT
LCGSPAVQTPVLVVLHGIGNTFQGGANCIMFVLCTRAVRTRLFSLCCCCCSSQPPTKSPAGTP
KAPAPSKPGESQESQGTPGELPST (SEQ ID NO:1243)
>gi|93277083|ref|NP_0010352691| melanin-concentrating hormone
receptor 2 {Homosapiens}
MNPFHASCWNTSAELLNKSWNKEFAYQTASVVDTVILPSMIGIICSTGLVGNILIVFTIIRSRK
KTVPDIYICNLAVADLVHIVGMPFLIHQWARGGEWVFGGPLCTIITSLDTCNQFACSAIMTVM
SVDRYFALVQPFRLTRWRTRYKTIRINLGLWAASFILALPVWVYSKVIKFKDGVESCAFDLTS
PDDVLWYTLYLTITTFFFPLPLILVCYILILCYTVVEMYQQNKDARCCNPSVPKQRVMKLTKM
VLVLVVVFILSAAPYHVIQLVNLQMEQPTLAFYVGYYLSICLSYASSSINPFLYILLSGNFQKR
LPQIQRRATEKEINNMGNTLKSHF (SEQ ID NO:1244)
>gi|93352554|ref|NP_0010043342| probable G-protein coupled
receptor 179 precursor {Homosapiens}
MGTRGAVMPPPMWGLLGCCFVCAWALGGPRPIRSLPPLSSQVKPGSVPMQVPLEGAEAALA
YLYSGDAQQLSQVNCSERYEARGAGAMPGLPPSLQGAAGTLAQAANFLNMLLQANDIRESS
VEEDVEWYQALVRSVAEGDPRVYRALLTFNPPPGASHLQLALQATRTGEETILQDLSGNWV
QEENPPGDLDTPALKKRVLTNDLGSLGSPKWPQADGYVGDTQQVRLSPPFLECQEGRLRPG
WLITLSATFYGLKPDLSPEVRGQVQMDVDLQSVDINQCASGPGWYSNTHLCDLNSTQCVPL
ESQGFVLGRYLCRCRPGFYGASPSGGLEESDFQTTGQFGFPEGRSGRLLQCLPCPEGCTSCMD
ATPCLVEEAAVLRAAVLACQACCMLAIFLSMLVSYRCRRNKRIVVASGVVLLETVLFGFLLLY
FPVFILYFKPSVFRCIALRWVRLLGFAIVYGTIILKLYRVLQLFLSRTAQRSALLSSGRLLRRLG
LLLLPVLGFLAVWTVGALERGIQHAPLVIRGHTPSGRHFYLCHHDRWDYIMVVAELLLLCW
GSFLCYATRAVLSAFHEPRYMGIALHNELLLSAAFHTARFVLVPSLHPDWTLLLFFFHTHSTV
TTTLALIFIPKFVVKLGAPPREEMVDEVCEDELDLQHSGSYLGSSIASAWSEHSLDPGDIRDELK
KLYAQLEVHKTKEMAANNPHLPKKRGSSCQGLGRSFMRYLAEFPEALARQHSRDSGSPGHG
SLPGSSRRRLLSSSLQEPEGTPALHKSRSTYDQRREQDPPLLDSLLRRKLAKKASRTESRESVE
GPPALGFRSASAHNLTVGERLPRARPASLQKSLSVASSREKALLMASQAYLEETYRQAKERE
ERKKAKAAMASLVRRPSARRLERPRGAPLSAPPSPAKSSSVDSSHTSGRLHEEARRRLPHPPI
RHQVSTPILALSGGLGEPRMLSPTSTLAPALLPALAPTPAPALAPVPVSPQSPNLLTYICPWEN
AELPAKQENVPQEGPSGPERGHHSPAPARARLWRALSVAVEKSRAGENEMDAEDAHHQRE
ANDVDEDRPKIFPKSHSLKAPVQQGSMRSLGLAIKALTRSRSTYREKESVEESPEGQNSGTAG
ESMGAPSRSPRLGRPKAVSKQAALIPSDDKESLQNQQNAHTSRMLQVCQREGSREQEDRGR
RMTQGLGERKAERAGKTGLAMLRQVSRDKNIKQSKETPVGWQELPKAGLQSLGSADHRVA
EVCPWEVTESETRQPDSGNKAEICPWETSEGAPESRALRQDPGDSQKKRGEARGKSEPIDVV
PMMRKKPERLVREQEAVCPWESADRGGLSPGSAPQDPGRIRDKSEAGDSVEARKVEKPGWE
AAGPEAHTPDITKAEPCPWEASEGGEDGKPAQEAVKDLPQEKQKTRKATFWKEQKPGGDLE
SLCPWESTDFRGPSAVSIQAPGSSECSGSLGSGIAEVCLWEAGDAPAIQKAEICPWELDDNVM
GQEMLSLGTGRESLQEKEKASRKGSFGEMGEQTVKAVQKLSQQQESVCPRESTVPGHSSPCL
DNSSSKAGSQFLCNGGSRATQVCPQEDLRPEAQEATPAKTEICPWEVNERTREEWTSAQVPR
GGESQKDKEKMPGKSEIEDVTAWEKPEGQIQKQEAVGPWESVDPGSFSPQPRPQDTERPQTL
LQMSGSVGSKAADICPLDVEENLTAGKAEICPWEVGAGAGEERALGAEAIRKSPNDTGKVS
ADLGPRERAVTAPEKPQKPTPEWEVACPWGSVGPGACSQHPGTLDADGPKAGFQELDHMG
CRPGEVCPWEAQEAATSEKAKICPWEVSEGTTGKGLDQKAGSESAEQREKALEKGRLTSLG
EDVSKGMAKLCQQQETICIVVENKDLRESPAQAPKISDLPSSMSSEVAEGHSLEATEKGDLRQ
DPKTGSFPEHITQEKAPAADTEEFTTEDGEKTSHELQSVCPWETTAPADSVSHLDRQRPDQPK
ASSQRLVSTGGRAADVCPWDVPDAGVYKSDSSAKAETCPWEVTERIPVKGVSRQDGKGDS
QEEKGRAPEKSEPKGVPVQKKPEMADFRQQEAVCPWESQDGKGLSPQPAPDASDRSRGSSE
AAGSVETRVAEVCLWEVVEAPSAKKAEICPWEAGGGAAEEGEQERESQGQGEMFLQKAGP
GGTEEHFSKAAAKPREQEAVCPGEGTGSGGLLPQSGALDPELKVSPKEAGSMGSRMAELCQ
WEITDPEGNKIKGTMADICPGEETGVPSEESGLLALTATRREFFPTAPEKPLCLLVHGPLDHFF
PESKIPCPKVSRPASTFTLEGVRELQGPSGLEPRTSLAPEPSLQEAESQSSSLTEDSGQVAFEAQ
YEEFTPPTVYPWDWE (SEQ ID NO:1245) >gi|106067657|ref|NP_0002242|
luteinizing hormone/choriogonadotropin receptor precursor
{Homosapiens}
MKQRFSALQLLKLLLLLQPPLPRALREALCPEPCNCVPDGALRCPGPTAGLTRLSLAYLPVKV
IPSQAFRGLNEVIKIEISQIDSLERIEANAFDNLLNLSEILIQNTKNLRYIEPGAFINLPRLKYLSIC
NTGIRKFPDVTKVFSSESNFILEICDNLHITTIPGNAFQGMNNESVTLKLYGNGFEEVQSHAFN
GTTLTSLELKENVHLEKMHNGAFRGATGPKTLDISSTKLQALPSYGLESIQRLIATSSYSLKKL
PSRETFVNLLEATLTYPSHCCAFRNLPTKEQNFSHSISENFSKQCESTVRKVNNKTLYSSMLA
ESELSGWDYEYGFCLPKTPRCAPEPDAFNPCEDIMGYDFLRVLIVVLINILAIMGNMTVLFVLL
TSRYKLTVPRFLMCNLSFADFCMGLYLLLIASVDSQTKGQYYNHAIDWQTGSGCSTAGFFTV
FASELSVYTLTVITLERWHTITYAIHLDQKLRLRHAILIMLGGWLFSSLIAMLPLVGVSNYMK
VSICFPMDVETTLSQVYILTILILNVVAFFIICACYIKIYFAVRNPELMATNKDTKIAKKMAILIF
TDFTCMAPISFFAISAAFKVPLITVTNSKVLLVLFYPINSCANPFLYAIFTKTFQRDFFLLLSKFG
CCKRRAELYRRKDFSAYTSNCKNGFTGSNKPSQSTLKLSTLHCQGTALLDKTRYTEC (SEQ ID
NO:1246) >gi|110611176|ref|NP_0008342| metabotropic glutamate
receptor 6 precursor {Homosapiens}
MARPRRAREPLLVALLPLAWLAQAGLARAAGSVRLAGGLTLGGLFPVHARGAAGRACGQL
KKEQGVHRLEAMLYALDRVNADPELLPGVRLGARLLDTCSRDTYALEQALSFVQALIRGRG
DGDEVGVRCPGGVPPLRPAPPERVVAVVGASASSVSIMVANVLRLFAIPQISYASTAPELSDS
TRYDFFSRVVPPDSYQAQAMVDIVRALGWNYVSTLASEGNYGESGVEAFVQISREAGGVCI
AQSIKIPREPKPGEFSKVIRRLMETPNARGIIIFANEDDIRRVLEAARQANLTGHFLWVGSDSW
GAKTSPILSLEDVAVGAITILPKRASIDGFDQYFMTRSLENNRRNIVVFAEFVVEENFNCKLTSSG
TQSDDSTRKCTGEERIGRDSTYEQEGKVQFVIDAVYAIAHALHSMHQALCPGHTGLCPAMEP
TDGRMLLQYIRAVRFNGSAGTPVMFNENGDAPGRYDIFQYQATNGSASSGGYQAVGQWAE
TLRLDVEALQWSGDPHEVPSSLCSLPCGPGERKKMVKGVPCCWHCEACDGYRFQVDEFTCE
ACPGDMRPTPNHTGCRPTPVVRLSWSSPWAAPPLLLAVLGIVATTTVVATFVRYNNTPIVRA
SGRELSYVLLTGIFLIYAITFLMVAEPGAAVCAARRLFLGLGTTLSYSALLTKTNRIYRIFEQG
KRSVTPPPFISPTSQLVITFSLTSLQVVGMIAWLGARPPHSVIDYEEQRTVDPEQARGVLKCD
MSDLSLIGCLGYSLLLMVTCTVYAIKARGVPETFNEAKPIGFTMYTTCHVVLAFVPIFFGTAQS
AEKIYIQTTTLTVSLSLSASVSLGMLYVPKTYVILFHPEQNVQKRKRSLKATSTVAAPPKGED
AEAHK (SEQ ID NO:1247) >gi|110611243|ref|NP_0025222| neurotensin
receptor type 1 {Homosapiens}
MRLNSSAPGTPGTPAADPFQRAQAGLEEALLAPGFGNASGNASERVLAAPSSELDVNTDIYS
KVLVTAVYLALFVVGTVGNTVTAFTLARKKSLQSLQSTVHYHLGSLALSDLLTLLLAMPVE
LYNFIVVVHHPWAFGDAGCRGYYFLRDACTYATALNVASLSVERYLAICHPFKAKTLMSRSR
TKKFISAIWLASALLAVPMLFTMGEQNRSADGQHAGGLVCTPTIHTATVKVVIQVNTFMSFIF
PMVVISVLNTHANKLTVMVRQAAEQGQVCTVGGEHSTFSMAIEPGRVQALRHGVRVLRAV
VIAFVVCWLPYHVRRLMFCYISDEQWTPFLYDFYHYFYMVTNALFYVSSTINPILYNLVSAN
FRHIFLATLACLCPVWRRRRKRPAFSRKADSVSSNHTLSSNATRETLY (SEQ ID NO:1248)
>gi|110618256|ref|NP_7782273| trace amine-associated receptor 9
{Homosapiens}
MVNNFSQAEAVELCYKNVNESCIKTPYSPGPRSILYAVLGFGAVLAAFGNLLVMIAILHFKQL
HTPTNFLIASLACADFLVGVTVMPFSTVRSVESCWYFGDSYCKFHTCFDTSFCFASLFHLCCIS
VDRYIAVTDPLTYPTKFTVSVSGICIVLSWFFSVTYSFSIFYTGANEEGIEELVVALTCVGGCQ
APLNQNVVVLLCFLLFFIPNVAMVFIYSKIFLVAKHQARKIESTASQAQSSSESYKERVAKRER
KAAKTLGIAMAAFLVSWLPYLVDAVIDAYMNFITPPYVYEILVWCVYYNSAMNPLIYAFFY
QWFGKAIKLIVSGKVLRTDSSTTNLFSEEVETD (SEQ ID NO:1249)
>gi|111118992|ref|NP_0006712| alpha-1A adrenergic receptor
isoform 1 {Homosapiens}
MVFLSGNASDSSNCTQPPAPVNISKAILLGVILGGLILFGVLGNILVILSVACHRHLHSVTHYYI
VNLAVADLLLTSTVLPFSAIFEVLGYWAFGRVFCNIVVAAVDVLCCTASIMGLCIISIDRYIGVS
YPLRYPTIVTQRRGLMALLCVWALSLVISIGPLFGWRQPAPEDETICQINEEPGYVLFSALGSF
YLPLAIILVMYCRVYVVAKRESRGLKSGLKTDKSDSEQVTLRIHRKNAPAGGSGMASAKTKT
HFSVRLLKFSREKKAAKTLGIVVGCFVLCWLPFFLVMPIGSFFPDFKPSETVFKIVFVVLGYLNS
CINPIIYPCSSQEFKKAFQNVLRIQCLCRKQSSKHALGYTLHPPSQAVEGQHKDMVRIPVGSRE
TFYRISKTDGVCEWKFFSSMPRGSARITVSKDQSSCTTARVRSKSFLQVCCCVGPSTPSLDKN
HQVPTIKVHTISLSENGEEV (SEQ ID NO:1250)
>gi|111118994|ref|NP_0016932| brain-specific angiogenesis
inhibitor 1 precursor {Homosapiens }
MRGQAAAPGPVWILAPLLLLLLLLGRRARAAAGADAGPGPEPCATLVQGKFFGYFSAAAVF
PANASRCSWTLRNPDPRRYTLYMKVAKAPVPCSGPGRVRTYQFDSFLESTRTYLGVESFDEV
LRLCDPSAPLAFLQASKQFLQMRRQQPPQHDGLRPRAGPPGPTDDFSVEYLVVGNRNPSRAA
CQMLCRWLDACLAGSRSSHPCGIMQTPCACLGGEAGGPAAGPLAPRGDVCLRDAVAGGPE
NCLTSLTQDRGGHGATGGWKLWSLWGECTRDCGGGLQTRTRTCLPAPGVEGGGCEGVLEE
GRQCNREACGPAGRTSSRSQSLRSTDARRREELGDELQQFGFPAPQTGDPAAEEWSPWSVCS
STCGEGWQTRTRFCVSSSYSTQCSGPLREQRLCNNSAVCPVHGAWDEWSPWSLCSSTCGRG
FRDRTRTCRPPQFGGNPCEGPEKQTKFCNIALCPGRAVDGNWNEWSSWSACSASCSQGRQQ
RTRECNGPSYGGAECQGHWVETRDCFLQQCPVDGKWQAWASWGSCSVTCGAGSQRRERV
CSGPFFGGAACQGPQDEYRQCGTQRCPEPHEICDEDNFGAVIVVKETPAGEVAAVRCPRNAT
GLILRRCELDEEGIAYWEPPTYIRCVSIDYRNIQMMTREHLAKAQRGLPGEGVSEVIQTLVEIS
QDGTSYSGDLLSTIDVLRNMTEIFRRAYYSPTPGDVQNFVQILSNLLAEENRDKWEEAQLAG
PNAKELFRLVEDFVDVIGFRMKDLRDAYQVTDNLVLSIHKLPASGATDISFPMKGWRATGD
WAKVPEDRVTVSKSVFSTGLTEADEASVFVVGTVLYRNLGSFLALQRNTTVLNSKVISVTVK
PPPRSLRTPLEIEFAHMYNGTTNQTCILWDETDVPSSSAPPQLGPWSWRGCRTVPLDALRTRC
LCDRLSTFAILAQLSADANMEKATLPSVTLIVGCGVSSLTLLMLVIIYVSVWRYIRSERSVILIN
FCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLTEAWQSYMAVTGHLRNRLIR
KRFLCLGWGLPALVVAISVGFTKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVLVNMVIGI
LVFNKLVSKDGITDKKLKERAGASLWSSCVVLPLLALTWMSAVLAVTDRRSALFQILFAVFD
SLEGFVIVMVHCILRREVQDAVKCRVVDRQEEGNGDSGGSFQNGHAQLMTDFEKDVDLAC
RSVLNKDIAACRTATITGTLKRPSLPEEEKLKLAHAKGPPTNFNSLPANVSKLHLHGSPRYPG
GPLPDFPNHSLTLKRDKAPKSSFVGDGDIFKKLDSELSRAQEKALDTSYVILPTATATLRPKPK
EEPKYSIHIDQMPQTRLIHLSTAPEASLPARSPPSRQPPSGGPPEAPPAQPPPPPPPPPPPPQQPLP
PPPNLEPAPPSLGDPGEPAAHPGPSTGPSTKNENVATLSVSSLERRKSRYAELDFEKIMHTRKR
HQDMFQDLNRKLQHAAEKDKEVLGPDSKPEKQQTPNKRPWESLRKAHGTPTWVKKELEPL
QPSPLELRSVEWERSGATIPLVGQDIIDLQTEV (SEQ ID NO:1251)
>gi|112807234|ref|NP_6837662| G-protein coupled receptor family
C group 6 member A precursor {Homosapiens}
MAFLIILITCFVIILATSQPCQTPDDFVAATSPGHIIIGGLFAIHEKMLSSEDSPRRPQIQECVGFEI
SVFLQTLAMIHSIEMINNSTLLPGVKLGYEIYDTCTEVTVAMAATLRFLSKFNCSRETVEFKC
DYSSYMPRVKAVIGSGYSEITMAVSRMLNLQLMPQVGYESTAEILSDKIRFPSFLRTVPSDFH
QIKAMAHLIQKSGWNWIGHTTDDDYGRLALNTFIIQAEANNVCIAFKEVLPAFLSDNTIEVRI
NRTLKKIILEAQVNVIVVFLRQFHVFDLFNKAIEMNINKMWIASDNWSTATKITTIPNVKKIG
KVVGFAFRRGNISSFHSFLQNLHLLPSDSHKLLHEYAMHLSACAYVKDTDLSQCIFNHSQRTL
AYKANKAIERNFVMRNDFLWDYAEPGLIHSIQLAVFALGYAIRDLCQARDCQNPNAFQPWE
LLGVLKNVTFTDGWNSFHFDAHGDLNTGYDVVLWKEINGHMTVTKMAEYDLQNDVFIIPD
QETKNEFRNLKQIQSKCSKECSPGQMKKTTRSQHICCYECQNCPENHYTNQTDMPHCLLCN
NKTHWAPVRSTMCFEKEVEYLNWNDSLAILLLILSLLGIIFVLVVGIIFTRNLNTPVVKSSGGL
RVCYVILLCHFLNFASTSFFIGEPQDFTCKTRQTMFGVSFTLCISCILTKSLKILLAFSFDPKLQK
FLKCLYRPILIIFTCTGIQVVICTLWLIFAAPTVEVNVSLPRVIILECEEGSILAFGTMLGYIAILA
FICFIFAFKGKYENYNEAKFITFGMLIYFIAWITFIPIYATTFGKYVPAVEIIVILISNYGILYCTFI
PKCYVIICKQEINTKSAFLKMIYSYSSHSVSSIALSPASLDSMSGNVTMTNPSSSGKSATWQKS
KDLQAQAFAHICRENATSVSKTLPRKRMSSI (SEQ ID NO:1252)
>gi|113722120|ref|NP_1154953| G-protein coupled receptor 98
precursor {Homosapiens }
MSVFLGPGMPSASLLVNLLSALLILFVFGETEIRFTGQTEFVVNETSTTVIRLIIERIGEPANVTA
IVSLYGEDAGDFFDTYAAAFIPAGETNRTVYIAVCDDDLPEPDETFIFHLTLQKPSANVKLGW
PRTVTVTILSNDNAFGIISFNMLPSIAVSEPKGRNESMPLTLIREKGTYGMVMVTFEVEGGPNP
PDEDLSPVKGNITFPPGRATVIYNLTVLDDEVPENDEIFLIQLKSVEGGAEINTSRNSIEIIIKKN
DSPVRFLQSIYLVPEEDHILIIPVVRGKDNNGNLIGSDEYEVSISYAVTTGNSTAHAQQNLDFID
LQPNTTVVFPPFIHESHLKFQIVDDTIPEIAESFHIMLLKDTLQGDAVLISPSVVQVTIKPNDKP
YGVLSFNSVLFERTVIIDEDRISRYEEITVVRNGGTHGNVSANWVLTRNSTDPSPVTADIRPSS
GVLHFAQGQMLATIPLTVVDDDLPEEAEAYLLQILPHTIRGGAEVSEPAELLFYIQDSDDVYG
LITFFPMENQKIESSPGERYLSLSFTRLGGTKGDVRLLYSVLYIPAGAVDPLQAKEGILNISRRN
DLIFPEQKTQVTTKLPIRNDAFLQNGAHFLVQLETVELLNIIPLIPPISPRFGEICNISLLVTPAIA
NGEIGFLSNLPIILHEPEDFAAEVVYIPLHRDGTDGQATVYWSLKPSGFNSKAVTPDDIGPFNG
SVLFLSGQSDTTINITIKGDDIPEMNETVTLSLDRVNVENQVLKSGYTSRDLIILENDDPGGVF
EFSPASRGPYVIKEGESVELHIIRSRGSLVKQFLHYRVEPRDSNEFYGNTGVLEFKPGEREIVIT
LLARLDGIPELDEHYWVVLSSHGERESKLGSATIVNITILKNDDPHGIIEFVSDGLIVMINESKG
DAIYSAVYDVVRNRGNFGDVSVSWVVSPDFTQDVFPVQGTVVFGDQEFSKNITIYSLPDEIPE
EMEEFTVILLNGTGGAKVGNRTTATLRIRRNDDPIYFAEPRVVRVQEGETANFTVLRNGSVD
VTCMVQYATKDGKATARERDFIPVEKGETLIFEVGSRQQSISIFVNEDGIPETDEPFYIILLNST
GDTVVYQYGVATVIIEANDDPNGIFSLEPIDKAVEEGKTNAFWILRHRGYFGSVSVSWQLFQ
NDSALQPGQEFYETSGTVNFMDGEEAKPIILHAFPDKIPEFNEFYFLKLVNISGGSPGPGGQLA
ETNLQVTVMVPFNDDPFGVFILDPECLEREVAEDVLSEDDMSYITNFTILRQQGVFGDVQLG
WEILSSEFPAGLPPMIDFLLVGIFPTTVHLQQHMRRHHSGTDALYFTGLEGAFGTVNPKYHPS
RNNTIANFTFSAWVMPNANTNGFIIAKDDGNGSIYYGVKIQTNESHVTLSLHYKTLGSNATYI
AKTTVMKYLEESVWLHLLIILEDGIIEFYLDGNAMPRGIKSLKGEAITDGPGILRIGAGINGND
RFTGLMQDVRSYERKLTLEEIYELHAMPAKSDLHPISGYLEFRQGETNKSFIISARDDNDEEG
EELFILKLVSVYGGARISEENTTARLTIQKSDNANGLFGFTGACIPEIAEEGSTISCVVERTRGA
LDYVHVFYTISQIETDGINYLVDDFANASGTITFLPWQRSEVLNIYVLDDDIPELNEYFRVTLV
SAIPGDGKLGSTPTSGASIDPEKETTDITIKASDHPYGLLQFSTGLPPQPKDAMTLPASSVPHIT
VEEEDGEIRLLVIRAQGLLGRVTAEFRTVSLTAFSPEDYQNVAGTLEFQPGERYKYIFINITDN
SIPELEKSFKVELLNLEGGVAELFRVDGSGSGDGDMEFFLPTIHKRASLGVASQILVTIAASDH
AHGVFEFSPESLFVSGTEPEDGYSTVTLNVIRHHGTLSPVTLHWNIDSDPDGDLAFTSGNITFE
IGQTSANITVEILPDEDPELDKAFSVSVLSVSSGSLGAHINATLTVLASDDPYGIFIFSEKNRPV
KVEEATQNITLSIIRLKGLMGKVLVSYATLDDMEKPPYFPPNLARATQGRDYIPASGFALFGA
NQSEATIAISILDDDEPERSESVFIELLNSTLVAKVQSRSIPNSPRLGPKVETIAQLIIIANDDAFG
TLQLSAPIVRVAENHVGPIINVTRTGGAFADVSVKFKAVPITAIAGEDYSIASSDVVLLEGETS
KAVPIYVINDIYPELEESFLVQLMNETTGGARLGALTEAVIIIEASDDPYGLFGFQITKLIVEEPE
FNSVKVNLPIIRNSGTLGNVTVQWVATINGQLATGDLRVVSGNVTFAPGETIQTLLLEVLAD
DVPEIEEVIQVQLTDASGGGTIGLDRIANIIIPANDDPYGTVAFAQMVYRVQEPLERSSCANIT
VRRSGGHFGRLLLFYSTSDIDVVALAMEEGQDLLSYYESPIQGVPDPLWRTWMNVSAVGEP
LYTCATLCLKEQACSAFSFFSASEGPQCFWMTSWISPAVNNSDFWTYRKNMTRVASLFSGQ
AVAGSDYEPVTRQWAIMQEGDEFANLTVSILPDDFPEMDESFLISLLEVHLMNISASLKNQPT
IGQPNISTVVIALNGDAFGVFVIYNISPNTSEDGLFVEVQEQPQTLVELMIHRTGGSLGQVAVE
WRVVGGTATEGLDFIGAGEILTFAEGETKKTVILTILDDSEPEDDESIIVSLVYTEGGSRILPSS
DTVRVNILANDNVAGIVSFQTASRSVIGHEGEILQFHVIRTFPGRGNVTVNWKIIGQNLELNFA
NFSGQLFFPEGSLNTTLFVHLLDDNIPEEKEVYQVILYDVRTQGVPPAGIALLDAQGYAAVLT
VEASDEPHGVLNFALSSRFVLLQEANITIQLFINREFGSLGAINVTYTTVPGMLSLKNQTVGNL
AEPEVDFVPIIGFLILEEGETAAAINITILEDDVPELEEYFLVNLTYVGLTMAASTSFPPRLDSEG
LTAQVIIDANDGARGVIEWQQSRFEVNETHGSLTLVAQRSREPLGHVSLFVYAQNLEAQVGL
DYIFTPMILHFADGERYKNVNIMILDDDIPEGDEKFQLILTNPSPGLELGKNTIALIIVLANDDG
PGVLSFNNSEHFFLREPTALYVQESVAVLYIVREPAQGLFGTVTVQFIVTEVNSSNESKDLTPS
KGYIVLEEGVRFKALQISAILDTEPEMDEYFVCTLFNPTGGARLGVHVQTLITVLQNQAPLGL
FSISAVENRATSIDIEEANRTVYLNVSRTNGIDLAVSVQWETVSETAFGMRGMDVVFSVFQSF
LDESASGWCFFTLENLIYGIMLRKSSVTVYRWQGIFIPVEDLNIENPKTCEAFNIGFSPYFVITH
EERNEEKPSLNSVFTFTSGFKLFLVQTIIILESSQVRYFTSDSQDYLIIASQRDDSELTQVFRWN
GGSFVLHQKLPVRGVLTVALFNKGGSVFLAISQANARLNSLLFRWSGSGFINFQEVPVSGTTE
VEALSSANDIYLIFAENVFLGDQNSIDIFIVVEMGQSSFRYFQSVDFAAVNRIHSFTPASGIAHIL
LIGQDMSALYCWNSERNQFSFVLEVPSAYDVASVTVKSLNSSKNLIALVGAHSHIYELAYISS
HSDFIPSSGELIFEPGEREATIAVNILDDTVPEKEESFKVQLKNPKGGAEIGINDSVTITILSNDD
AYGIVAFAQNSLYKQVEEMEQDSLVTLNVERLKGTYGRITIAWEADGSISDIFPTSGVILFTEG
QVLSTITLTILADNIPELSEVVIVTLTRITTEGVEDSYKGATIDQDRSKSVITTLPNDSPFGLVG
WRAASVFIRVAEPKENTTTLQLQIARDKGLLGDIAIHLRAQPNFLLHVDNQATENEDYVLQE
TIIIMKENIKEAHAEVSILPDDLPELEEGFIVTITEVNLVNSDFSTGQPSVRRPGMEIAEIMIEEN
DDPRGIFMFHVTRGAGEVITAYEVPPPLNVLQVPVVRLAGSFGAVNVYWKASPDSAGLEDF
KPSHGILEFADKQVTAMIEITIIDDAEFELTETFNISLISVAGGGRLGDDVVVTVVIPQNDSPFG
VFGFEEKTVMIDESLSSDDPDSYVTLTVVRSPGGKGTVRLEWTIDEKAKHNLSPLNGTLHFD
ETESQKTIVLHTLQDTVLEEDRRFTIQLISIDEVEISPVKGSASIIIRGDKRASGEVGIAPSSRHILI
GEPSAKYNGTAIISLVRGPGILGEVTVFWRIFPPSVGEFAETSGKLTMRDEQSAVIVVIQALND
DIPEEKSFYEFQLTAVSEGGVLSESSSTANITVVASDSPYGRFAFSHEQLRVSEAQRVNITIIRSS
GDFGHVRLWYKTMSGTAEAGLDFVPAAGELLFEAGEMRKSLHVEILDDDYPEGPEEFSLTIT
KVELQGRGYDFTIQENGLQIDQPPEIGNISIVRIIIMKNDNAEGIIEFDPKYTAFEVEEDVGLIMI
PVVRLHGTYGYVTADFISQSSSASPGGVDYILHGSTVTFQHGQNLSFINISIIDDNESEFEEPIEI
LLTGATGGAVLGRHLVSRIIIAKSDSPFGVIRFLNQSKISIANPNSTMILSLVLERTGGLLGEIQV
NWETVGPNSQEALLPQNRDIADPVSGLFYFGEGEGGVRTIILTIYPHEEIEVEETFIIKLHLVKG
EAKLDSRAKDVTLTIQEFGDPNGVVQFAPETLSKKTYSEPLALEGPLLITFFVRRVKGTFGEIM
VYWELSSEFDITEDFLSTSGFFTIADGESEASFDVHLLPDEVPEIEEDYVIQLVSVEGGAELDLE
KSITWFSVYANDDPHGVFALYSDRQSILIGQNLIRSIQINITRLAGTFGDVAVGLRISSDHKEQP
IVTENAERQLVVKDGATYKVDVVPIKNQVFLSLGSNFTLQLVTVMLVGGRFYGMPTILQEA
KSAVLPVSEKAANSQVGFESTAFQLMNITAGTSHVMISRRGTYGALSVAWTTGYAPGLEIPE
FIVVGNMTPTLGSLSFSHGEQRKGVFLWTFPSPGWPEAFVLHLSGVQSSAPGGAQLRSGFIVA
EIEPMGVFQFSTSSRNIIVSEDTQMIRLHVQRLFGFHSDLIKVSYQTTAGSAKPLEDFEPVQNG
ELFFQKFQTEVDFEITIINDQLSEIEEFFYINLTSVEIRGLQKFDVNWSPRLNLDFSVAVITILDN
DDLAGMDISFPETTVAVAVDTTLIPVETESTTYLSTSKTTTILQPTNVVAIVTEATGVSAIPEKL
VTLHGTPAVSEKPDVATVTANVSIHGTFSLGPSIVYIEEEMKNGTFNTAEVLIRRTGGFTGNV
SITVKTFGERCAQMEPNALPFRGIYGISNLTWAVEEEDFEEQTLTLIFLDGERERKVSVQILDD
DEPEGQEFFYVFLTNPQGGAQIVEEKDDTGFAAFAMVIITGSDLHNGIIGFSEESQSGLELREG
AVMRRLHLIVTRQPNRAFEDVKVFVVRVTLNKTVVVLQKDGVNLVEELQSVSGTTTCTMGQ
TKCFISIELKPEKVPQVEVYFFVELYEATAGAAINNSARFAQIKILESDESQSLVYFSVGSRLAV
AHKKATLISLQVARDSGTGLMMSVNFSTQELRSAETIGRTIISPAISGKDFVITEGTLVFEPGQR
STVLDVILTPETGSLNSFPKRFQIVLFDPKGGARIDKVYGTANITLVSDADSQAIVVGLADQLH
QPVNDDILNRVLHTISMKVATENTDEQLSAMMHLIEKITTEGKIQAFSVASRTLFYEILCSLIN
PKRKDTRGFSHFAEVTENFAFSLLTNVTCGSPGEKSKTILDSCPYLSILALHWYPQQINGHKFE
GKEGDYIRIPERLLDVQDAEIMAGKSTCKLVQFTEYSSQQWFISGNNLPTLKNKVLSLSVKGQ
SSQLLTNDNEVLYRIYAAEPRIIPQTSLCLLWNQAAASWLSDSQFCKVVEETADYVECACSH
MSVYAVYARTDNLSSYNEAFFTSGFICISGLCLAVLSHIFCARYSMFAAKLLTHMMAASLGT
QILFLASAYASPQLAEESCSAMAAVTHYLYLCQFSWMLIQSVNFVVYVLVMNDEHTERRYLL
FFLLSWGLPAFVVILLIVILKGIYHQSMSQIYGLIHGDLCFIPNVYAALFTAALVPLTCLVVVFV
VFIHAYQVKPQWKAYDDVFRGRTNAAEIPLILYLFALISVTWLWGGLHMAYRHFVVMLVLF
VIFNSLQGLYVFMVYFILHNQMCCPMKASYTVEMNGHPGPSTAFFTPGSGMPPAGGEISKST
QNLIGAMEEVPPDWERASFQQGSQASPDLKPSPQNGATFPSSGGYGQGSLIADEESQEFDDLI
FALKTGAGLSVSDNESGQGSQEGGTLTDSQIVELRRIPIADTHL (SEQ ID NO:1253)
>gi|114205383|ref|NP_0029712| secretin receptor precursor
{Homosapiens}
MRPHLSPPLQQLLLPVLLACAAHSTGALPRLCDVLQVLWEEQDQCLQELSREQTGDLGTEQP
VPGCEGMWDNISCWPSSVPGRMVEVECPRFLRMLTSRNGSLFRNCTQDGWSETFPRPNLAC
GVNVNDSSNEKRHSYLLKLKVMYTVGYSSSLVMLLVALGILCAFRRLHCTRNYIHMHLFVS
FILRALSNFIKDAVLFSSDDVTYCDAHRAGCKLVMVLFQYCIMANYSWLLVEGLYLHTLLAI
SFFSERKYLQGFVAFGWGSPAIFVALWAIARHFLEDVGCWDINANASIVVWIIRGPVILSILINFI
LFINILRILMRKLRTQETRGNEVSHYKRLARSTLLLIPLFGIHYIVFAFSPEDAMEIQLFFELALG
SFQGLVVAVLYCFLNGEVQLEVQKKWQQWHLREFPLHPVASFSNSTKASHLEQSQGTCRTSI I
(SEQ ID NO:1254) >gi|115387099|ref|NP_0016942| brain-specific
angiogenesis inhibitor 2 precursor {Homosapiens}
MENTGWMGKGHRMTPACPLLLSVILSLRLATAFDPAPSACSALASGVLYGAFSLQDLFPTIA
SGCSWTLENPDPTKYSLYLRFNRQEQVCAHFAPRLLPLDHYLVNFTCLRPSPEEAVAQAESE
VGRPEEEEAEAAAGLELCSGSGPFTFLHFDKNFVQLCLSAEPSEAPRLLAPAALAFRFVEVLLI
NNNNSSQFTCGVLCRWSEECGRAAGRACGFAQPGCSCPGEAGAGSTTTTSPGPPAAHTLSNA
LVPGGPAPPAEADLHSGSSNDLFTTEMRYGEEPEEEPKVKTQWPRSADEPGLYMAQTGDPA
AEEWSPWSVCSLTCGQGLQVRTRSCVSSPYGTLCSGPLRETRPCNNSATCPVHGVWEEWGS
WSLCSRSCGRGSRSRMRTCVPPQHGGKACEGPELQTKLCSMAACPVEGQWLEWGPWGPCS
TSCANGTQQRSRKCSVAGPAWATCTGALTDTRECSNLECPATDSKWGPWNAWSLCSKTCD
TGWQRRFRMCQATGTQGYPCEGTGEEVKPCSEKRCPAFHEMCRDEYVMLMTWKKAAAGE
IIYNKCPPNASGSASRRCLLSAQGVAYWGLPSFARCISHEYRYLYLSLREHLAKGQRMLAGE
GMSQVVRSLQELLARRTYYSGDLLFSVDILRNVTDTFKRATYVPSADDVQRFFQVVSFMVD
AENKEKWDDAQQVSPGSVHLLRVVEDFIHLVGDALKAFQSSLIVTDNLVISIQREPVSAVSSD
ITFPMRGRRGMKDWVRHSEDRLFLPKEVLSLSSPGKPATSGAAGSPGRGRGPGTVPPGPGHS
HQRLLPADPDESSYFVIGAVLYRTLGLILPPPRPPLAVTSRVMTVTVRPPTQPPAEPLITVELSY
IINGTTDPHCASWDYSRADASSGDWDTENCQTLETQAAHTRCQCQHLSTFAVLAQPPKDLTL
ELAGSPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLS
KGVCTMTAAFLHFFFLSSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVS
VGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIVLVNMLIGIIVFNKLMARDGISDKSKKQ
RAGSERCPWASLLLPCSACGAVPSPLLSSASARNAMASLWSSCVVLPLLALTWMSAVLAMT
DRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQMGVCRADESEDSPDSCKNGQL
QILSDFEKDVDLACQTVLFKEVNTCNPSTITGTLSRLSLDEDEEPKSCLVGPEGSLSFSPLPGNI
LVPMAASPGLGEPPPPQEANPVYMCGEGGLRQLDLTWLRPTEPGSEGDYMVLPRRTLSLQP
GGGGGGGEDAPRARPEGTPRRAAKTVAHTEGYPSFLSVDHSGLGLGPAYGSLQNPYGMTFQ
PPPPTPSARQVPEPGERSRTMPRTVPGSTMKMGSLERKKLRYSDLDFEKVMHTRKRHSELYH
ELNQKFHTFDRYRSQSTAKREKRWSVSSGGAAERSVCTDKPSPGERPSLSQHRRHQSWSTFK
SMTLGSLPPKPRERLTLHRAAAWEPTEPPDGDFQTEV (SEQ ID NO:1255)
>gi|116063556|ref|NP_0713322| probable G-protein coupled
receptor 88 {Homosapiens}
MTNSSSTSTSSTTGGSLLLLCEEEESWAGRRIPVSLLYSGLAIGGTLANGMVIYLVSSFRKLQT
TSNAFIVNGCAADLSVCALWMPQEAVLGLLPTGSAEPPADWDGAGGSYRLLRGGLLGLGLT
VSLLSHCLVALNRYLLITRAPATYQALYQRRHTAGMLALSWALALGLVLLLPPWAPRPGAA
PPRVHYPALLAAAALLAQTALLLHCYLGIVRRVRVSVKRVSVLNFHLLHQLPGCAAAAAAF
PGAQHAPGPGGAAHPAQAQPLPPALHPRRAQRRLSGLSVLLLCCVFLLATQPLVWVSLASGF
SLPVPWGVQAASWLLCCALSALNPLLYTWRNEEFRRSVRSVLPGVGDAAAAAVAATAVPA
VSQAQLGTRAAGQHW (SEQ ID NO:1256)
>gi|116284382|ref|NP_0010706621| G-protein coupled bile acid
receptor 1 {Homosapiens}
MTPNSTGEVPSPIPKGALGLSLALASLIITANLLLALGIAWDRRLRSPPAGCFFLSLLLAGLLTG
LALPTLPGLWNQSRRGYWSCLLVYLAPNFSFLSLLANLLLVHGERYMAVLRPLQPPGSIRLA
LLLTWAGPLLFASLPALGWNHWTPGANCSSQAIFPAPYLYLEVYGLLLPAVGAAAFLSVRVL
ATAHRQLQDICRLERAVCRDEPSALARALTWRQARAQAGAMLLFGLCWGPYVATLLLSVL
AYEQRPPLGPGTLLSLLSLGSASAAAVPVAMGLGDQRYTAPWRAAAQRCLQGLWGRASRD
SPGPSIAYHPSSQSSVDLDLN (SEQ ID NO:1257)
>gi|116517328|ref|NP_7225803| probable G-protein coupled
receptor 115 precursor {Homosapiens}
MKMKSQATMICCLVFFLSTECSHYRSKIHLKAGDKLQSPEGKPKTGRIQEKCEGPCISSSNCS
QPCAKDFHGEIGFTCNQKKWQKSAETCTSLSVEKLFKDSTGASRLSVAAPSIPLHILDFRAPET
IESVAQGIRKNCPFDYACITDMVKSSETTSGNIAFIVELLKNISTDLSDNVTREKMKSYSEVAN
HILDTAAISNWAFIPNKNASSDLLQSVNLFARQLHIHNNSENIVNELFIQTKGFHINHNTSEKSL
NFSMSMNNTTEDILGMVQIPRQELRKLWPNASQAISIAFPTLGAILREAHLQNVSLPRQVNGL
VLSVVLPERLQEIILTFEKINKTRNARAQCVGWHSKKRRWDEKACQMMLDIRNEVKCRCNY
TSVVMSFSILMSSKSMTDKVLDYITCIGLSVSILSLVLCLIIEATVWSRVVVTEISYMRHVCIVN
IAVSLLTANVWFIIGSHFNIKAQDYNMCVAVTFFSHFFYLSLFFWMLFKALLIIYGILVIFRRM
MKSRMMVIGFAIGYGCPLHAVTTVAITEPEKGYMRPEACWLNWDNTKALLAFAIPAFVIVA
VNLIVVLVVAVNTQRPSIGSSKSQDVVIIMRISKNVAILTPLLGLTWGFGIATLIEGTSLTFHIIF
ALLNAFQGFFILLFGTIMDHKIRDALRMRMSSLKGKSRAAENASLGPTNGSKLMNRQG (SEQ ID
NO:1258) >gi|117940060|ref|NP_0009053| opioid receptor, mu 1
isoform MOR-1 {Homosapiens}
MDSSAAPTNASNCTDALAYSSCSPAPSPGSWVNLSHLDGNLSDPCGPNRTDLGGRDSLCPPT
GSPSMITAITIMALYSIVCVVGLFGNFLVMYVIVRYTKMKTATNIYIFNLALADALATSTLPFQ
SVNYLMGTWPFGTILCKIVISIDYYNMFTSIFTLCTMSVDRYIAVCHPVKALDFRTPRNAKIIN
VCNWILSSAIGLPVMFMATTKYRQGSIDCTLTFSHPTWYVVENLLKICVFIFAFIMPVLIITVCY
GLMILRLKSVRMLSGSKEKDRNLRRITRMVLVVVAVFIVCWTPIHIYVIIKALVTIPETTFQTV
SWHFCIALGYTNSCLNPVLYAFLDENFKRCFREFCIPTSSNIEQQNSTRIRQNTRDHPSTANTV
DRTNHQLENLEAETAPLP >gi|119220588|ref|NP_1158922|
melanin-concentrating hormone receptor 2 {Homosapiens}
MNPFHASCWNTSAELLNKSWNKEFAYQTASVVDTVILPSMIGIICSTGLVGNILIVFTIIRSRK
KTVPDIYICNLAVADLVHIVGMPFLIHQWARGGEWVFGGPLCTIITSLDTCNQFACSAIMTVM
SVDRYFALVQPFRLTRWRTRYKTIRINLGLWAASFILALPVWVYSKVIKFKDGVESCAFDLTS
PDDVLWYTLYLTITTFFFPLPLILVCYILILCYTVVEMYQQNKDARCCNPSVPKQRVMKLTKM
VLVLVVVFILSAAPYHVIQLVNLQMEQPTLAFYVGYYLSICLSYASSSINPFLYILLSGNFQKR
LPQIQRRATEKEINNMGNTLKSHF (SEQ ID NO:1259)
>gi|119508433|ref|NP_0059032| melanocortin receptor 4
{Homosapiens }
MVNSTHRGMHTSLHLWNRSSYRLHSNASESLGKGYSDGGCYEQLFVSPEVFVTLGVISLLEN
ILVIVAIAKNKNLHSPMYFFICSLAVADMLVSVSNGSETIVITLLNSTDTDAQSFTVNIDNVIDS
VICSSLLASICSLLSIAVDRYFTIFYALQYHNIMTVKRVGIIISCIVVAACTVSGILFIIYSDSSAVII
CLITMFFTMLALMASLYVHMFLMARLHIKRIAVLPGTGAIRQGANMKGAITLTILIGVFVVC
WAPFFLHLIFYISCPQNPYCVCFMSHFNLYLILIMCNSIIDPLIYALRSQELRKTFKEIICCYPLG
GLCDLSSRY (SEQ ID NO:1260) >gi|119943116|ref|NP_0010733281|
G-protein coupled receptor 64 isoform 2 {Homosapiens}
MVFSVRQCGHVGRTEEVLLTFKIFLVIICLHVVLVTSLEEDTDNSSLSPPPAKLSVVSFAPSSN
GTPEVETTSLNDVTLSLLPSNETGVKPQRNICNLSSICNDSAFFRGEIMFQYDKESTVPQNQHI
TNGTLTGVLSLSELKRSELNKTLQTLSETYFIMCATAEAQSTLNCTFTIKLNNTMNACAVIAA
LERVKIRPMEHCCCSVRIPCPSSPEELEKLQCDLQDPIVCLADHPRGPPFSSSQSIPVVPRATVL
SQVPKATSFAEPPDYSPVTHNVPSPIGEIQPLSPQPSAPIASSPAIDMPPQSETISSPMPQTHVSG
TPPPVKASFSSPTVSAPANVNTTSAPPVQTDIVNTSSISDLENQVLQMEKALSLGSLEPNLAGE
MINQVSRLLHSPPDMLAPLAQRLLKVVDDIGLQLNFSNTTISLTSPSLALAVIRVNASSFNTTT
FVAQDPANLQVSLETQAPENSIGTITLPSSLMNNLPAHDMELASRVQFNFFETPALFQDPSLE
NLSLISYVISSSVANLTVRNLTRNVTVTLKHINPSQDELTVRCVFVVDLGRNGGRGGWSDNGC
SVKDRRLNETICTCSHLTSFGVLLDLSRTSVLPAQMMALTFITYIGCGLSSIFLSVTLVTYIAFE
KIRRDYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYFLLVSFTVVMGLEAF
HMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTISPDNYGLGSYGKFPNGSPDDFCWI
NNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQDLRSIAGLTFLLGI
TWGFAFFAWGPVNVTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYLCCGKLRLAENSD
WSKTATNGLKKQTVNQGVSSSSNSLQSSSNSTNSTTLLVNNDCSVHASGNGNASTERNGVSF
SVQNGDVCLHDFTGKQHMFNEKEDSCNGKGRMALRRTSKRGSLHFIEQM (SEQ ID NO:1261)
>gi|125625352|ref|NP_0556943| P2Y14 receptor {Homosapiens }
MINSTSTQPPDESCSQNLLITQQIIPVLYCMVFIAGILLNGVSGWIFFYVPSSKSFIIYLKNIVIAD
FVMSLTFPFKILGDSGLGPWQLNVFVCRVSAVLFYVNMYVSIVFFGLISFDRYYKIVKPLWTS
FIQSVSYSKLLSVIVWMLMLLLAVPNIILTNQSVREVTQIKCIELKSELGRKWHKASNYIFVAI
FVVIVFLLLIVFYTAITKKIFKSHLKSSRNSTSVKKKSSRNIFSIVFVFFVCFVPYHIARIPYTKSQT
EAHYSCQSKEILRYMKEFTLLLSAANVCLDPIIYFFLCQPFREILCKKLHIPLKAQNDLDISRIK
RGNTTLESTDTL (SEQ ID NO:1262) >gi|125660451|ref|NP_6717323|
MAS-related GPR, member X1 {Homosapiens}
MDPTISTLDTELTPINGTEETLCYKQTLSLTVLTCIVSLVGLTGNAVVLWLLGCRMRRNAFSI
YILNLAAADFLFLSGRLIYSLLSFISIPHTISKILYPVMMFSYFAGLSFLSAVSTERCLSVLWPIVV
YRCHRPTHLSAVVCVLLWALSLLRSILEWMLCGFLFSGADSAWCQTSDFITVAWLIFLCVVL
CGSSLVLLIRILCGSRKIPLTRLYVTILLTVLVFLLCGLPFGIQFFLFLWIHVDREVLFCHVHLVS
IFLSALNSSANPIIYFFVGSFRQRQNRQNLKLVLQRALQDASEVDEGGGQLPEEILELSGSRLE Q
(SEQ ID NO:1263) >gi|133930786|ref|NP_1159602| EGF-like
module-containing mucin-like hormone receptor-like 3 {Homosapiens}
MQGPLLLPGLCFLLSLFGAVTQKTKTSCAKCPPNASCVNNTHCTCNHGYTSGSGQKLFTFPL
ETCNDINECTPPYSVYCGFNAVCYNVEGSFYCQCVPGYRLHSGNEQFSNSNENTCQDTTSSK
TTEGRKELQKIVDKFESLLTNQTLWRTEGRQEISSTATTILRDVESKVLETALKDPEQKVLKIQ
NDSVAIETQAITDNCSEERKTFNLNVQMNSMDIRCSDIIQGDTQGPSAIAFISYSSLGNIINATF
FEEMDKKDQVYLNSQVVSAAIGPKRNVSLSKSVTLTFQHVKMTPSTKKVFCVYVVKSTGQGS
QWSRDGCFLIHVNKSHTMCNCSHLSSFAVLMALTSQEEDPVLTVITYVGLSVSLLCLLLAAL
TFLLCKAIRNTSTSLHLQLSLCLFLAHLLFLVGIDRTEPKVLCSIIAGALHYLYLAAFTWMLLE
GVHLFLTARNLTVVNYSSINRLMKWIMFPVGYGVPAVTVAISAASWPHLYGTADRCWLHLD
QGFMWSFLGPVCAIFSANLVLFILVFVVILKRKLSSLNSEVSTIQNTRMLAFKATAQLFILGCT
WCLGLLQVGPAAQVMAYLFTIINSLQGFFIFLVYCLLSQQVQKQYQKWFREIVKSKSESETY
TLSSKMGPDSKPSEGDVFPGQVKRKY (SEQ ID NO:1264)
>gi|134244291|ref|NP_0047583| endothelin B receptor-like protein
2 precursor {Homosapiens}
MRWLWPLAVSLAVILAVGLSRVSGGAPLHLGRHRAETQEQQSRSKRGTEDEEAKGVQQYV
PEEWAEYPRPIHPAGLQPTKPLVATSPNPGKDGGTPDSGQELRGNLTGAPGQRLQIQNPLYPV
TESSYSAYAIMLLALVVFAVGIVGNLSVMCIVWHSYYLKSAWNSILASLALWDFLVLFFCLPI
VIFNEITKQRLLGDVSCRAVPFMEVSSLGVTTFSLCALGIDRFHVATSTLPKVRPIERCQSILAK
LAVIVVVGSMTLAVPELLLWQLAQEPAPTMGTLDSCIMKPSASLPESLYSLVMTYQNARMW
WYFGCYFCLPILFTVTCQLVTWRVRGPPGRKSECRASKHEQCESQLNSTVVGLTVVYAFCTL
PENVCNIVVAYLSTELTRQTLDLLGLINQFSTFFKGAITPVLLLCICRPLGQAFLDCCCCCCCE
ECGGASEASAANGSDNKLKTEVSSSIYFHKPRESPPLLPLGTPC (SEQ ID NO:1265)
>gi|134244587|ref|NP_0042213| endothelial differentiation,
sphingolipid G- protein-coupled receptor, 5 {Homosapiens}
MGSLYSEYLNPNKVQEHYNYTKETLETQETTSRQVASAFIVILCCAIVVENLLVLIAVARNSK
FHSAMYLFLGNLAASDLLAGVAFVANTLLSGSVTLRLTPVQWFAREGSAFITLSASVFSLLAI
AIERHVAIAKVKLYGSDKSCRMLLLIGASWLISLVLGGLPILGWNCLGHLEACSTVLPLYAKH
YVLCVVTIFSIILLAIVALYVRIYCVVRSSHADMAAPQTLALLKTVTIVLGVFIVCWLPAFSILL
LDYACPVHSCPILYKAHYFFAVSTLNSLLNPVIYTWRSRDLRREVLRPLQCWRPGVGVQGRR
RGGTPGHHLLPLRSSSSLERGMHMPTSPTFLEGNTVV (SEQ ID NO:1266)
>gi|134288847|ref|NP_7225814| probable G-protein coupled
receptor 111 {Homosapiens}
MTHILLLYYLVFLLPTESCRTLYQAASKSKEKVPARPHGVCDGVCTDYSQCTQPCPPDTQGN
MGFSCRQKTVVHKITDTCQTLNALNIFEEDSRLVQPFEDNIKISVYTGKSETITDMLLQKCPTD
LSCVIRNIQQSPWIPGNIAVIVQLLHNISTAIWTGVDEAKMQSYSTIANHILNSKSISNWTFIPD
RNSSYILLHSVNSFARRLFIDKHPVDISDVFIHTMGTTISGDNIGKNFTFSMRINDTSNEVTGRV
LISRDELRKVPSPSQVISIAFPTIGAILEASLLENVTVNGLVLSAILPKELKRISLIFEKISKSEERR
TQCVGWHSVENRWDQQACKMIQENSQQAVCKCRPSKLFTSFSILMSPHILESLILTYITYVGL
GISICSLILCLSIEVLVWSQVTKTEITYLRHVCIVNIAATLLMADVWFIVASFLSGPITHHKGCV
AATFFVHFFYLSVFFVVMLAKALLILYGIMIVFHTLPKSVLVASLFSVGYGCPLAIAAITVAATE
PGKGYLRPEICWLNWDMTKALLAFVIPALAIVVVNLITVTLVIVKTQRAAIGNSMFQEVRAIV
RISKNIAILTPLLGLTWGFGVATVIDDRSLAFHIIFSLLNAFQGFFILVFGTILDPKIREALKG
(SEQ ID NO:1267) >gi|141802362|ref|NP_7225772| probable
G-protein coupled receptor 113 isoform 3 {Homosapiens}
MTTRKLSAHSAATPGYKAVTHKHHTGWARMAKTGLPEKGQSQAGGESGSGQLLDQENGA
GESALVSVYVHLDFPDKTWPPELSRTLTLPAASASSSPRPLLTGLRLTTGEYMSCFEAQGFKW
NLYEVVRVPLKATDVARLPYQLSISCATSPGFQLSCCIPSTNLAYTAAWSPGEGSKASSFNES
GSQCFVLAVQRCPMADTTYACDLQSLGLAPLRVPISITIIQDGDITCPEDASVLTWNVTKAGH
VAQAPCPESKRGIVRRLCGADGVWGPVHSSCTDARLLALFTRTKLLQAGQGSPAEEVPQILA
QLPGQAAEASSPSDLLTLLSTMKYVAKVVAEARIQLDRRALKNLLIATDKVLDMDTRSLWT
LAQARKPWAGSTLLLAVETLACSLCPQDHPFAFSLPNVLLQSQLFGPTFPADYSISFPTRPPLQ
AQIPRHSLAPLVRNGTEISITSLVLRKLDHLLPSNYGQGLGDSLYATPGLVLVISIMAGDRAFS
QGEVIMDFGNTDGSPHCVFVVDHSLFQGRGGWSKEGCQAQVASASPTAQCLCQHLTAFSVL
MSPHTVPEEPALALLTQVGLGASILALLVCLGVYWLVWRVVVRNKISYFRHAALLNMVFCL
LAADTCFLGAPFLSPGPRSPLCLAAAFLCHFLYLATFFWMLAQALVLAHQLLFVFHQLAKHR
VLPLMVLLGYLCPLGLAGVTLGLYLPQGQYLREGECWLDGKGGALYTFVGPVLAIIGVNGL
VLAMAMLKLLRPSLSEGPPAEKRQALLGVIKALLILTPIFGLTWGLGLATLLEEVSTVPHYIFT
ILNTLQGVFILLFGCLMDRKIQEALRKRFCRAQAPSSTISLATNEGCILEHSKGGSDTARKTDA SE
(SEQ ID NO:1268) >gi|144922665|ref|NP_0010773781| probable
G-protein coupled receptor 123 {Homosapiens}
MDLKTVLSLPRYPGEFLHPVVYACTAVMLLCLLASFVTYIVHQSAIRISRKGRHTLLNFCFHA
ALTFTVFAGGINRTKYPILCQAVGIVLHYSTLSTMLWIGVTARNIYKQVTKKAPLCLDTDQPP
YPRQPLLRFYLVSGGVPFIICGVTAATNIRNYGTEDEDTAYCWMAWEPSLGAFYGPAAIITLV
TCVYFLGTYVQLRRHPGRRYELRTQPEEQRRLATPEGGRGIRPGTPPAHDAPGASVLQNEHS
FQAQLRAAAFTLFLFTATWAFGALAVSQGHFLDMVFSCLYGAFCVTLGLFVLIHHCAKRED
VWQCWWACCPPRKDAHPALDANGAALGRAACLHSPGLGQPRGFAHPPGPCKMTNLQAAQ
GHASCLSPATPCCAKMHCEPLTADEAHVHLQEEGAFGHDPHLHGCLQGRTKPPYFSRHPAE
EPEYAYHIPSSLDGSPRSSRTDSPPSSLDGPAGTHTLACCTQGDPFPMVTQPEGSDGSPALYSC
PTQPGREAALGPGHLEMLRRTQSLPFGGPSQNGLPKGKLLEGLPFGTDGTGNIRTGPWKNET TV
(SEQ ID NO:1269) >gi|145309304|ref|NP_0013982| cadherin EGF LAG
seven-pass G-type receptor 3 precursor {Homosapiens }
MMARRPPWRGLGGRSTPILLLLLLSLFPLSQEELGGGGHQGWDPGLAATTGPRAHIGGGALA
LCPESSGVREDGGPGLGVREPIFVGLRGRRQSARNSRGPPEQPNEELGIEHGVQPLGSRERET
GQGPGSVLYWRPEVSSCGRTGPLQRGSLSPGALSSGVPGSGNSSPLPSDFLIRHHGPKPVSSQ
RNAGTGSRKRVGTARCCGELWATGSKGQGERATTSGAERTAPRRNCLPGASGSGPELDSAP
RTARTAPASGSAPRESRTAPEPAPKRMRSRGLFRCRFLPQRPGPRPPGLPARPEARKVTSANR
ARFRRAANRHPQFPQYNYQTLVPENEAAGTAVLRVVAQDPDAGEAGRLVYSLAALMNSRS
LELFSIDPQSGLIRTAAALDRESMERHYLRVTAQDHGSPRLSATTMVAVTVADRNDHSPVFE
QAQYRETLRENVEEGYPILQLRATDGDAPPNANLRYRFVGPPAARAAAAAAFEIDPRSGLIST
SGRVDREHMESYELVVEASDQGQEPGPRSATVRVHITVLDENDNAPQFSEKRYVAQVREDV
RPHTVVLRVTATDRDKDANGLVHYNIISGNSRGHFAIDSLTGEIQVVAPLDFEAEREYALRIR
AQDAGRPPLSNNTGLASIQVVDINDHIPIFVSTPFQVSVLENAPLGHSVIHIQAVDADHGENAR
LEYSLTGVAPDTPFVINSATGWVSVSGPLDRESVEHYFFGVEARDHGSPPLSASASVTVTVLD
VNDNRPEFTMKEYHLRLNEDAAVGTSVVS VTAVDRDANSAISYQITGGNTRNRFAISTQGGV
GLVTLALPLDYKQERYFKLVLTASDRALHDHCYVHINITDANTHRPVFQSAHYSVSVNEDRP
MGSTIVVISASDDDVGENARITYLLEDNLPQFRIDADSGAITLQAPLDYEDQVTYTLAITARD
NGIPQKADTTYVEVMVNDVNDNAPQFVASHYTGLVSEDAPPFTSVLQISATDRDAHANGRV
QYTFQNGEDGDGDFTIEPTSGIVRTVRRLDREAVSVYELTAYAVDRGVPPLRTPVSIQVMVQ
DVNDNAPVFPAEEFEVRVKENSIVGSVVAQITAVDPDEGPNAHIMYQIVEGNIPELFQMDIFS
GELTALIDLDYEARQEYVIVVQATSAPLVSRATVHVRLVDQNDNSPVLNNFQILFNNYVSNR
SDTFPSGIIGRIPAYDPDVSDHLFYSFERGNELQLLVVNQTSGELRLSRKLDNNRPLVASMLVT
VTDGLHSVTAQCVLRVVIITEELLANSLTVRLENMWQERFLSPLLGRFLEGVAAVLATPAED
VFIFNIQNDTDVGGTVLNVSFSALAPRGAGAGAAGPWFSSEELQEQLYVRRAALAARSLLDV
LPFDDNVCLREPCENYMKCVSVLRFDSSAPFLASASTLFRPIQPIAGLRCRCPPGFTGDFCETE
LDLCYSNPCRNGGACARREGGYTCVCRPRFTGEDCELDTEAGRCVPGVCRNGGTCTDAPNG
GFRCQCPAGGAFEGPRCEVAARSFPPSSFVMFRGLRQRFHLTLSLSFATVQQSGLLFYNGRLN
EKHDFLALELVAGQVRLTYSTGESNTVVSPTVPGGLSDGQWHTVHLRYYNKPRTDALGGA
QGPSKDKVAVLSVDDCDVAVALQFGAEIGNYSCAAAGVQTSSKKSLDLTGPLLLGGVPNLP
ENFPVSHKDFIGCMRDLHIDGRRVDMAAFVANNGTMAGCQAKLHFCDSGPCKNSGFCSER
WGSFSCDCPVGFGGKDCQLTMAHPHHFRGNGTLSWNFGSDMAVSVPWYLGLAFRTRATQG
VLMQVQAGPHSTLLCQLDRGLLSVTVTRGSGRASHLLLDQVTVSDGRWHDLRLELQEEPGG
RRGHHVLMVSLDFSLFQDTMAVGSELQGLKVKQLHVGGLPPGSAEEAPQGLVGCIQGVWL
GSTPSGSPALLPPSHRVNAEPGCVVTNACASGPCPPHADCRDLWQTFSCTCQPGYYGPGCVD
ACLLNPCQNQGSCRHLPGAPHGYTCDCVGGYFGHHCEHRMDQQCPRGWWGSPTCGPCNC
DVHKGFDPNCNKTNGQCHCKEFHYRPRGSDSCLPCDCYPVGSTSRSCAPHSGQCPCRPGAL
GRQCNSCDSPFAEVTASGCRVLYDACPKSLRSGVWWPQTKFGVLATVPCPRGALGAAVRLC
DEAQGWLEPDLFNCTSPAFRELSLLLDGLELNKTALDTMEAKKLAQRLREVTGHTDHYFSQ
DVRVTARLLAHLLAFESHQQGFGLTATQDAHFNENLLWAGSALLAPETGDLWAALGQRAP
GGSPGSAGLVRHLEEYAATLARNMELTYLNPMGLVTPNIMLSIDRMEHPSSPRGARRYPRYH
SNLFRGQDAWDPHTHVLLPSQSPRPSPSEVLPTSSSIENSTTSSVVPPPAPPEPEPGISIIILLVYR
TLGGLLPAQFQAERRGARLPQNPVMNSPVVSVAVFHGRNFLRGILESPISLEFRLLQTANRSK
AICVQWDPPGLAEQHGVWTARDCELVHRNGSHARCRCSRTGTFGVLMDASPRERLEGDLEL
LAVFTHVVVAVSVAALVLTAAILLSLRSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQL
VCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVEPRNVDRGAMRFYHALGWGVPAVLLGLA
VGLDPEGYGNPDFCWISVHEPLIVVSFAGPVVLVIVMNGTMFLLAARTSCSTGQREAKKTSAL
TLRSSFLLLLLVSASWLFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVLNADARAAWM
PACLGRKAAPEEARPAPGLGPGAYNNTALFEESGLIRITLGASTVSSVSSARSGRTQDQDSQR
GRSYLRDNVLVRHGSAADHTDHSLQAHAGPTDLDVAMFHRDAGADSDSDSDLSLEEERSLS
IPSSESEDNGRTRGRFQRPLCRAAQSERLLTHPKDVDGNDLLSYWPALGECEAAPCALQTWG
SERRLGLDTSKDAANNNQPDPALTSGDETSLGRAQRQRKGILKNRLQYPLVPQTRGAPELSW
CRAATLGHRAVPAASYGRIYAGGGTGSLSQPASRYSSREQLDLLLRRQLSRERLEEAPAPVL
RPLSRPGSQECMDAAPGRLEPKDRGSTLPRRQPPRDYPGAMAGRFGSRDALDLGAPREWLS
TLPPPRRTRDLDPQPPPLPLSPQRQLSRDPLLPSRPLDSLSRSSNSREQLDQVPSRHPSREALGP
LPQLLRAREDSVSGPSHGPSTEQLDILSSILASFNSSALSSVQSSSTPLGPHTTATPSATASVLGP
STPRSATSHSISELSPDSEVPRSEGHS (SEQ ID NO:1270)
>gi|145309315|ref|NP_5431413| probable G-protein coupled
receptor 62 {Homosapiens}
MANSTGLNASEVAGSLGLILAAVVEVGALLGNGALLVVVLRTPGLRDALYLAHLCVVDLLA
AASIMPLGLLAAPPPGLGRVRLGPAPCRAARFLSAALLPACTLGVAALGLARYRLIVHPLRPG
SRPPPVLVLTAVWAAAGLLGALSLLGTPPAPPPAPARCSVLAGGLGPFRPLWALLAFALPAL
LLLGAYGGIFVVARRAALRPPRPARGSRLHSDSLDSRLSILPPLRPRLPGGKAALAPALAVGQ
FAACWLPYGCACLAPAARAAEAEAAVTWVAYSAFAAHPFLYGLLQRPVRLALGRLSRRAL
PGPVRACTPQAWHPRALLQCLQRPPEGPAVGPSEAPEQTPELAGGRSPAYQGPPESSLS (SEQ ID
NO:1271) >gi|148664220|ref|NP_6594523| mas-related G-protein
coupled receptor member F {Homosapiens}
MAGNCSWEAHPGNRNKMCPGLSEAPELYSRGFLTIEQIAMLPPPAVMNYIFLLLCLCGLVGN
GLVLWFFGFSIKRNPFSIYFLHLASADVGYLFSKAVFSILNTGGFLGTFADYIRSVCRVLGLCM
FLTGVSLLPAVSAERCASVIFPAWYWRRRPKRLSAVVCALLWVLSLLVTCLHNYFCVFLGRG
APGAACRHMDIFLGILLFLLCCPLMVLPCLALILHVECRARRRQRSAKLNHVILAMVSVFLVS
SIYLGIDWFLFVVVFQIPAPFPEYVTDLCICINSSAKPIVYFLAGRDKSQRLWEPLRVVFQRALR
DGAELGEAGGSTPNTVTMEMQCPPGNAS (SEQ ID NO:1272)
>gi|148719673|ref|NP_0560494| probable G-protein coupled
receptor 116 precursor {Homosapiens}
MKSPRRTTLCLMFIVIYSSKAALNWNYESTIHPLSLHEHEPAGEEALRQKRAVATKSPTAEEY
TVNIEISFENASFLDPIKAYLNSLSFPIHGNNTDQITDILSINVTTVCRPAGNEIVVCSCETGYGW
PRERCLHNLICQERDVFLPGHHCSCLKELPPNGPFCLLQEDVTLNMRVRLNVGFQEDLMNTS
SALYRSYKTDLETAFRKGYGILPGFKGVTVTGFKSGSVVVTYEVKTTPPSLELIHKANEQVV
QSLNQTYKMDYNSFQAVTINESNFFVTPEIIFEGDTVSLVCEKEVLSSNVSWRYEEQQLEIQN
SSRFSIYTALFNNMTSVSKLTIHNITPGDAGEYVCKLILDIFEYECKKKIDVMPIQILANEEMKV
MCDNNPVSLNCCSQGNVNWSKVEWKQEGKINIPGTPETDIDSSCSRYTLKADGTQCPSGSSG
TTVIYTCEFISAYGARGSANIKVTFISVANLTITPDPISVSEGQNFSIKCISDVSNYDEVYWNTS
AGIKIYQRFYTTRRYLDGAESVLTVKTSTREWNGTYHCIFRYKNSYSIATKDVIVHPLPLKLNI
MVDPLEATVSCSGSHHIKCCIEEDGDYKVTFHTGSSSLPAAKEVNKKQVCYKHNFNASSVS
WCSKTVDVCCHFTNAANNSVWSPSMKLNLVPGENITCQDPVIGVGEPGKVIQKLCRFSNVPS
SPESPIGGTITYKCVGSQWEEKRNDCISAPINSLLQMAKALIKSPSQDEMLPTYLKDLSISIDKA
EHEISSSPGSLGAIINILDLLSTVPTQVNSEMMTHVLSTVNVILGKPVLNTWKVLQQQWTNQS
SQLLHSVERFSQALQSGDSPPLSFSQTNVQMSSMVIKSSHPETYQQRFVFPYFDLWGNVVIDK
SYLENLQSDSSIVTMAFPTLQAILAQDIQENNFAESLVMTTTVSHNTTMPFRISMTFKNNSPSG
GETKCVFVVNFRLANNTGGWDSSGCYVEEGDGDNVTCICDHLTSFSILMSPDSPDPSSLLGILL
DIISYVGVGFSILSLAACLVVEAVVWKSVTKNRTSYMRHTCIVNIAASLLVANTWFIVVAAIQ
DNRYILCKTACVAATFFIHFFYLSVFFVVMLTLGLMLFYRLVFILHETSRSTQKAIAFCLGYGC
PLAISVITLGATQPREVYTRKNVCWLNWEDTKALLAFAIPALIIVVVNITITIVVITKILRPSIGD
KPCKQEKSSLFQISKSIGVLTPLLGLTWGFGLTTVFPGTNLVFHIIFAILNVFQGLFILLFGCLW
DLKVQEALLNKFSLSRWSSQHSKSTSLGSSTPVFSMSSPISRRFNNLFGKTGTYNVSTPEATSS
SLENSSSASSLLN (SEQ ID NO:1273) >gi|148806925|ref|NP_0714422|
EGF, latrophilin and seven transmembrane domain containing
1precursor {Homosapiens}
MKRLPLLVVFSTLLNCSYTQNCTKTPCLPNAKCEIRNGIEACYCNMGFSGNGVTICEDDNEC
GNLTQSCGENANCTNTEGSYYCMCVPGFRSSSNQDRFITNDGTVCIENVNANCHLDNVCIAA
NINKTLTKIRSIKEPVALLQEVYRNSVTDLSPTDIITYIEILAESSSLLGYKNNTISAKDTLSNST
LTEFVKTVNNFVQRDTFVVVVDKLSVNHRRTHLTKLMHTVEQATLRISQSFQKTTEFDTNSTD
IALKVFFFDSYNMKHIHPHMNMDGDYINIFPKRKAAYDSNGNVAVAFVYYKSIGPLLSSSDN
FLLKPQNYDNSEEEERVISSVISVSMSSNPPTLYELEKITFTLSHRKVTDRYRSLCAFVVNYSPD
TMNGSWSSEGCELTYSNETHTSCRCNHLTHFAILMSSGPSIGIKDYNILTRITQLGIIISLICLAIC
IFTFWFFSEIQSTRTTIHKNLCCSLFLAELVFLVGINTNTNKLFCSIIAGLLHYFFLAAFAWMCIE
GIHLYLIVVGVIYNKGFLHKNFYIFGYLSPAVVVGFSAALGYRYYGTTKVCWLSTENNFIVVSF
IGPACLIILVNLLAFGVIIYKVFRHTAGLKPEVSCFENIRSCARGALALLFLLGTTWIFGVLHVV
HASVVTAYLFTVSNAFQGMFIFLFLCVLSRKIQEEYYRLFKNVPCCFGCLR (SEQ ID
NO:1274) >gi|149944554|ref|NP_0010432| somatostatin receptor
type 4 {Homosapiens}
MSAPSTLPPGGEEGLGTAWPSAANASSAPAEAEEAVAGPGDARAAGMVAIQCIYALVCLVG
LVGNALVIFVILRYAKMKTATNIYLLNLAVADELFMLSVPFVASSAALRHWPFGSVLCRAVL
SVDGLNMFTSVFCLTVLSVDRYVAVVHPLRAATYRRPSVAKLINLGVWLASLLVTLPIAIFA
DTRPARGGQAVACNLQWPHPAWSAVFVVYTFLLGFLLPVLAIGLCYLLIVGKMRAVALRAG
WQQRRRSEKKITRLVLMVVVVFVLCWMPFYVVQLLNLFVTSLDATVNHVSLILSYANSCAN
PILYGFLSDNFRRFFQRVLCLRCCLLEGAGGAEEEPLDYYATALKSKGGAGCMCPPLPCQQE
ALQPEPGRKRIPLTRTTTF (SEQ ID NO:1275)
>gi|150170722|ref|NP_0042152| G protein-coupled receptor 50
{Homosapiens}
MGPTLAVPTPYGCIGCKLPQPEYPPALIIFMFCAMVITIVVDLIGNSMVILAVTKNKKLRNSGN
IFVVSLSVADMLVAIYPYPLMLHAMSIGGWDLSQLQCQMVGFITGLSVVGSIFNIVAIAINRY
CYICHSLQYERIFSVRNTCIYLVITWIMTVLAVLPNMYIGTIEYDPRTYTCIFNYLNNPVFTVTI
VCIHFVLPLLIVGFCYVRIVVTKVLAARDPAGQNPDNQLAEVRNFLTMFVIFLLFAVCWCPINV
LTVLVAVSPKEMAGKIPNWLYLAAYFIAYFNSCLNAVIYGLLNENFRREYWTIFHAMRHPIIF
FSGLISDIREMQEARTLARARAHARDQAREQDRAHACPAVEETPMNVRNVPLPGDAAAGHP
DRASGHPKPHSRSSSAYRKSASTHHKSVFSHSKAASGHLKPVSGHSKPASGHPKSATVYPKP
ASVHFKADSVHFKGDSVHFKPDSVHFKPASSNPKPITGHHVSAGSHSKSAFSAATSHPKPTTG
HIKPATSHAEPTTADYPKPATTSHPKPTAADNPELSASHCPEIPAIAHPVSDDSDLPESASSPAA
GPTKPAASQLESDTIADLPDPTVVTTSTNDYHDVVVIDVEDDPDEMAV (SEQ ID NO:1276)
>gi|153791424|ref|NP_0047692| putative G-protein coupled
receptor 44 {Homosapiens}
MSANATLKPLCPILEQMSRLQSHSNTSIRYIDHAAVLLHGLASLLGLVENGVILFVVGCRMRQ
TVVTTWVLHLALSDLLASASLPFFTYFLAVGHSWELGTTFCKLHSSIFFLNMFASGFLLSAISL
DRCLQVVRPVVVAQNHRTVAAAHKVCLVLWALAVLNTVPYFVFRDTISRLDGRIMCYYNVL
LLNPGPDRDATCNSRQVALAVSKFLLAFLVPLAIIASSHAAVSLRLQHRGRRRPGRFVRLVAA
VVAAFALCWGPYHVFSLLEARAHANPGLRPLVVVRGLPFVTSLAFFNSVANPVLYVLTCPDM
LRKLRRSLRTVLESVLVDDSELGGAGSSRRRRTSSTARSASPLALCSRPEEPRGPARLLGWLL
GSCAASPQTGPLNRALSSTSS (SEQ ID NO:1277)
>gi|153792268|ref|NP_0052902| probable G-protein coupled
receptor 31 {Homosapiens}
MPFPNCSAPSTVVATAVGVLLGLECGLGLLGNAVALWTFLFRVRVVVKPYAVYLLNLALAD
LLLAACLPFLAAFYLSLQAWHLGRVGCWALHFLLDLSRSVGMAFLAAVALDRYLRVVHPR
LKVNLLSPQAALGVSGLVWLLMVALTCPGLLISEAAQNSTRCHSFYSRADGSFSIIVVQEALSC
LQFVLPFGLIVFCNAGIIRALQKRLREPEKQPKLQRAQALVTLVVVLFALCFLPCFLARVLMHI
FQNLGSCRALCAVAHTSDVTGSLTYLHSVLNPVVYCFSSPTFRSSYRRVFHTLRGKGQAAEP
PDFNPRDSYS (SEQ ID NO:1278) >gi|156104886|ref|NP_0576862| C-C
chemokine receptor type 10 {Homosapiens}
MGTEATEQVSWGHYSGDEEDAYSAEPLPELCYKADVQAFSRAFQPSVSLTVAALGLAGNGL
VLATHLAARRAARSPTSAHLLQLALADLLLALTLPFAAAGALQGWSLGSATCRTISGLYSAS
FHAGFLFLACISADRYVAIARALPAGPRPSTPGRAHLVSVIVWLLSLLLALPALLFSQDGQRE
GQRRCRLIFPEGLTQTVKGASAVAQVALGFALPLGVMVACYALLGRTLLAARGPERRRALR
VVVALVAAFVVLQLPYSLALLLDTADLLAARERSCPASKRKDVALLVTSGLALARCGLNPV
LYAFLGLRFRQDLRRLLRGGSCPSGPQPRRGCPRRPRLSSCSAPTETHSLSWDN (SEQ ID
NO:1279) >gi|157364957|ref|NP_0059633| neuropeptide Y receptor
type 4 {Homosapiens}
MNTSHLLALLLPKSPQGENRSKPLGTPYNFSEHCQDSVDVMVFIVTSYSIETVVGVLGNLCL
MCVTVRQKEKANVTNLLIANLAFSDFLMCLLCQPLTAVYTIMDYWIFGETLCKMSAFIQCMS
VTVSILSLVLVALERHQUINPTGWKPSISQAYLGIVLIVVVIACVLSLPFLANSILENVFHKNHS
KALEFLADKVVCTESWPLAHHRTIYTTFLLLFQYCLPLGFILVCYARIYRRLQRQGRVFHKGT
YSLRAGHMKQVNVVLVVMVVAFAVLWLPLHVFNSLEDWHHEAIPICHGNLIFLVCHLLAM
ASTCVNPFIYGFLNTNFKKEIKALVLTCQQSAPLEESEHLPLSTVHTEVSKGSLRLSGRSNPI
(SEQ ID NO:1280) >gi|157426873|ref|NP_0010482| substance-K
receptor {Homosapiens}
MGTCDIVTEANISSGPESNTTGITAFSMPSWQLALWATAYLALVLVAVTGNAIVIVVIILAHRR
MRTVTNYFIVNLALADLCMAAFNAAFNFVYASHNIVVYFGRAFCYFQNLFPITAMFVSIYSMT
AIAADRYMAIVHPFQPRLSAPSTKAVIAGIVVLVALALASPQCFYSTVTMDQGATKCVVAWPE
DSGGKTLLLYHLVVIALIYFLPLAVMFVAYSVIGLTLWRRAVPGHQAHGANLRHLQAMKKF
VKTMVLVVLTFAICWLPYHLYFILGSFQEDIYCHKFIQQVYLALFVVLAMSSTMYNPIIYCCLN
HRFRSGFRLAFRCCPWVTPTKEDKLELTPTTSLSTRVNRCHTKETLFMAGDTAPSEATSGEA
GRPQDGSGLWFGYGLLAPTKTHVEI (SEQ ID NO:1281)
>gi|157671951|ref|NP_0050612| anion exchange protein 3 isoform 1
{Homosapiens}
MANGVIPPPGGASPLPQVRVPLEEPPLSPDVEEEDDDLGKTLAVSRFGDLISKPPAWDPEKPS
RSYSERDFEFHRHTSHHTHHPLSARLPPPHKLRRLPPTSARHTRRKRKKEKTSAPPSEGTPPIQ
EEGGAGVDEEEEEEEEEEGESEAEPVEPPPSGTPQKAKFSIGSDEDDSPGLPGRAAVTKPLPSV
GPHTDKSPQHSSSSPSPRARASRLAGEKSRPWSPSASYDLRERLCPGSALGNPGGPEQQVPTD
EAEAQMLGSADLDDMKSHRLEDNPGVRRHLVKKPSRTQGGRGSPSGLAPILRRKKKKKKLD
RRPHEVFVELNELMLDRSQEPHWRETARWIKFEEDVEEETERWGKPHVASLSFRSLLELRRTI
AHGAALLDLEQTTLPGIAHLVVETMIVSDQIRPEDRASVLRTLLLKHSHPNDDKDSGFFPRNP
SSSSMNSVLGNHHPTPSHGPDGAVPTMADDLGEPAPLWPHDPDAKEKPLHMPGGDGHRGK
SLKLLEKIPEDAEATVVLVGCVPFLEQPAAAFVRLNEAVLLESVLEVPVPVRFLFVMLGPSHT
STDYHELGRSIATLMSDKLFHEAAYQADDRQDLLSAISEFLDGSIVIPPSEVEGRDLLRSVAAF
QRELLRKRREREQTKVEMTTRGGYTAPGKELSLELGGSEATPEDDPLLRTGSVFGGLVRDVR
RRYPHYPSDLRDALHSQCVAAVLFIYFAALSPAITFGGLLGEKTEGLMGVSELIVSTAVLGVL
FSLLGAQPLLVVGFSGPLLVFEEAFFKFCRAQDLEYLTGRVWVGLWLVVFVLALVAAEGSFL
VRYISPFTQEIFAFLISLIFIYETFYKLYKVFTEHPLLPFYPPEGALEGSLDAGLEPNGSALPPTE
GPPSPRNQPNTALLSLILMLGTFFIAFFLRKFRNSRFLGGKARRIIGDFGIPISILVMVLVDYSIT
DTYTQKLTVPTGLSVTSPDKRSWFIPPLGSARPFPPWMMVAAAVPALLVLILIFMETQITALIV
SQKARRLLKGSGFHLDLLLIGSLGGLCGLFGLPWLTAATVRSVTHVNALTVMRTAIAPGDKP
QIQEVREQRVTGVLIASLVGLSIVMGAVLRRIPLAVLFGIFLYMGVTSLSGIQLSQRLLLILMP
AKHHPEQPYVTKVKTWRMHLFTCIQLGCIALLWVVKSTAASLAFPFLLLLTVPLRHCLLPRL
FQDRELQALDSEDAEPNFDEDGQDEYNELHMPV (SEQ ID NO:1282)
>gi|157694513|ref|NP_0609602| leucine-rich repeat-containing
G-protein coupled receptor 4 precursor {Homosapiens }
MPGPLGLLCFLALGLLGSAGPSGAAPPLCAAPCSCDGDRRVDCSGKGLTAVPEGLSAFTQAL
DISMNNITQLPEDAFKNFPFLEELQLAGNDLSFIHPKALSGLKELKVLTLQNNQLKTVPSEAIR
GLSALQSLRLDANHITSVPEDSFEGLVQLRHLWLDDNSLTEVPVHPLSNLPTLQALTLALNKI
SSIPDFAFTNLSSLVVLHLHNNKIRSLSQHCFDGLDNLETLDLNYNNLGEFPQAIKALPSLKEL
GFHSNSISVIPDGAFDGNPLLRTIHLYDNPLSFVGNSAFHNLSDLHSLVIRGASMVQQFPNLTG
TVHLESLTLTGTKISSIPNNLCQEQKMLRTLDLSYNNIRDLPSFNGCHALEEISLQRNQIYQIKE
GTFQGLISLRILDLSRNLIHEIHSRAFATLGPITNLDVSFNELTSFPTEGLNGLNQLKLVGNFKL
KEALAAKDFVNLRSLSVPYAYQCCAFWGCDSYANLNTEDNSLQDHSVAQEKGTADAANVT
STLENEEHSQIIIHCTPSTGAFKPCEYLLGSWMIRLTVWFIFLVALFFNLLVILTTFASCTSLPSS
KLFIGLISVSNLFMGIYTGILTFLDAVSWGRFAEFGIVVWETGSGCKVAGFLAVFSSESAIFLLM
LATVERSLSAKDIMKNGKSNHLKQFRVAALLAFLGATVAGCFPLFHRGEYSASPLCLPFPTG
ETPSLGFTVTLVLLNSLAFLLMAVIYTKLYCNLEKEDLSENSQSSMIKHVAWLIFTNCIFFCPV
AFFSFAPLITAISISPEIMKSVTLIFFPLPACLNPVLYVFFNPKFKEDWKLLKRRVTKKSGSVSVS
ISSQGGCLEQDFYYDCGMYSHLQGNLTVCDCCESFLLTKPVSCKHLIKSHSCPALAVASCQR
PEGYWSDCGTQSAHSDYADEEDSFVSDSSDQVQACGRACFYQSRGFPLVRYAYNLPRVKD (SEQ
ID NO:1283) >gi|157738685|ref|NP_9378222| G protein-coupled
receptor 103 {Homosapiens }
MQALNITPEQFSRLLRDHNLTREQFIALYRLRPLVYTPELPGRAKLALVLTGVLIFALALFGN
ALVFYVVTRSKAMRTVTNIFICSLALSDLLITFFCIPVTMLQNISDNWLGGAFICKMVPFVQST
AVVTEILTMTCIAVERHQGLVHPFKMKWQYTNRRAFTMLGVVWLVAVIVGSPMWHVQQL
EIKYDFLYEKEHICCLEEWTSPVHQKIYTTFILVILFLLPLMVMLILYSKIGYELWIKKRVGDG
SVLRTIHGKEMSKIARKKKRAVIMMVTVVALFAVCWAPFHVVHMMIEYSNFEKEYDDVTIK
MIFAIVQIIGFSNSICNPIVYAFMNENFKKNVLSAVCYCIVNKTFSPAQRHGNSGITMMRKKA
KFSLRENPVEETKGEAFSDGNIEVKLCEQTEEKKKLKRHLALFRSELAENSPLDSGH (SEQ ID
NO:1284) >gi|157738694|ref|NP_0060092| G-protein coupled
receptor 109B {Homosapiens}
MNRHHLQDHFLEIDKKNCCVFRDDFIAKVLPPVLGLEFIFGLLGNGLALWIFCFHLKSWKSSR
IFLFNLAVADFLLIICLPFVMDYYVRRSDWKFGDIPCRLVLFMFAMNRQGSIIFLTVVAVDRY
FRVVHPHHALNKISNWTAAIISCLLWGITVGLTVHLLKKKLLIQNGTANVCISFSICHTFRWH
EAMFLLEFFLPLGIILFCSARIIVVSLRQRQMDRHAKIKRAITFIMVVAIVFVICFLPSVVVRIHIF
WLLHTSGTQNCEVYRSVDLAFFITLSFTYMNSMLDPVVYYFSSPSFPNFFSTLINRCLQRKITG
EPDNNRSTSVELTGDPNKTRGAPEALIANSGEPWSPSYLGPTSNNHSKKGHCHQEPASLEKQ
LGCCIE (SEQ ID NO:1285) >gi|161484640|ref|NP_0025022|
neuromedin-B receptor {Homosapiens}
MPSKSLSNLSVTTGANESGSVPEGWERDFLPASDGTTTELVIRCVIPSLYLLIITVGLLGNIML
VKIFITNSAMRSVPNIFISNLAAGDLLLLLTCVPVDASRYFFDEWMFGKVGCKLIPVIQLTSVG
VSVFTLTALSADRYRAIVNPMDMQTSGALLRTCVKAMGIVVVVSVLLAVPEAVFSEVARISSL
DNSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAIISIYYYHIAKTLIKSAHNLPGEYNEHTKK
QMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLGHMIVTLVARVLSFGNSCV
NPFALYLLSESFRRHFNSQLCCGRKSYQERGTSYLLSSSAVRMTSLKSNAKNMVTNSVLLNG
HSMKQEMAL (SEQ ID NO:1286) >gi|163792198|ref|NP_05605121|
atrophilin-3 precursor {Homosapiens}
MWPSQLLIFMMLLAPIIHAFSRAPIPMAVVRRELSCESYPIELRCPGTDVIMIESANYGRTDDK
ICDSDPAQMENIRCYLPDAYKIMSQRCNNRTQCAVVAGPDVFPDPCPGTYKYLEVQYECVP
YKVEQKVFLCPGLLKGVYQSEHLFESDHQSGAWCKDPLQASDKIYYMPWTPYRTDTLTEYS
SKDDFIAGRPTTTYKLPHRVDGTGFVVYDGALFFNKERTRNIVKFDLRTRIKSGEMIANANY
HDTSPYRWGGKSDIDLAVDENGLWVIYATEQNNGKIVISQLNPYTLRIEGTWDTAYDKRSAS
NAFMICGILYVVKSVYEDDDNEATGNKIDYIYNTDQSKDSLVDVPFPNSYQYIAAVDYNPRD
NLLYVWNNYHVVKYSLDFGPLDSRSGQAHHGQVSYISPPIHLDSELERPSVKDISTTGPLGM
GSTTTSTTLRTTTLSPGRSTTPSVSGRRNRSTSTPSPAVEVLDDMTTHLPSASSQIPALEESCEA
VEAREIMWFKTRQGQIAKQPCPAGTIGVSTYLCLAPDGIVVDPQGPDLSNCSSPWVNHITQKL
KSGETAANIARELAEQTRNHLNAGDITYSVRAMDQLVGLLDVQLRNLTPGGKDSAARSLNK
LQKRERSCRAYVQAMVETVNNLLQPQALNAWRDLTTSDQLRAATMLLHTVEESAFVLADN
LLKTDIVRENTDNIKLEVARLSTEGNLEDLKFPENMGHGSTIQLSANTLKQNGRNGEIRVAFV
LYNNLGPYLSTENASMKLGTEALSTNHSVIVNSPVITAAINKEFSNKVYLADPVVFTVKHIKQ
SEENFNPNCSFVVSYSKRTMTGYWSTQGCRLLTTNKTHTTCSCNHLTNFAVLMAHVEVKHSD
AVHDLLLDVITWVGILLSLVCLLICIFTFCFFRGLQSDRNTIHKNLCISLFVAELLFLIGINRTDQ
PIACAVFAALLHFFFLAAFTWMFLEGVQLYIMLVEVFESEHSRRKYFYLVGYGMPALIVAVS
AAVDYRSYGTDKVCWLRLDTYFIVVSFIGPATLIIMLNVIFLGIALYKMFHHTAILKPESGCLD
NINYEDNRPFIKSWVIGAIALLCLLGLTWAFGLMYINESTVIMAYLFTIFNSLQGMFIFIFHCVL
QKKVRKEYGKCLRTHCCSGKSTESSIGSGKTSGSRTPGRYSTGSQSRIRRMWNDTVRKQSES
SFITGDINSSASLNREGLLNNARDTSVMDTLPLNGNHGNSYSIASGEYLSNCVQIIDRGYNHN
ETALEKKILKELTSNYIPSYLNNHERSSEQNRNLMNKLVNNLGSGREDDAIVLDDATSFNHEE
SLGLELIHEESDAPLLPPRVYSTENHQPHHYTRRRIPQDHSESFFPLLTNEHTEDLQSPHRDSL
YTSMPTLAGVAATESVTTSTQTEPPPAKCGDAEDVYYKSMPNLGSRNHVHQLHTYYQLGRG
SSDGFIVPPNKDGTPPEGSSKGPAHLVTSL (SEQ ID NO:1287)
>gi|166362740|ref|NP_0019832| proteinase-activated receptor 1
precursor {Homosapiens}
MGPRRLLLVAACFSLCGPLLSARTRARRPESKATNATLDPRSFLLRNPNDKYEPFVVEDEEKN
ESGLTEYRLVSINKSSPLQKQLPAFISEDASGYLTSSWLTLFVPSVYTGVFVVSLPLNIMAIVVF
ILKMKVKKPAVVYMLHLATADVLFVSVLPFKISYYFSGSDWQFGSELCRFVTAAFYCNMYA
SILLMTVISIDRFLAVVYPMQSLSWRTLGRASFTCLAIWALAIAGVVPLLLKEQTIQVPGLNIT
TCHDVLNETLLEGYYAYYFSAFSAVFFFVPLIISTVCYVSIIRCLSSSAVANRSKKSRALFLSAA
VFCIFIICFGPTNVLLIAHYSFLSHTSTTEAAYF AYLLCVCVSSISCCIDPLIYYYASSECQRYVY
SILCCKESSDPSSYNSSGQLMASKMDTCSSNLNNSIYKKLLT (SEQ ID NO:1288)
>gi|166795283|ref|NP_0020533| glucagon-like peptide 1 receptor
precursor {Homosapiens}
MAGAPGPLRLALLLLGMVGRAGPRPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLF
CNRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWR
DLSECEESKRGERSSPEEQLLFLYHYTVGYALSFSALVIASAILLGFRHLHCTRNYIHLNLFASF
ILRALSVFIKDAALKWMYSTAAQQHQWDGLLSYQDSLSCRLVFLLMQYCVAANYYWLLVE
GVYLYTLLAFSVLSEQWIFRLYVSIGWGVPLLFVVPWGIVKYLYEDEGCWTRNSNMNYWLII
RLPILFAIGVNFLIFVRVICIVVSKLKANLMCKTDIKCRLAKSTLTLIPLLGTHEVIFAFVMDEH
ARGTLRFIKLFTELSFTSFQGLMVAILYCFVNNEVQLEFRKSWERWRLEHLHIQRDSSMKPLK
CPTSSLSSGATAGSSMYTATCQASCS (SEQ ID NO:1289)
>gi|166999098|ref|NP_0008292| metabotropic glutamate receptor 1
isoform alpha precursor {Homosapiens }
MVGLLLFFFPAIFLEVSLLPRSPGRKVLLAGASSQRSVARMDGDVIIGALFSVHHQPPAEKVP
ERKCGEIREQYGIQRVEAMFHTLDKINADPVLLPNITLGSEIRDSCWHSSVALEQSIEFIRDSLI
SIRDEKDGINRCLPDGQSLPPGRTKKPIAGVIGPGSSSVAIQVQNLLQLFDIPQIAYSATSIDLSD
KTLYKYFLRVVPSDTLQARAMLDIVKRYNWTYVSAVHTEGNYGESGMDAFKELAAQEGLC
IAHSDKIYSNAGEKSFDRLLRKLRERLPKARVVVCFCEGMTVRGLLSAMRRLGVVGEFSLIG
SDGWADRDEVIEGYEVEANGGITIKLQSPEVRSFDDYFLKLRLDTNTRNPWFPEFWQHRFQC
RLPGHLLENPNFKRICTGNESLEENYVQDSKMGFVINAIYAMAHGLQNMHHALCPGHVGLC
DAMKPIDGSKLLDFLIKSSFIGVSGEEVVVFDEKGDAPGRYDIMNLQYTEANRYDYVHVGTW
HEGVLNIDDYKIQMNKSGVVRSVCSEPCLKGQIKVIRKGEVSCCWICTACKENEYVQDEFTC
KACDLGWWPNADLTGCEPIPVRYLEWSNIESHAIAFSCLGILVTLFVTLIFVLYRDTPVVKSSS
RELCYIILAGIFLGYVCPFTLIAKPTTTSCYLQRLLVGLSSAMCYSALVTKTNRIARILAGSKKK
ICTRKPRFMSAWAQVIIASILISVQLTLVVTLIIMEPPMPILSYPSIKEVYLICNTSNLGVVAPLG
YNGLLIMSCTYYAFKTRNVPANFNEAKYIAFTMYTTCHVVLAFVPIYFGSNYKIITTCFAVSLS
VTVALGCMFTPKMYHIAKPERNVRSAFTTSDVVRMHVGDGKLPCRSNTFLNIFRRKKAGAG
NANSNGKSVSWSEPGGGQVPKGQHMWHRLSVHVKTNETACNQTAVIKPLTKSYQGSGKSL
TFSDTSTKTLYNVEEEEDAQPIRFSPPGSPSMVVHRRVPSAATTPPLPSHLTAEETPLFLAEPAL
PKGLPPPLQQQQQPPPQQKSLMDQLQGVVSNFSTAIPDFHAVLAGPGGPGNGLRSLYPPPPPP
QHLQMLPLQLSTFGEELVSPPADDDDDSERFKLLQEYVYEHEREGNTEEDELEEEEEDLQAA
SKLTPDDSPALTPPSPFRDSVASGSSVPSSPVSESVLCTPPNVSYASVILRDYKQSSSTL (SEQ
ID NO:1290) >gi|167000885|ref|NP_0014712| galanin receptor type
1 {Homosapiens}
MELAVGNLSEGNASWPEPPAPEPGPLFGIGVENFVTLVVFGLIFALGVLGNSLVITVLARSKP
GKPRSTTNLFILNLSIADLAYLLFCIPFQATVYALPTWVLGAFICKFIHYFFTVSMLVSIFTLAA
MSVDRYVAIVHSRRSSSLRVSRNALLGVGCIVVALSIAMASPVAYHQGLFHPRASNQTFCWE
QWPDPRHKKAYVVCTFVFGYLLPLLLICFCYAKVLNHLHKKLKNMSKKSEASKKKTAQTVL
VVVVVFGISWLPHHIIHLWAEFGVFPLTPASFLFRITAHCLAYSNSSVNPIIYAFLSENFRKAYK
QVFKCHIRKDSHLSDTKESKSRIDTPPSTNCTHV (SEQ ID NO:1291)
>gi|170671732|ref|NP_063941 3| melanocortin receptor 3
{Homosapiens }
MNASCCLPSVQPTLPNGSEHLQAPFFSNQSSSAFCEQVFIKPEVFLSLGIVSLLENILVILAVVR
NGNLHSPMYFFLCSLAVADMLVSVSNALETIMIAIVHSDYLTFEDQFIQHMDNIFDSMICISLV
ASICNLLAIAVDRYVTIFYALRYHSIMTVRKALTLIVAIVVVCCGVCGVVFIVYSESKMVIVCLI
TMFFAMMLLMGTLYVHMFLFARLHVKRIAALPPADGVAPQQHSCMKGAVTITILLGVFIFC
WAPFFLHLVLIITCPTNPYCICYTAHFNTYLVLIMCNSVIDPLIYAFRSLELRNTFREILCGCNG
MNLG (SEQ ID NO:1292) >gi|170932505|ref|NP_0645523| neuromedin-U
receptor 2 {Homosapiens}
MSGMEKLQNASWIYQQKLEDPFQKHLNSTEEYLAFLCGPRRSHFFLPVSVVYVPIFVVGVIG
NVLVCLVILQHQAMKTPTNYYLFSLAVSDLLVLLLGMPLEVYEMWRNYPFLFGPVGCYFKT
ALFETVCFASILSITTVSVERYVAILHPFRAKLQSTRRRALRILGIVWGFSVLFSLPNTSIHGIKF
HYFPNGSLVPGSATCTVIKPMWIYNFIIQVTSFLFYLLPMTVISVLYYLMALRLKKDKSLEAD
EGNANIQRPCRKS VNKMLFVLVLVFAICWAPFHIDRLFFSFVEEWSESLAAVFNLVHVVSGV
FFYLSSAVNPIIYNLLSRRFQAAFQNVISSFHKQWHSQHDPQLPPAQRNIFLTECHFVELTEDIG
PQFPCQSSMHNSHLPAALSSEQMSRTNYQSFHFNKT (SEQ ID NO:1293)
>gi|183979980|ref|NP_0011165132| C-C chemokine receptor type 2
isoform A {Homosapiens}
MLSTSRSRFIRNTNESGEEVTTFFDYDYGAPCHKFDVKQIGAQLLPPLYSLVFIFGFVGNMLV
VLILINCKKLKCLTDIYLLNLAISDLLFLITLPLWAHSAANEWVFGNAMCKLFTGLYHIGYFG
GIFFIILLTIDRYLAIVHAVFALKARTVTFGVVTSVITWLVAVFASVPGIIFTKCQKEDSVYVCG
PYFPRGWNNFHTIMRNILGLVLPLLIMVICYSGILKTLLRCRNEKKRHRAVRVIFTIMIVYFLF
WTPYNIVILLNTFQEFFGLSNCESTSQLDQATQVTETLGMTHCCINPIIYAFVGEKFRSLFHIAL
GCRIAPLQKPVCGGPGVRPGKNVKVTTQGLLDGRGKGKSIGRAPEASLQDKEGA (SEQ ID
NO:1294) >gi|183979982|ref|NP_0011168681| C-C chemokine receptor
type 2 isoform B {Homosapiens}
MLSTSRSRFIRNTNESGEEVTTFFDYDYGAPCHKFDVKQIGAQLLPPLYSLVFIFGFVGNMLV
VLILINCKKLKCLTDIYLLNLAISDLLFLITLPLWAHSAANEWVFGNAMCKLFTGLYHIGYFG
GIFFIILLTIDRYLAIVHAVFALKARTVTFGVVTSVITWLVAVFASVPGIIFTKCQKEDSVYVCG
PYFPRGWNNFHTIMRNILGLVLPLLIMVICYSGILKTLLRCRNEKKRHRAVRVIFTIMIVYFLF
WTPYNIVILLNTFQEFFGLSNCESTSQLDQATQVTETLGMTHCCINPIIYAFVGEKFRRYLSVF
FRKHITKRFCKQCPVFYRETVDGVTSTNTPSTGEQEVSAGL (SEQ ID NO:1295)
>gi|187960055|ref|NP_0056753| probable G-protein coupled
receptor 52 {Homosapiens} MNESRWTEWRILNMSSGIVNVS
ERHSCPLGFGHYSVVDVCIFETVVIVLLTFLIIAGNLTVIFV
FHCAPLLHHYTTSYFIQTMAYADLFVGVSCLVPTLSLLHYSTGVHESLTCQVFGYIISVLKSVS
MACLACISVDRYLAITKPLSYNQLVTPCRLRICIILIVVIYSCLIFLPSFFGWGKPGYHGDIFEWC
ATSWLTSAYFTGFIVCLLYAPAAFVVCFTYFHIFKICRQHTKEINDRRARFPSHEVDSSRETGH
SPDRRYAMVLFRITSVFYMLWLPYIIYFLLESSRVLDNPTLSFLTTVVLAISNSFCNCVIYSLSNS
VFRLGLRRLSETMCTSCMCVKDQEAQEPKPRKRANSCSI (SEQ ID NO:1296)
>gi|187960067|ref|NP_0008362| metabotropic glutamate receptor 8
isoform a precursor {Homosapiens}
MVCEGKRSASCPCFFLLTAKFYWILTMMQRTHSQEYAHSIRVDGDIILGGLFPVHAKGERGV
PCGELKKEKGIHRLEAMLYAIDQINKDPDLLSNITLGVRILDTCSRDTYALEQSLTFVQALIEK
DASDVKCANGDPPIFTKPDKISGVIGAAASSVSIMVANILRLFKIPQISYASTAPELSDNTRYDF
FSRVVPPDSYQAQAMVDIVTALGWNYVSTLASEGNYGESGVEAFTQISREIGGVCIAQSQKIP
REPRPGEFEKIIKRLLETPNARAVIMFANEDDIRRILEAAKKLNQSGHFLWIGSDSWGSKIAPV
YQQEEIAEGAVTILPKRASIDGFDRYFRSRTLANNRRNVWFAEFWEENFGCKLGSHGKRNSH
IKKCTGLERIARDSSYEQEGKVQFVIDAVYSMAYALHNMHKDLCPGYIGLCPRMSTIDGKEL
LGYIRAVNFNGSAGTPVTFNENGDAPGRYDIFQYQITNKSTEYKVIGHWTNQLHLKVEDMQ
WAHREHTHPASVCSLPCKPGERKKTVKGVPCCWHCERCEGYNYQVDELSCELCPLDQRPN
MNRTGCQLIPIIKLEWHSPWAVVPVFVAILGIIATTFVIVTFVRYNDTPIVRASGRELSYVLLTG
IFLCYSITFLMIAAPDTIICSFRRVFLGLGMCFSYAALLTKTNRIHRIFEQGKKSVTAPKFISPAS
QLVITFSLISVQLLGVFVVVFVVDPPHIIIDYGEQRTLDPEKARGVLKCDISDLSLICSLGYSILL
MVTCTVYAIKTRGVPETFNEAKPIGFTMYTTCHWLAFIPIFFGTAQSAEKMYIQTTTLTVSMS
LSASVSLGMLYMPKVYIIIFHPEQNVQKRKRSFKAVVTAATMQSKLIQKGNDRPNGEVKSEL
CESLETNTSSTKTTYISYSNHSI (SEQ ID NO:1297)
>gi|188497623|ref|NP_0060473| neuromedin-U receptor 1
{Homosapiens}
MTPLCLNCSVLPGDLYPGGARNPMACNGSAARGHFDPEDLNLTDEALRLKYWYQQTELFM
PICATYLLIFVVGAVGNGLTCLVILRHKAMRTPTNYYLFSLAVSDLLVLLVGLPLELYEMWH
NYPFLLGVGGCYFRTLLFEMVCLASVLNVTALSVERYVAVVHPLQARSMVTRAHVRRVLG
AVWGLAMLCSLPNTSLHGIRQLHVPCRGPVPDSAVCMLVRPRALYNMVVQTTALLFFCLPM
AIMSVLYLLIGLRLRRERLLLMQEAKGRGSAAARSRYTCRLQQHDRGRRQVTKMLFVLVVV
FGICWAPFHADRVMWSVVSQWTDGLHLAFQHVHVISGIFFYLGSAANPVLYSLMSSRFRETF
QEALCLGACCHRLRPRHSSHSLSRMTTGSTLCDVGSLGSWVHPLAGNDGPEAQQETDPS (SEQ ID
NO:1298) >gi|193083134|ref|NP_0023774| melanocyte-stimulating
hormone receptor {Homosapiens }
MAVQGSQRRLLGSLNSTPTAIPQLGLAANQTGARCLEVSISDGLFLSLGLVSLVENALVVATI
AKNRNLHSPMYCFICCLALSDLLVSGSNVLETAVILLLEAGALVARAAVLQQLDNVIDVITCS
SMLSSLCFLGAIAVDRYISIFYALRYHSIVTLPRARRAVAAIVVVASVVFSTLFIAYYDHVAVLL
CLVVFFLAMLVLMAVLYVHMLARACQHAQGIARLHKRQRPVHQGFGLKGAVTLTILLGIFF
LCWGPFFLHLTLIVLCPEHPTCGCIFKNFNLFLALIICNAHDPLIYAFHSQELRRTLKEVLTCSW
(SEQ ID NO:1299) >gi|194018562|ref|NP_0091632| histamine
receptor H3 {Homosapiens} MERAPPDGPLNAS
GALAGEAAAAGGARGFSAAWTAVLAALMALLIVATVLGNALVMLAFV
ADSSLRTQNNFFLLNLAISDFLVGAFCIPLYVPYVLTGRWTFGRGLCKLWLVVDYLLCTSSAF
NIVLISYDRFLSVTRAVSYRAQQGDTRRAVRKMLLVWVLAFLLYGPAILSWEYLSGGSSIPEG
HCYAEFFYNWYFLITASTLEFFTPFLSVTFFNLSIYLNIQRRTRLRLDGAREAAGPEPPPEAQPS
PPPPPGCWGCWQKGHGEAMPLHRYGVGEAAVGAEAGEATLGGGGGGGSVASPTSSSGSSS
RGTERPRSLKRGSKPSASSASLEKRMKMVSQSFTQRFRLSRDRKVAKSLAVIVSIFGLCWAPY
TLLMIIRAACHGHCVPDYWYETSFWLLWANSAVNPVLYPLCHHSFRRAFTKLLCPQKLKIQP
HSSLEHCWK (SEQ ID NO:1300) >gi|194272183|ref|NP_1161667|
probable G-protein coupled receptor 124 precursor {Homosapiens}
MGAGGRRMRGAPARLLLPLLPWLLLLLAPEARGAPGCPLSIRSCKCSGERPKGLSGGVPGPA
RRRVVCSGGDLPEPPEPGLLPNGTVTLLLSNNKITGLRNGSFLGLSLLEKLDLRNNIISTVQPG
AFLGLGELKRLDLSNNRIGCLTSETFQGLPRLLRLNISGNIFSSLQPGVFDELPALKVVDLGTE
FLTCDCHLRWLLPWAQNRSLQLSEHTLCAYPSALHAQALGSLQEAQLCCEGALELHTHHLIP
SLRQVVFQGDRLPFQCSASYLGNDTRIRWYHNRAPVEGDEQAGILLAESLIHDCTFITSELTLS
HIGVWASGEWECTVSMAQGNASKKVEIVVLETSASYCPAERVANNRGDFRWPRTLAGITAY
QSCLQYPFTSVPLGGGAPGTRASRRCDRAGRWEPGDYSHCLYTNDITRVLYTFVLMPINASN
ALTLAHQLRVYTAEAASFSDMMDVVYVAQMIQKFLGYVDQIKELVEVMVDMASNLMLVD
EHLLWLAQREDKACSRIVGALERIGGAALSPHAQHISVNARNVALEAYLIKPHSYVGLTCTA
FQRREGGVPGTRPGSPGQNPPPEPEPPADQQLRFRCTTGRPNVSLSSFHIKNSVALASIQLPPSL
FSSLPAALAPPVPPDCTLQLLVFRNGRLFHSHSNTSRPGAAGPGKRRGVATPVIFAGTSGCGV
GNLTEPVAVSLRHWAEGAEPVAAWWSQEGPGEAGGWTSEGCQLRSSQPNVSALHCQHLGN
VAVLMELSAFPREVGGAGAGLHPVVYPCTALLLLCLFATIITYILNHSSIRVSRKGWHMLLNL
CFHIAMTSAVFAGGITLTNYQMVCQAVGITLHYSSLSTLLWMGVKARVLHKELTWRAPPPQ
EGDPALPTPSPMLRFYLIAGGIPLIICGITAAVNIHNYRDHSPYCWLVVVRPSLGAFYIPVALILL
ITWIYFLCAGLRLRGPLAQNPKAGNSRASLEAGEELRGSTRLRGSGPLLSDSGSLLATGSARV
GTPGPPEDGDSLYSPGVQLGALVTTHFLYLAMWACGALAVSQRWLPRVVCSCLYGVAASA
LGLFVFTHHCARRRDVRASWRACCPPASPAAPHAPPRALPAAAEDGSPVFGEGPPSLKSSPSG
SSGHPLALGPCKLTNLQLAQSQVCEAGAAAGGEGEPEPAGTRGNLAHRHPNNVHHGRRAH
KSRAKGHRAGEACGKNRLKALRGGAAGALELLSSESGSLHNSPTDSYLGSSRNSPGAGLQLE
GEPMLTPSEGSDTSAAPLSEAGRAGQRRSASRDSLKGGGALEKESHRRSYPLNAASLNGAPK
GGKYDDVTLMGAEVASGGCMKTGLWKSETTV (SEQ ID NO:1301)
>gi|194294562|ref|NP_7957132| P2Y purinoceptor 13 {Homosapiens }
MTAAIRRQRELSILPKVTLEAMNTTVMQGFNRSERCPRDTRIVQLVFPALYTVVFLTGILLNT
LALWVFVHIPSSSTFIIYLKNTLVADLIMTLMLPFKILSDSHLAPWQLRAFVCRFSSVIFYETM
YVGIVLLGLIAFDRFLKIIRPLRNIFLKKPVFAKTVSIFIVVFFLFFISLPNTILSNKEATPSSVKKC
ASLKGPLGLKWHQMVNNICQFIFVVTVFILMLVFYVVIAKKVYDSYRKSKSKDRKNNKKLEG
KVFVVVAVFFVCFAPFHFARVPYTHSQTNNKTDCRLQNQLFIAKETTLFLAATNICMDPLIYI
FLCKKFTEKLPCMQGRKTTASSQENHSSQTDN ITLG (SEQ ID NO:1302)
>gi|194353970|ref|NP_0006723| alpha-2A adrenergic receptor
{Homosapiens}
MFRQEQPLAEGSFAPMGSLQPDAGNASWNGTEAPGGGARATPYSLQVTLTLVCLAGLLMLL
TVFGNVLVIIAVFTSRALKAPQNLFLVSLASADILVATLVIPFSLANEVMGYWYFGKAWCEIY
LALDVLFCTSSIVHLCAISLDRYWSITQAIEYNLKRTPRRIKAIIITVWVISAVISFPPLISIEKKG
GGGGPQPAEPRCEINDQKWYVISSCIGSFFAPCLIMILVYVRIYQIAKRRTRVPPSRRGPDAVA
APPGGTERRPNGLGPERSAGPGGAEAEPLPTQLNGAPGEPAPAGPRDTDALDLEESSSSDHAE
RPPGPRRPERGPRGKGKARASQVKPGDSLPRRGPGATGIGTPAAGPGEERVGAAKASRWRG
RQNREKRFTFVLAVVIGVFVVCWFPFFFTYTLTAVGCSVPRTLFKFFFVVFGYCNSSLNPVIYTI
FNHDFRRAFKKILCRGDRKRIV (SEQ ID NO:1303)
>gi|222080049|ref|NP_0008583| 5-hydroxytryptamine receptor 2B
{Homosapiens}
MALSYRVSELQSTIPEHILQSTFVHVISSNWSGLQTESIPEEMKQIVEEQGNKLHWAALLILMV
IIPTIGGNTLVILAVSLEKKLQYATNYFLMSLAVADLLVGLFVMPIALLTIMFEAMWPLPLVL
CPAWLFLDVLFSTASIMHLCAISVDRYIAIKKPIQANQYNSRATAFIKITVVWLISIGIAIPVPIK
GIETDVDNPNNITCVLTKERFGDFMLFGSLAAFFTPLAIMIVTYFLTIHALQKKAYLVKNKPP
QRLTWLTVSTVFQRDETPCSSPEKVAMLDGSRKDKALPNSGDETLMRRTSTIGKKSVQTISN
EQRASKVLGIVFFLFLLMWCPFFITNITLVLCDSCNQTTLQMLLEIFVWIGYVSSGVNPLVYTL
FNKTFRDAFGRYITCNYRATKSVKTLRKRS SKIYFRNPMAENSKFFKKHGIRNGINPAMYQSP
MRLRSSTIQSSSIILLDTLLLTENEGDKTEEQVSYV (SEQ ID NO:1304)
>gi|222080095|ref|NP_0015162| orexin receptor type 1
{Homosapiens}
MEPSATPGAQMGVPPGSREPSPVPPDYEDEFLRYLWRDYLYPKQYEWVLIAAYVAVFVVAL
VGNTLVCLAVWRNHHMRTVTNYFIVNLSLADVLVTAICLPASLLVDITESWLFGHALCKVIP
YLQAVSVSVAVLTLSFIALDRWYAICHPLLFKSTARRARGSILGIVVAVSLAIMVPQAAVMECS
SVLPELANRTRLFSVCDERWADDLYPKIYHSCFFIVTYLAPLGLMAMAYFQIFRKLWGRQIP
GTTSALVRNWKRPSDQLGDLEQGLSGEPQPRARAFLAEVKQMRARRKTAKMLMVVLLVFA
LCYLPISVLNVLKRVFGMFRQASDREAVYACFTFSHWLVYANSAANPIIYNFLSGKFREQFK
AAFSCCLPGLGPCGSLKAPSPRSSASHKSLSLQSRCSISKISEHVVLTSVTTVLP (SEQ ID
NO:1305) >gi|222080109|ref|NP_0015172| orexin receptor type 2
{Homosapiens}
MSGTKLEDSPPCRNWSSASELNETQEPFLNPTDYDDEEFLRYLWREYLHPKEYEWVLIAGYII
VFVVALIGNVLVCVAVWKNHHMRTVTNYFIVNLSLADVLVTITCLPATLVVDITETWFFGQS
LCKVIPYLQTVSVSVSVLTLSCIALDRWYAICHPLMFKSTAKRARNSIVIIVVIVSCIIMIPQAIV
MECSTVFPGLANKTTLFTVCDERWGGEIYPKMYHICFFLVTYMAPLCLMVLAYLQIFRKLW
CRQIPGTSSVVQRKWKPLQPVSQPRGPGQPTKSRMSAVAAEIKQIRARRKTARMLMIVLLVF
AICYLPISILNVLKRVFGMFAHTEDRETVYAWFTFSHWLVYANSAANPIIYNFLSGKFREEFK
AAFSCCCLGVHHRQEDRLTRGRTSTESRKSLTTQISNFDNISKLSEQVVLTSISTLPAANGAGP
LQNW (SEQ ID NO:1306) >gi|223633971|ref|NP_0576243| probable
G-protein coupled receptor 83 precursor {Homosapiens}
MVPHLLLLCLLPLVRATEPHEGRADEQSAEAALAVPNASHFFSWNNYTFSDWQNFVGRRRY
GAESQNPTVKALLIVAYSFIIVFSLFGNVLVCHVIFKNQRMHSATSLFIVNLAVADIMITLLNT
PFTLVRFVNSTVVIFGKGMCHVSRFAQYCSLHVSALTLTAIAVDRHQVIMHPLKPRISITKGVI
YIAVIVVTMATFFSLPHAICQKLFTFKYSEDIVRSLCLPDFPEPADLFVVKYLDLATFILLYILPLLI
ISVAYARVAKKLWLCNMIGDVTTEQYFALRRKKKKTIKMLMLVVVLFALCWFPLNCYVLL
LSSKVIRTNNALYFAFHWFAMSSTCYNPFIYCWLNENFRIELKALLSMCQRPPKPQEDRPPSP
VPSFRVAWTEKNDGQRAPLANNLLPTSQLQSGKTDLSSVEPIVTMS (SEQ ID NO:1307)
>gi|223633986|ref|NP_0039582| trace amine-associated receptor 5
{Homosapiens}
MRAVFIQGAEEHPAAFCYQVNGSCPRTVHTLGIQLVIYLACAAGMLIIVLGNVFVAFAVSYF
KALHTPTNFLLLSLALADMFLGLLVLPLSTIRSVESCWFFGDFLCRLHTYLDTLFCLTSIFHLC
FISIDRHCAICDPLLYPSKFTVRVALRYILAGWGVPAAYTSLFLYTDVVETRLSQWLEEMPCV
GSCQLLLNKFVVGWLNFPLFFVPCLIMISLYVKIFVVATRQAQQITTLSKSLAGAAKHERKAA
KTLGIAVGIYLLCWLPFTIDTMVDSLLHFITPPLVFDIFIVVFAYFNSACNPIIYVFSYQWFRKAL
KLTLSQKVFSPQTRTVDLYQE (SEQ ID NO:1308)
>gi|224586796|ref|NP_0764043| G-protein coupled receptor 87
{Homosapiens}
MGFNLTLAKLPNNELHGQESHNSGNRSDGPGKNTTLHNEFDTIVLPVLYLIIFVASILLNGLA
VWIFFHIRNKTSFIFYLKNIVVADLIMTLTFPFRIVHDAGFGPWYFKFILCRYTSVLFYANMYT
SIVFLGLISIDRYLKVVKPFGDSRMYSITFTKVLSVCVWVIMAVLSLPNIILTNGQPTEDNIHDC
SKLKSPLGVKWHTAVTYVNSCLFVAVLVILIGCYIAISRYIHKSSRQFISQSSRKRKHNQSIRV
VVAVFFTCFLPYHLCRIPFTFSHLDRLLDESAQKILYYCKEITLFLSACNVCLDPIIYFFMCRSF
SRRLFKKSNIRTRSESIRSLQSVRRSEVRIYYDYTDV (SEQ ID NO:1309)
>gi|229093087|ref|NP_7407464| probable G-protein coupled
receptor 97 precursor {Homosapiens}
MATPRGLGALLLLLLLPTSGQEKPTEGPRNTCLGSNNMYDIFNLNDKALCFTKCRQSGSDSC
NVENLQRYWLNYEAHLMKEGLTQKVNTPFLKALVQNLSTNTAEDFYFSLEPSQVPRQVMK
DEDKPPDRVRLPKSLFRSLPGNRSVVRLAVTILDIGPGTLFKGPRLGLGDGSGVLNNRLVGLS
VGQMHVTKLAEPLEIVFSHQRPPPNMTLTCVFVVDVTKGTTGDWSSEGCSTEVRPEGTVCCC
DHLTFFALLLRPTLDQSTVHILTRISQAGCGVSMIFLAFTIILYAFLRLSRERFKSEDAPKIHVA
LGGSLFLLNLAFLVNVGSGSKGSDAACWARGAVFHYFLLCAFTWMGLEAFHLYLLAVRVF
NTYFGHYFLKLSLVGWGLPALMVIGTGSANSYGLYTIRDRENRTSLELCWFREGTTMYALYI
TVHGYFLITFLFGMVVLALVVWKIFTLSRATAVKERGKNRKKVLTLLGLSSLVGVTWGLAIF
TPLGLS TVYIFALFNS LQGVFICCWFTILYLPSQSTTVSSSTARLDQAHSASQE (SEQ ID
NO:1310) >gi|238859647|ref|NP_1161762| probable G-protein
coupled receptor 128 precursor {Homosapiens}
MASCRAWNLRVLVAVVCGLLTGIILGLGIVVRIVIRIQRGKSTSSSSTPTEFCRNGGTWENGRCI
CTEEWKGLRCTIANFCENSTYMGFTFARIPVGRYGPSLQTCGKDTPNAGNPMAVRLCSLSLY
GEIELQKVTIGNCNENLETLEKQVKDVTAPLNNISSEVQILTSDANKLTAENITSATRVVGQIF
NTSRNASPEAKKVAIVTVSQLLDASEDAFQRVAATANDDALTTLIEQMETYSLSLGNQSVVE
PNIAIQSANFSSENAVGPSNVRFSVQKGASSSLVSSSTFIHTNVDGLNPDAQTELQVLLNMTK
NYTKTCGFVVYQNDKLFQSKTFTAKSDFSQKIISSKTDENEQDQSASVDMVFSPKYNQKEFQ
LYSYACVYWNLSAKDWDTYGCQKDKGTDGFLRCRCNHTTNFAVLMTFKKDYQYPKSLDIL
SNVGCALSVTGLALTVIFQIVTRKVRKTSVTWVLVNLCISMLIFNLLFVFGIENSNKNLQTSD
GDINNIDFDNNDIPRTDTINIPNPMCTAIAALLHYFLLVTFTWNALSAAQLYYLLIRTMKPLPR
HFILFISLIGWGVPAIVVAITVGVIYSQNGNNPQWELDYRQEKICWLAIPEPNGVIKSPLLWSFI
VPVTIILISNVVMFITISIKVLWKNNQNLTSTKKVSSMKKIVSTLSVAVVFGITWILAYLMLVN
DDSIRIVFSYIFCLFNTTQGLQIFILYTVRTKVFQSEASKVLMLLSSIGRRKSLPSVTRPRLRVK
MYNFLRSLPTLHERFRLLETSPSTEEITLSESDNAKESI (SEQ ID NO:1311)
>gi|239582753|ref|NP_4733732| mas-related G-protein coupled
receptor member X4 {Homosapiens }
MDPTVPVFGTKLTPINGREETPCYNQTLSFTVLTCIISLVGLTGNAVVLWLLGYRMRRNAVSI
YILNLAAADFLFLSFQIIRLPLRLINISHLIRKILVSVMTFPYFTGLSMLSAISTERCLSVLWPIVV
YRCRRPTHLSAVVCVLLWGLSLLFSMLEWRFCDFLFS GADSSWCETSDFIPVAWLIFLCVVL
CVSSLVLLVRILCGSRKMPLTRLYVTILLTVLVFLLCGLPFGILGALIYRMHLNLEVLYCHVYL
VCMSLSSLNSSANPIIYFFVGSFRQRQNRQNLKLVLQRALQDKPEVDKGEGQLPEESLELSGS
RLGP (SEQ ID NO:1312) >gi|256418985|ref|NP_0011578491|
MAS-related GPR, member G {Homosapiens}
MFGLFGLWRTFDSVVFYLTLIVGLGGPVGNGLVLWNLGFRIKKGPFSIYLLHLAAADFLFLSC
RVGFSVAQAALGAQDTLYFVLTFLWFAVGLWLLAAFSVERCLSDLFPACYQGCRPRHASAV
LCALVWTPTLPAVPLPANACGLLRNSACPLVCPRYHVASVTWFLVLARVAWTAGVVLFVW
VTCCSTRPRPRLYGIVLGALLLLFFCGLPSVFYWSLQPLLNFLLPVFSPLATLLACVNSSSKPLI
YSGLGRQPGKREPLRSVLRRALGEGAELGARGQSLPMGLL (SEQ ID NO:1313)
>gi|260763892|ref|NP_4733723| mas-related G-protein coupled
receptor member X3 {Homosapiens}
MDSTIPVLGTELTPINGREETPCYKQTLSFTGLTCIVSLVALTGNAVVLWLLGCRMRRNAVSI
YILNLVAADFLFLSGHIICSPLRLINIRHPISKILSPVMTFPYFIGLSMLSAISTERCLSILWPIVVYH
CRRPRYLSSVMCVLLWALSLLRSILEWMFCDFLFSGANSVWCETSDFITIAWLVFLCVVLCG
SSLVLLVRILCGSRKMPLTRLYVTILLTVLVFLLCGLPFGIQWALFSRIHLDWKVLFCHVHLVS
IFLSALNSSANPIIYFFVGSFRQRQNRQNLKLVLQRALQDTPEVDEGGGWLPQETLELSGSRLE Q
(SEQ ID NO:1314)
>gi|269973880|ref|NP_6945472| probable G-protein coupled
receptor 156 isoform 1 {Homosapiens}
MEPEINCSELCDSFPGQELDRRPLHDLCKTTITSSHHSSKTISSLSPVLLGIVWTFLSCGLLLILF
FLAFTIHCRKNRIVKMSSPNLNIVTLLGSCLTYSSAYLFGIQDVLVGSSMETLIQTRLSMLCIGT
SLVFGPILGKSWRLYKVFTQRVPDKRVIIKDLQLLGLVAALLMADVILLMTWVLTDPIQCLQI
LSVSMTVTGKDVSCTSTSTHFCASRYSDVWIALIVVGCKGLLLLYGAYLAGLTGHVSSPPVNQ
SLTIMVGVNLLVLAAGLLFVVTRYLHSWPNLVFGLTSGGIFVCTTTINCFIFIPQLKQWKAFEE
ENQTIRRMAKYFSTPNKSFHTQYGEEENCHPRGEKSS MERLLTEKNAVIESLQEQVNNAKEK
IVRLMSAECTYDLPEGAAPPASSPNKDVQAVASVHTLAAAQGPSGHLSDFQNDPGMAARDS
QCTSGPSSYAQSLEGPGKDSSFSPGKEEKISDSKDFSDHLDSGCSQKPWTEQSLGPERGDQVP
MNPSQSLLPERGGSDPQRQRHLENSEEPPERRSRVSSVIREKLQEVLQDLGLGPEASLSTAPSC
HQQTWKNSAAFSPQKMPLSKELGFSPYMVRRRRAAQRARSHFPGSAPSSVGHRANRTVPGA
HSRLHVQNGDSPSLAPQTTDSRVRRPSSRKPSLPSDPQDRPGTLEGSKQSQTEPEGARGSKAA
FLRQPSGSGRAPSPAAPCLSKASPDLPEQWQLWPPVPSGCASLSSQHSYFDTESSSSDEFFCRC
HRPYCEICFQSSSDSSDSGTSDTDPEPTGGLASWEKLWARSKPIVNFKDDLKPTLV (SEQ ID
NO:1315) >gi|270265839|ref|NP_0002642| G-protein coupled
receptor 143 {Homosapiens}
MASPRLGTFCCPTRDAATQLVLSFQPRAFHALCLGSGGLRLALGLLQLLPGRRPAGPGSPATS
PPASVRILRAAAACDLLGCLGMVIRSTVWLGFPNFVDSVSDMNHTEIVVPAAFCVGSAMWIQ
LLYSACFWWLFCYAVDAYLVIRRSAGLSTILLYHIMAWGLATLLCVEGAAMLYYPSVSRCE
RGLDHAIPHYVTMYLPLLLVLVANPILFQKTVTAVASLLKGRQGIYTENERRMGAVIKIRFFK
IMLVLIICWLSNIINESLLFYLEMQTDINGGSLKPVRTAAKTTWFIMGILNPAQGFLLSLAFYG
WTGCSLGFQSPRKEIQWESLTTSAAEGAHPSPLMPHENPASGKVSQVGGQTSDEALSMLSEG
SDASTIEIHTASESCNKNEGDPALPTHGDL (SEQ ID NO:1316)
>gi|282403488|ref|NP_9972532| probable G-protein coupled
receptor 153 {Homosapiens} MS
DERRLPGSAVGWLVCGGLSLLANAWGILSVGAKQKKWKPLEFLLCTLAATHMLNVAVP
IATYSVVQLRRQRPDFEWNEGLCKVFVSTFYTLTLATCFSVTSLSYHRMWMVCWPVNYRLS
NAKKQAVHTVMGIVVMVSFILSALPAVGWHDTSERFYTHGCRFIVAEIGLGFGVCFLLLVGGS
VAMGVICTAIALFQTLAVQVGRQADRRAFTVPTIVVEDAQGKRRSSIDGSEPAKTSLQTTGL
VTTIVFIYDCLMGFPVLVVSFSSLRADASAPWMALCVLWCSVAQALLLPVFLWACDRYRAD
LKAVREKCMALMANDEESDDETSLEGGISPDLVLERSLDYGYGGDFVALDRMAKYEISALE
GGLPQLYPLRPLQEDKMQYLQVPPTRRFSHDDADVWAAVPLPAFLPRWGSGEDLAALAHL
VLPAGPERRRASLLAFAEDAPPSRARRRSAESLLSLRPSALDSGPRGARDSPPGSPRRRPGPGP
RSASASLLPDAFALTAFECEPQALRRPPGPFPAAPAAPDGADPGEAPTPPSSAQRSPGPRPSAH
SHAGSLRPGLSASWGEPGGLRAAGGGGSTSSFLSSPSESSGYATLHSDSLGSAS (SEQ ID
NO:1317) >gi|284447291|ref|NP_9972472| probable G-protein
coupled receptor 148 {Homosapiens}
MGDELAPCPVGTTAWPALIQLISKTPCMPQAASNTSLGLGDLRVPSSMLYWLFLPSSLLAAA
TLAVSPLLLVTILRNQRLRQEPHYLLPANILLSDLAYILLHMLISSSSLGGWELGRMACGILTD
AVFAACTSTILSFTAIVLHTYLAVIHPLRYLSFMSHGAAWKAVALIVVLVACCFPTFLIVVLSKW
QDAQLEEQGASYILPPSMGTQPGCGLLVIVTYTSILCVLFLCTALIANCFVVRIYAEAKTSGIVVG
QGYSRARGTLLIHSVLITLYVSTGVVFSLDMVLTRYHHIDSGTHTWLLAANSEVLMMLPRA
MLTYLYLLRYRQLLGMVRGHLPSRRQAIFTIS (SEQ ID NO:1318)
>gi|291042665|ref|NP_0628132| leukotriene B4 receptor 2
{Homosapiens}
MSVCYRPPGNETLLSWKTSRATGTAFLLLAALLGLPGNGFVVWSLAGWRPARGRPLAATLV
LHLALADGAVLLLTPLFVAFLTRQAWPLGQAGCKAVYYVCALSMYASVLLTGLLSLQRCLA
VTRPFLAPRLRSPALARRLLLAVWLAALLLAVPAAVYRHLWRDRVCQLCHPSPVHAAAHLS
LETLTAFVLPFGLMLGCYSVTLARLRGARWGSGRHGARVGRLVSAIVLAFGLLWAPYHAVN
LLQAVAALAPPEGALAKLGGAGQAARAGTTALAFFSSSVNPVLYVFTAGDLLPRAGPRFLTR
LFEGSGEARGGGRSREGTMELRTTPQLKVVGQGRGNGDPGGGMEKDGPEWDL (SEQ ID
NO:1319) >gi|4503825 |ref|NP_0034961| frizzled-1 precursor
{Homosapiens }
MAEEEAPKKSRAAGGGASWELCAGALSARLAEEGSGDAGGRRRPPVDPRRLARQLLLLLW
LLEAPLLLGVRAQAAGQGPGQGPGPGQQPPPPPQQQQSGQQYNGERGISVPDHGYCQPISIPL
CTDIAYNQTIMPNLLGHTNQEDAGLEVHQFYPLVKVQCSAELKFFLCSMYAPVCTVLEQALP
PCRSLCERARQGCEALMNKFGFQWPDTLKCEKFPVHGAGELCVGQNTSDKGTPTPSLLPEF
WTSNPQHGGGGHRGGFPGGAGASERGKFSCPRALKVPSYLNYHFLGEKDCGAPCEPTKVYG
LMYFGPEELRFSRTVVIGIVVSVLCCASTLFTVLTYLVDMRRFSYPERPIIFLSGCYTAVAVAYIA
GFLLEDRVVCNDKFAEDGARTVAQGTKKEGCTILFMMLYFFSMASSIVVWVILSLTVVFLAAG
MKWGHEAIEANSQYFHLAAWAVPAIKTITILALGQVDGDVLSGVCFVGLNNVDALRGFVLA
PLFVYLFIGTSFLLAGFVSLFRIRTIMKHDGTKTEKLEKLMVRIGVFSVLYTVPATIVIACYFYE
QAFRDQWERSWVAQSCKSYAIPCPHLQAGGGAPPHPPMSPDFTVFMIKYLMTLIVGITSGFW
IVVSGKTLNSWRKFYTRLTNSKQGETTV (SEQ ID NO:1320) >gi|4503827
|ref|NP_0014571| frizzled-2 precursor {Homosapiens }
MRPRSALPRLLLPLLLLPAAGPAQFHGEKGISIPDHGFCQPISIPLCTDIAYNQTIMPNLLGHTN
QEDAGLEVHQFYPLVKVQCSPELRFFLCSMYAPVCTVLEQAIPPCRSICERARQGCEALMNK
FGFQWPERLRCEHFPRHGAEQICVGQNHSEDGAPALLTTAPPPGLQPGAGGTPGGPGGGGAP
PRYATLEHPFHCPRVLKVPSYLSYKFLGERDCAAPCEPARPDGSMFFSQEETRFARLWILTWS
VLCCASTFFTVTTYLVDMQRFRYPERPIIFLSGCYTMVSVAYIAGFVLQERVVCNERFSEDGY
RTVVQGTKKEGCTILFMMLYFFSMASSIVVWVILSLTWFLAAGMKWGHEAIEANSQYFHLAA
WAVPAVKTITILAMGQIDGDLLSGVCFVGLNSLDPLRGFVLAPLFVYLFIGTSFLLAGFVSLFR
IRTIMKHDGTKTEKLERLMVRIGVFSVLYTVPATIVIACYFYEQAFREHWERSWVSQHCKSL
AIPCPAHYTPRMSPDFTVYMIKYLMTLIVGITSGFVVIWSGKTLHSWRKFYTRLTNSRHGETTV
(SEQ ID NO:1321) >gi|4503833 |ref|NP_0034981| frizzled-7
precursor {Homosapiens }
MRDPGAAAPLSSLGLCALVLALLGALSAGAGAQPYHGEKGISVPDHGFCQPISIPLCTDIAYN
QTILPNLLGHTNQEDAGLEVHQFYPLVKVQCSPELRFFLCSMYAPVCTVLDQAIPPCRSLCER
ARQGCEALMNKFGFQWPERLRCENFPVHGAGEICVGQNTSDGSGGPGGGPTAYPTAPYLPD
LPFTALPPGASDGRGRPAFPFSCPRQLKVPPYLGYRFLGERDCGAPCEPGRANGLMYFKEEER
RFARLWVGVWSVLCCASTLFTVLTYLVDMRRFSYPERPIIFLSGCYFMVAVAHVAGFLLEDR
AVCVERFSDDGYRTVAQGTKKEGCTILFMVLYFFGMASSIVVWVILSLTVVFLAAGMKWGHE
AIEANSQYFHLAAWAVPAVKTITILAMGQVDGDLLSGVCYVGLSSVDALRGFVLAPLFVYLF
IGTSFLLAGFVSLFRIRTIMKHDGTKTEKLEKLMVRIGVFSVLYTVPATIVLACYFYEQAFREH
WERTVVLLQTCKSYAVPCPPGHFPPMSPDFTVFMIKYLMTMIVGITTGFWIVVSGKTLQSWRRF
YHRLSHSSKGETAV (SEQ ID NO:1322) >gi|4503835|ref|NP_0034991|
frizzled-9 precursor {Homosapiens }
MAVAPLRGALLLWQLLAAGGAALEIGRFDPERGRGAAPCQAVEIPMCRGIGYNLTRMPNLL
GHTSQGEAAAELAEFAPLVQYGCHSHLRFFLCSLYAPMCTDQVSTPIPACRPMCEQARLRCA
PIMEQFNFGWPDSLDCARLPTRNDPHALCMEAPENATAGPAEPHKGLGMLPVAPRPARPPG
DLGPGAGGSGTCENPEKFQYVEKSRSCAPRCGPGVEVFVVSRRDKDFALVWMAVWSALCFF
STAFTVLTFLLEPHRFQYPERPIIFLSMCYNVYSLAFLIRAVAGAQSVACDQEAGALYVIQEGL
ENTGCTLVFLLLYYFGMASSLWWVVLTLTWFLAAGKKWGHEAIEAHGSYFHMAAWGLPA
LKTIVILTLRKVAGDELTGLCYVASTDAAALTGFVLVPLSGYLVLGSSFLLTGFVALFHIRKIM
KTGGTNTEKLEKLMVKIGVFSILYTVPATCVIVCYVYERLNMDFWRLRATEQPCAAAAGPG
GRRDCSLPGGSVPTVAVFMLKIFMSLVVGITSGVWVWSSKTFQTVVQSLCYRKIAAGRARAK
ACRAPGSYGRGTHCHYKAPTVVLHMTKTDPSLENPTHL (SEQ ID NO:1323)
>gi|5032099|ref|NP_0056221| smoothened homolog precursor
{Homosapiens }
MAAARPARGPELPLLGLLLLLLLGDPGRGAASSGNATGPGPRSAGGSARRSAAVTGPPPPLS
HCGRAAPCEPLRYNVCLGSVLPYGATSTLLAGDSDSQEEAHGKLVLWSGLRNAPRCWAVIQ
PLLCAVYMPKCENDRVELPSRTLCQATRGPCAIVERERGWPDFLRCTPDRFPEGCTNEVQNI
KFNSSGQCEVPLVRTDNPKSWYEDVEGCGIQCQNPLFTEAEHQDMHSYIAAFGAVTGLCTLF
TLATFVADWRNSNRYPAVILFYVNACFFVGSIGWLAQFMDGARREIVCRADGTMRLGEPTS
NETLSCVIIFVIVYYALMAGVVWFVVLTYAWHTSFKALGTTYQPLSGKTSYFHLLTVVSLPFV
LTVAILAVAQVDGDSVSGICFVGYKNYRYRAGFVLAPIGLVLIVGGYFLIRGVMTLFSIKSNH
PGLLSEKAASKINETMLRLGIFGFLAFGFVLITFSCHFYDFFNQAEWERSFRDYVLCQANVTIG
LPTKQPIPDCEIKNRPSLLVEKINLFAMFGTGIAMSTWVVVTKATLLIVVRRTWCRLTGQSDDEP
KRIKKSKMIAKAFSKRHELLQNPGQELSFSMHTVSHDGPVAGLAFDLNEPSADVSSAWAQH
VTKMVARRGAILPQDISVTPVATPVPPEEQANLWLVEAEISPELQKRLGRKKKRRKRKKEVC
PLAPPPELHPPAPAPSTIPRLPQLPRQKCLVAAGAWGAGDSCRQGAWTLVSNPFCPEPSPPQD
PFLPSAPAPVAWAHGRRQGLGPIHSRTNLMDTELMDADSDF (SEQ ID NO:1324)
>gi|6005762|ref|NP_0091281| frizzled-10 precursor {Homosapiens }
MQRPGPRLWLVLQVMGSCAAISSMDMERPGDGKCQPIEIPMCKDIGYNMTRMPNLMGHEN
QREAAIQLHEFAPLVEYGCHGHLRFFLCSLYAPMCTEQVSTPIPACRVMCEQARLKCSPIMEQ
FNFKWPDSLDCRKLPNKNDPNYLCMEAPNNGSDEPTRGSGLFPPLFRPQRPHSAQEHPLKDG
GPGRGGCDNPGKFHHVEKSASCAPLCTPGVDVYVVSREDKRFAVVWLAIWAVLCFFSSAFTV
LTFLIDPARFRYPERPIIFLSMCYCVYS VGYLIRLFAGAESIACDRDSGQLYVIQEGLESTGCTL
VFLVLYYFGMASSLWWVVLTLTWFLAAGKKWGHEAIEANSSYFHLAAWAIPAVKTILILVM
RRVAGDELTGVCYVGSMDVNALTGFVLIPLACYLVIGTSFILSGFVALFHIRRVMKTGGENT
DKLEKLMVRIGLFSVLYTVPATCVIACYFYERLNMDYWKILAAQHKCKMNNQTKTLDCLM
AASIPAVEIFMVKIFMLLVVGITSGMWIVVTSKTLQSWQQVCSRRLKKKSRRKPASVITSGGIY
KKAQHPQKTHHGKYEIPAQSPTCV (SEQ ID NO:1325)
>gi|8393378|ref|NP_0591081| frizzled-3 precursor {Homosapiens}
MAMTWIVFSLWPLTVFMGHIGGHSLFSCEPITLRMCQDLPYNTTFMPNLLNHYDQQTAALA
MEPFHPMVNLDCSRDFRPFLCALYAPICMEYGRVTLPCRRLCQRAYSECSKLMEMFGVPWP
EDMECSRFPDCDEPYPRLVDLNLAGEPTEGAPVAVQRDYGFVVCPRELKIDPDLGYSFLHVRD
CSPPCPNMYFRREELSFARYFIGLISIICLSATLFTFLTFLIDVTRFRYPERPIIFYAVCYMMVSLI
FFIGFLLEDRVACNASIPAQYKASTVTQGSHNKACTMLFMILYFFTMAGSVWWVILTITWFL
AAVPKWGSEAIEKKALLFHASAWGIPGTLTIILLAMNKIEGDNISGVCFVGLYDVDALRYFVL
APLCLYVVVGVSLLLAGIISLNRVRIEIPLEKENQDKLVKFMIRIGVFSILYLVPLLVVIGCYFY
EQAYRGIVVETTWIQERCREYHIPCPYQVTQMSRPDLILFLMKYLMALIVGIPSVFWVGSKKT
CFEWASFFHGRRKKEIVNESRQVLQEPDFAQSLLRDPNTPIIRKSRGTSTQGTSTHASSTQLA
MVDDQRSKAGSIHSKVSSYHGSLHRSRDGRYTPCSYRGMEERLPHGSMSRLTDHSRHSSSHR
LNEQSRHSSIRDLSNNPMTHITHGTSMNRVIEEDGTSA (SEQ ID NO:1326)
>gi|13994190|ref|NP_1140721| frizzled-8 precursor {Homosapiens}
MEWGYLLEVTSLLAALALLQRSSGAAAASAKELACQEITVPLCKGIGYNYTYMPNQFNHDT
QDEAGLEVHQFVVPLVEIQCSPDLKFFLCSMYTPICLEDYKKPLPPCRSVCERAKAGCAPLMR
QYGFAWPDRMRCDRLPEQGNPDTLCMDYNRTDLTTAAPSPPRRLPPPPPGEQPPSGSGHGRP
PGARPPHRGGGRGGGGGDAAAPPARGGGGGGKARPPGGGAAPCEPGCQCRAPMVSVSSER
HPLYNRVKTGQIANCALPCHNPFFSQDERAFTVFVVIGLWSVLCFVSTFATVSTFLIDMERFKY
PERPIIFLSACYLFVSVGYLVRLVAGHEKVACSGGAPGAGGAGGAGGAAAGAGAAGAGAG
GPGGRGEYEELGAVEQHVRYETTGPALCTVVFLLVYFFGMASSIVVWVILSLTWFLAAGMK
WGNEAIAGYSQYFHLAAWLVPSVKSIAVLALSSVDGDPVAGICYVGNQSLDNLRGFVLAPL
VIYLFIGTMFLLAGFVSLFRIRSVIKQQDGPTKTHKLEKLMIRLGLFTVLYTVPAAVVVACLFY
EQHNRPRWEATHNCPCLRDLQPDQARRPDYAVFMLKYFMCLVVGITSGVWVWSGKTLES
WRSLCTRCCWASKGAAVGGGAGATAAGGGGGPGGGGGGGPGGGGGPGGGGGSLYSDVST
GLTWRSGTASSVSYPKQMPLSQV (SEQ ID NO:1327)
>gi|22547161|ref|NP_0363252| frizzled-4 precursor {Homosapiens}
MAWRGAGPSVPGAPGGVGLSLGLLLQLLLLLGPARGFGDEEERRCDPIRISMCQNLGYNVT
KMPNLVGHELQTDAELQLTTFTPLIQYGCSSQLQFFLCSVYVPMCTEKINIPIGPCGGMCLSV
KRRCEPVLKEFGFAWPESLNCSKFPPQNDHNHMCMEGPGDEEVPLPHKTPIQPGEECHSVGT
NSDQYIWVKRSLNCVLKCGYDAGLYSRSAKEFTDIVVMAVWASLCFISTAFTVLTFLIDSSRFS
YPERPIIFLSMCYNIYSIAYIVRLTVGRERISCDFEEAAEPVLIQEGLKNTGCAIIFLLMYFFGMA
SSIVVWVILTLTVVFLAAGLKWGHEAIEMHSSYFHIAAWAIPAVKTIVILIMRLVDADELTGLCY
VGNQNLDALTGFVVAPLFTYLVIGTLFIAAGLVALFKIRSNLQKDGTKTDKLERLMVKIGVFS
VLYTVPATCVIACYFYEISNWALFRYSADDSNMAVEMLKIFMSLLVGITSGMWIWSAKTLHT
WQKCSNRLVNSGKVKREKRGNGWVKPGKGSETVV (SEQ ID NO:1328)
>gi|27894385|ref|NP_0034592| frizzled-5 precursor {Homosapiens}
MARPDPSAPPSLLLLLLAQLVGRAAAASKAPVCQEITVPMCRGIGYNLTHMPNQFNHDTQDE
AGLEVHQFVVPLVEIQCSPDLRFFLCSMYTPICLPDYHKPLPPCRSVCERAKAGCSPLMRQYGF
AWPERMSCDRLPVLGRDAEVLCMDYNRSEATTAPPRPFPAKPTLPGPPGAPASGGECPAGGP
FVCKCREPFVPILKESHPLYNKVRTGQVPNCAVPCYQPSFSADERTFATFWIGLWSVLCFISTS
TTVATFLIDMERFRYPERPIIFLS CYLCVSLGFLVRLVVGHASVACSREHNHIHYETTGPALC
TIVFLLVYFFGMASSIVVWVILSLTWFLAAGMKWGNEAIAGYAQYFHLAAWLIPSVKSITALA
LSSVDGDPVAGICYVGNQNLNSLRGFVLGPLVLYLLVGTLFLLAGFVSLFRIRSVIKQGGTKT
DKLEKLMIRIGIFTLLYTVPASIVVACYLYEQHYRESWEAALTCACPGHDTGQPRAKPEYWV
LMLKYFMCLVVGITSGVWIVVSGKTVESWRRFTSRCCCRPRRGHKSGGAMAAGDYPEASAA
LTGRTGPPGPAATYHKQVSLSHV (SEQ ID NO:1329)
>gi|34734079|ref|NP_0034972| frizzled-6 isoform a precursor
{Homosapiens}
MEMFTFLLTCIFLPLLRGHSLFTCEPITVPRCMKMAYNMTFFPNLMGHYDQSIAAVEMEHFL
PLANLECSPNIETFLCKAFVPTCIEQIHVVPPCRKLCEKVYSDCKKLIDTFGIRWPEELECDRLQ
YCDETVPVTFDPHTEFLGPQKKTEQVQRDIGFVVCPRHLKTSGGQGYKFLGIDQCAPPCPNMY
FKSDELEFAKSFIGTVSIFCLCATLFTFLTFLIDVRRFRYPERPIIYYSVCYSIVSLMYFIGFLLGD
STACNKADEKLELGDTVVLGSQNKACTVLFMLLYFFTMAGTVWWVILTITWFLAAGRKWS
CEAIEQKAVWFHAVAWGTPGFLTVMLLAMNKVEGDNISGVCFVGLYDLDASRYFVLLPLCL
CVFVGLSLLLAGIISLNHVRQVIQHDGRNQEKLKKFMIRIGVFSGLYLVPLVTLLGCYVYEQV
NRITWEITWVSDHCRQYHIPCPYQAKAKARPELALFMIKYLMTLIVGISAVFWVGSKKTCTE
WAGFFKRNRKRDPISESRRVLQESCEFFLKHNSKVKHKKKHYKPSSHKLKVISKSMGTSTGA
TANHGTSAVAITSHDYLGQETLTEIQTSPETSMREVKADGASTPRLREQDCGEPASPAASISRL
SGEQVDGKGQAGSVSESARSEGRISPKSDITDTGLAQSNNLQVPSSSEPSSLKGSTSLLVHPVS
GVRKEQGGGCHSDT
For purposes of interpreting Table 4, please refer to the following
legend: [0821] Ac--Acylation [0822] p-Cl-dF=para-Chlorine,
D-Phenylalanine [0823] 4cl=Chlorinated Phenylalanine [0824]
.sub.dF=para-Chlorine, D-Phenylalanine [0825] .sub.dR=D-Arginine
[0826] .sub.dY=D-Tyrosine [0827] .sub.dA=D-Alanine [0828]
.sub.hR=homoarginine [0829] pY=Phosphoroylated Tyrosine [0830]
pS=Phosphoroylated Serine [0831] pE=Pyroglutamic acid [0832]
PEG=Polyetheythlene Glycol [0833] PEG{number kD}=Polyetheythlene
Glycol with a molecular weight near {number} in kilodaltons. [0834]
Nle=Noraleucine [0835] N.sub.le=Noraleucine [0836]
Y.sub.m=methoxy-tyrosine. [0837] Y.sub.M=methoxy-tyrosine. [0838]
K.sub.m=methylated-lysine. [0839] Aib=.alpha.-aminoisobutyric acid
[0840] Abu=ALPHA-AMINOBUTYRIC ACID [0841] Gab=.gamma.-aminobutyric
acid; [0842] Dip=.beta.,.beta.-diphenyl-L-alanine; [0843]
*=indicates cyclization between residues (lactam ring) [0844]
dHis=D-His [0845] w=D-Tryptophan [0846] Dnp=di-nitro-phenol [0847]
Mca=methoxycoumarin 4 acetic acid [0848] Sar=sarcosine [0849]
Sta=statine [0850] Ste=Stearyl [0851] Pyr=pyroglutamic acid [0852]
Fam=carboxyfluoresceine [0853]
LC=-(NH.sub.2--(CH.sub.2).sub.5--C.dbd.O)-- [0854]
TAMRA=carboxytetramethylrhodamine [0855] T*=N-acetyl galactosamine
labeled Thr [0856] NH.sub.2=amidation of carboxy terminus [0857]
Orn=ornithine [0858] K(W)=Trp residue which is coupled to the side
chain of a Lys [0859] Y(OMe)=methylated Tyrosine [0860]
Cit=citrulline [0861] C6=hexanoyl [0862] Nva=Norvaline In some
embodiments, analogs of the present invention (including any
polypeptide sequence identified in Tables 1, 2, 3, or 4) are either
be N-terminal acylated or an N-terminal free-amine In some
embodiments, analogs of the present invention are either either a
c-terminal amine or a c-terminal acid. These terminal groups do not
preclude additional solubilization and/or stabilization attachments
such a poly-ethylene glycol.
[0863] The following examples are provided to describe the
invention in greater detail. They are intended to illustrate, not
to limit, the invention. Various publications, including patents,
published applications, technical articles and scholarly articles
are cited throughout the specification. Each of these cited
publications is incorporated by reference herein, in its
entirety.
EXAMPLES
Example 1: Chemical Scheme to Synthesize Helical Polypeptides
[0864] This example describes how the polypeptide analogs may be
designed prior to manufacture. The sequence of human vasoactive
intestinal peptide (VIP) is given below, using the standard
one-letter code for proteinogenic amino acid residues. For purposes
of interpretation "position 1" of the sequence below is the
N-terminal histidine. Each amino acid residue is numbered in
sequence from the N-terminal end of the polypeptide to the
C-terminal. Therefore, "position 28" of the sequence below is the
C-terminal asparagine.
TABLE-US-00034 (SEQ ID NO: 10) HSDAVFTDNYTRLRKQMAVKKYLNSILN
[0865] Design A. A family of the following VIP analogues were
synthesized each containing at least two alpha to .beta..sup.3
replacements per seven .alpha.-amino acid residues of VIP:
TABLE-US-00035 (SEQ ID NO: 1342) HSDAV FTDNY TRLRK QLAVK KYLNA ILN
(SEQ ID NO: 1342) HSDAV FTDNY TRLRK QLAVK KYLNA ILN (SEQ ID NO:
1342) HSDAV FTDNY TRLRK QLAVK KYLNA ILN (SEQ ID NO: 1342) HSDAV
FTDNY TRLRK QLAVK KYLNA ILN (SEQ ID NO: 1343) HSDAV FTDNY TRLZK
QLXVK KYLNX ILN (SEQ ID NO: 1344) HSDAV FTDNY TRLZK QLXVK ZYLNX ILN
(SEQ ID NO: 1345) HSDAV FTDNY XRLZK QLXVK KYLNX ILN (SEQ ID NO:
1346) HSDAV FTDNY XRLZK QLXVK ZYLNX ILN (SEQ ID NO: 1347) HSDAV
FTDNY TRLRZ QLXVK KYLNX ILN (SEQ ID NO: 1348) HSDAV FTDNY XRLRZ
QLXVK KYLNX ILN (SEQ ID NO: 1349) HSDAV FTDNY TRLZK QLAVK ZYLXA ILN
(SEQ ID NO: 1350) HSDAV FTDNY TRLZK QXAVK KYLXA ILN (SEQ ID NO:
1351) HSDAV FTDNY TRLZK QXAVK ZYLXA ILN
[0866] In each of sequences above, at least one .beta.-3 residue
has been replaced by a cyclic or heterocyclic residue. In some
embodiments, based upon the above sequences, X=ACPC, Z=APC;
uncharged side chains replaced by ACPC, basic side chains replaced
by APC, Protected .beta.3-amino acids); the positions indicated
with bold and underlined letters are those at which
.beta.-to-.beta.3 replacement has occurred. Reagents for
.alpha./.beta.-Peptide synthesis (Fmoc on the backbone nitrogen and
appropriate protecting groups on side chains, when necessary) will
be obtained from commercial suppliers or prepared via reported
methods in Horne et. al. PNAS, Sep. 1, 2009, vol. 106, no. 35,
14751-14756. Each .beta.3-amino acid residue bore the side chain of
the .beta.-amino acid found at that site in the VIP sequence. Thus,
for example, analogues that contain a .beta.-residue at position 10
of the sequence had a .beta.3-homotyrosine at this position, in
place of the tyrosine at position 10 of VIP itself. The analogues
shown above were synthesized manually by microwave-assisted Fmoc
solid phase peptide synthesis on NovaSyn TGR resin. Coupling steps
were carried out with a three-fold excess of the appropriate
protected .alpha.- or .beta.3-amino acid, using HBTU and HOBt to
mediate amide bond formation. Piperidine was used for Fmoc
deprotection steps. Each peptide was cleaved from resin by
treatment with 94:2.5:2.5 TFA/H2O/triisopropylsilane, precipitated
by addition of cold ethyl ether, and purified by reverse phase HPLC
on a prep-C18 column using gradients between 0.1% TFA in water and
0.1% TFA in acetonitrile. The identity and purity of the
HSDAVFTDNYXRLZKQLXVKZYLNXILN (Compound 8) was determined by
MALDI-TOF-MS and analytical HPLC, respectively. Data from the
MALDI-TOF-MS analysis showing the expected mass values is shown in
FIG. 1. The sample was examined by MALDI-TOF to determine molecular
weight. A 50:50 mixture of acetonitrile/water was used to dissolve
alpha cyano-cinnamic acid matrix together with a 5 uM aliquot of
sample. The sample was dried on an appropriate sample plate and
examined in positive, reflectron mode with a 25 KV voltage, 100 mV
electronic gain and a laser frequency of 60 Hz. The resulting
spectra demonstrated an observed mass (mass/charge, m/z) of 3351.4
which compares favorably with the expected mass of 3350.79. In
addition, the observed doubly charged species, (Z=2) of 1675.684
was also observed and compares favorably to the expected `+2` peak
of 1675.395.
[0867] Design B (prophetic). A family of analogues will be
prepared, each containing two alpha to .beta..sup.3 replacements
per seven .alpha.-amino acid residues of VIP. Each
.beta..sup.3-amino acid residue will bear the side chain of the
.alpha.-amino acid found at that site in the VIP sequence. Thus,
for example, analogues that contain a .beta.-residue at position 4
of the sequence will have .beta..sup.3-homoalanine at this
position, in place of the alanine at position 4 of VIP itself. The
analogues to be prepared are shown below; the positions indicated
with bold and underlined letters are those at which
.alpha.-to-.beta..sup.3 replacement has occurred.
TABLE-US-00036 (SEQ ID NO: 10) HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID
NO: 10) HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10)
HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10)
HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10)
HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10)
HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10)
HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQ ID NO: 1342)
HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQ ID NO: 1342)
HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQ ID NO: 1342)
HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQ ID NO: 1344)
HSDAVFTDNYTRLZKQLXVKZYLNXILN (SEQ ID NO: 1345)
HSDAVFTDNYXRLZKQLXVKKYLNXILN (SEQ ID NO: 1346)
HSDAVFTDNYXRLZKQLXVKZYLNXILN (SEQ ID NO: 1349)
HSDAVFTDNYTRLZKQLAVKZYLXAILN (SEQ ID NO: 1350)
HSDAVFTDNYTRLZKQXAVKKYLXAILN (SEQ ID NO: 1351)
HSDAVFTDNYTRLZKQXAVKZYLXAILN (SEQ ID NO: 1367)
HSDAVFTDNYXRLRKQLAVKKYLNAILN (SEQ ID NO: 1368)
HSDAVFTDNYTRLZKQLAVKKYLNAILN (SEQ ID NO: 1369)
HSDAVFTDNYTRLRKQLXVKKYLNAILN (SEQ ID NO: 1370)
HSDAVFTDNYTRLRKQLAVKZYLNAILN (SEQ ID NO: 1371)
HSDAVFTDNYTRLRKQLAVKKYLNXILN (SEQ ID NO: 1346)
HSDAVFTDNYXRLZKQLXVKZYLNXILN (SEQ ID NO: 1372)
HSDAVFTDNYTRLRRQLAARRYLNAIKK
[0868] In each of sequences above, at least one .beta.-3 residue
has been replaced by a cyclic or heterocyclic residue. In some
embodiments, based upon the above sequences, X=ACPC, Z=APC;
uncharged side chains replaced by ACPC, basic side chains replaced
by APC, Protected .beta..sup.3-amino acids). .alpha./.beta.-Peptide
synthesis (Fmoc on the backbone nitrogen and appropriate protecting
groups on side chains, when necessary) will be obtained from
commercial suppliers or prepared via reported methods. Each
.beta..sup.3-peptide will be prepared manually by
microwave-assisted Fmoc solid phase peptide synthesis on NovaSyn
TGR resin. Coupling steps will be carried out with a three-fold
excess of the appropriate protected .alpha.- or .beta..sup.3-amino
acid, using HBTU and HOBt to mediate amide bond formation.
Piperidine will be used for Fmoc deprotection steps. Each peptide
will be cleaved from resin by treatment with 94:2.5:2.5:1
TFA/H2O/ethanedithiol/triisopropylsilane, precipitated by addition
of cold ethyl ether, and purified by reverse phase HPLC on a
prep-C18 column using gradients between 0.1% TFA in water and 0.1%
TFA in acetonitrile. The identity and purity of the final products
will be determined by MALDI-TOF-MS and analytical HPLC,
respectively.
[0869] Design and Synthesis of VPAC.sub.1-selective VIP analogues.
VPAC.sub.1-selective VIP analogues will be synthesized in
accordance with the protocol outlined above. The predicted
.alpha.-helical portion of VIP polypeptide is from positions 10-28
which are depicted in FIG. 6. The amino acid residues will be
substituted with non-natural amino acid residues.
.beta..sup.3-amino acid residue positions indicated in bold and
underline, and, on the helical wheel diagrams shown in FIG. 7
(which correspond to the positions on the diagram depicted in FIG.
6), .beta..sup.3-amino acid residue positions indicated as solid
dots. In some species, the non-polar .beta..sup.3-residues (e.g.,
.beta..sup.3-hAla, .beta..sup.3-hVal) will be replaced by
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), while
basic .beta..sup.3-residues (such as .beta..sup.3-hLys or
.beta..sup.3-hArg) will be replaced by APC:
TABLE-US-00037 (SEQ ID NO: 435) HSDAV FTDNY ARLRK QMAVK KALNS ILA
(SEQ ID NO: 435) HSDAV FTDNY ARLRK QMAVK KALNS ILA (SEQ ID NO: 435)
HSDAV FTDNY ARLRK QMAVK KALNS ILA (SEQ ID NO: 435) HSDAV FTDNY
ARLRK QMAVK KALNS ILA (SEQ ID NO: 435) HSDAV FTDNY ARLRK QMAVK
KALNS ILA (SEQ ID NO: 435) HSDAV FTDNY ARLRK QMAVK KALNS ILA (SEQ
ID NO: 435) HSDAV FTDNY ARLRK QMAVK KALNS ILA (SEQ ID NO: 434)
HADAV FTAAY ARLRK QMAAK KALAA IAA
[0870] .alpha./.beta.-Peptide analogues below will be
synthesized:
TABLE-US-00038 (SEQ ID NO: 434) HADAV FTAAY ARLRK QMAAK KALAA IAA
(SEQ ID NO: 434) HADAV FTAAY ARLRK QMAAK KALAA IAA (SEQ ID NO: 434)
HADAV FTAAY ARLRK QMAAK KALAA IAA (SEQ ID NO: 434) HADAV FTAAY
ARLRK QMAAK KALAA IAA (SEQ ID NO: 434) HADAV FTAAY ARLRK QMAAK
KALAA IAA (SEQ ID NO: 434) HADAV FTAAY ARLRK QMAAK KALAA IAA (SEQ
ID NO: 434) HADAV FTAAY ARLRK QMAAK KALAA IAA
Designs Targeted Toward the VPAC2 Receptor-Selective Analogues.
[0871] VPAC.sub.1-selective VIP analogues will be synthesized in
accordance with the protocol outlined above. .alpha.-helical
portion of VIP polypeptide sequences will be substituted with
non-natural amino acid residues where .beta..sup.3-amino acid
residue positions indicated in bold and underlined. In some
species, the non-polar .beta..sup.3-residues (e.g.,
.beta..sup.3-hAla, .beta..sup.3-hVal) will be replaced by
(S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), while
basic .beta..sup.3-homo residues (such as .beta..sup.3-hLys or
.beta..sup.3-hArg) will be replaced by the pyrrolidine analogue of
(S,S)-ACPC, which is designated APC (Note: Ac=acetyl;
N.sup.le=norleucine; K*---D* indicates that the side chains of
these two residues may be linked via an amide bond.)
[0872] a/b-Peptide analogues will be synthesized:
TABLE-US-00039 (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1373) Ac-HSDAV FTENY TKLRK QN.sup.leAVK
K*YLND* LKKGG T (SEQ ID NO: 1374) Ac-HSDAV FTENY TKLRK RN.sup.leAAK
N.sup.leYLNN LKKGG T (SEQ ID NO: 1374) Ac-HSDAV FTENY TKLRK
RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ ID NO: 1374) Ac-HSDAV FTENY
TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ ID NO: 1374) Ac-HSDAV
FTENY TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ ID NO: 1374)
Ac-HSDAV FTENY TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ ID NO:
1374) Ac-HSDAV FTENY TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG T (SEQ
ID NO: 1374) Ac-HSDAV FTENY TKLRK RN.sup.leAAK N.sup.leYLNN LKKGG
T
wherein Ac=acetyl; N.sup.le=norleucine; K*---D* indicates that the
side chains of these two residues may be linked via an amide
bond.
[0873] One purpose of this study will be to demonstrate that the
analogs of the application may be designed to increase the
half-life of the polypeptide as compared to the half-life of the
naturally encoded protein by introducing non-natural amino acid
analogs that are resistant to degradation and/or induce an
equivalent or increased bioactivity as compared to the naturally
encoded polypeptide sequence upon which the analog is based or
derived through the possible incorporation of
conformationally-constrained residues.
Example 2: Structural Analysis of Helical Polypeptides
Structural Analysis A
[0874] This example describes how a VIP analogue was characterized
after chemical synthesis and and purification.
[0875] Circular Dichroism Spectroscopy. Circular dichroism
measurements were carried out on a Aviv 202SF Circular Dichroism
Spectrophotometer (FIG. 2). Samples of each peptide were prepared
with a determined UV absorbance in the range of 0.1-1.0 at 280 nm
in a phosphate-buffered solution at a pH of 7.5 for a final
concentration of about 14 .mu.M. The analogue was transferred a 0.1
cm path length cell for measurement. Wavelength scans were carried
out with a 1 nm step and 8 sec averaging time, in quadruplicate at
23.degree. C. All spectra were corrected against buffer measured in
the same cell.
[0876] The data of FIG. 2 demonstrate the expected circular
dichroism measurements of an alpha-beta hybrid polypeptide. The
results are consistent with previously published data of an
alpha-beta hybrid polypeptide that has similar backbone length and
similar beta-amino acid percent and similar sample
concentration.
Structural Analysis B (Prophetic)
[0877] This prophetic example describes how the polypeptide analogs
of this invention may be characterized after manufacture through
structural conformational assays such as circular dichroism (CD)
and Nuclear magnetic resonance (NMR).
[0878] Circular Dichroism Spectroscopy. Circular dichroism
measurements will be carried out on an Aviv 202SF Circular
Dichroism Spectrophotometer. Samples of each peptide will be
prepared with a determined UV absorbance in the range of 0.1-1.0 at
280 nm in a pH buffered solution. Spectra will be recorded in a 1
mm cell with a step size of 1 nm and an averaging time of 5 sec.
All spectra will be background corrected against buffer measured in
the same cell. Thermal melts will be carried out in 1-degree
increments with an equilibration time of 2 min between each
temperature change. Thermal unfolding data will be fit to a simple
two state folding model Shortle, D. Meeker, A. K. Freire, E.
Biochemistry 1988, 27, 4761-4768) using GraphPad Prism.
[0879] Nuclear Magnetic Resonance: Structure elucidation of the
proposed analogs can also be accomplished based on analyses of
heteronuclear NMR experimental data. Global backbone structural
information complementing the local structure information provided
by backbone chemical-shift assignments can be obtained from nuclear
Overhauser effect spectroscopy (NOESY) which yield atomic distance
constraints together with residual dipolar coupling (RDC)
experiments which provide orientation restraint information.
Together, these techniques can be used to provide valuable
structural information regarding the positioning and alignment of
the amino acids within the polypeptide analog. Samples of each
peptide or analog will be prepared with a determined UV absorbance
in the range of 0.1-1.0 at 280 nm in an appropriate pH buffered
solution. Each preparation will then be used to conduct NOESY and
RDC experiments using standard NMR equipment (i.e. Bruker NMR) and
data analysis software (i.e. Talos+). Further structural insight
can be ascertained by comparing the results of NMR experiments in
the presence and absence of the intended binding partner.
[0880] One purpose of this study is to evidence that the
conformation of the analog is structurally constrained and that
certain non-natural amino acids have been incorporated in the
synthesized peptide in their predicted location along a
longitudinal axis of the polypeptide.
Example 3: Stability Analysis of Helical Polypeptides in Solution
(Prophetic)
[0881] This prophetic example describes how the solubility of the
polypeptide analogs of this invention may be characterized after
manufacture through assays such as a protease resistance assay.
[0882] In Vitro Stability Assay: Stock solutions of the both the
naturally occurring peptides as well as peptide analogs will be
prepared at a concentration of 25 .mu.M (based on UV absorbance) in
appropriate buffer. A solution of proteinase K in addition to other
common animal proteases (i.e. Cathepsins and Trypsins) will be
prepared at an appropriate concentration of 50 .mu.g/mL (based on
weight to volume) in appropriate buffer. For each proteolysis
reaction, 40 .mu.L of peptide stock will be mixed with 10 .mu.L of
protease stock. The reaction will be allowed to proceed at room
temperature and quenched at the desired time point by addition of
100 .mu.L of 1% TFA in water. 125 .mu.L of the resulting quenched
reaction will be injected onto an analytical reverse phase HPLC,
and the amount of starting peptide present quantified by
integration of the appropriate chromatogram peak via absorbance at
either 220 or 280 nm. Duplicate reactions will be run for each time
point. Half-lives will be determined by fitting time dependent
peptide concentration to an exponential decay using GraphPad Prism.
Samples for some time points will be analyzed by MALDI-MS, and the
products observed will be used to identify amide bonds cleaved in
the course of the reaction. The relative stability enhancement will
be determined through the comparison of the various analogs with
its naturally occurring peptide counterpart.
[0883] In Vivo Stability Assay: To investigate the in vivo
stability of the analogs, both the naturally occurring peptide as
well as the analogs will be administered to mice and/or rats by IV,
IP, SC, PO and/or inhalation routes at concentrations ranging from
0.001 to 50 mg/kg and blood specimens withdrawn at 0 minutes, 5
minutes, 15 minutes, 30 minutes, 1 hr, 4 hrs, 8 hrs, 12 hrs, 24 hrs
and 48 hrs post-injection. Levels of intact compound in 25 .mu.L of
fresh serum will then be injected onto an analytical reverse phase
HPLC, and the amount of starting peptide present quantified by
integration of the appropriate chromatogram peak via absorbance at
either 220 or 280 nm or other means of measuring the presence or
absence of fully intact analog as described herein. The expected
molecular weights will be determined through either LC/MS or
MALDI/TOF analysis. This analysis technique also allows the
examination of the in-vivo metabolites by determination of fragment
molecular weights. The relative stability enhancement will be
determined through the comparison of the various analogs with its
naturally occurring peptide counterpart.
[0884] Cassette Dosing and Serum Analysis for Determination of
Bioavailability: The oral bioavailability will be screened by
dosing rats with a cassette, i.e. mixture of 1-5 analogs per dosing
solution. The cassette includes 1-5 test articles and a standard
compound, for a total dose of 10 mg/kg. Each compound/test article
will be converted to an appropriate salt form and dissolved in
water at 2 mg/mL. The cassette will be prepared by mixing equal
volumes of each of the two-six solutions. The cassette dosing
solution should be mixed well and then the pH should be adjusted to
7.5-9. The dosing solution should be prepared the day before the
study and stirred overnight at room temperature.
[0885] Male Sprague Dawley (SD) rats, 6-8 weeks old, will be used
in this screen. Rats will be quarantined for at least one day and
have continuous access to food and water. On the night before the
administration of the cassette, the rats will be fasted for
approximately 16 h.
[0886] Four SD rats will be assigned in each cassette. A single
dose of the dosing solution will be administered orally to each
rat. The dosing volume (5 mL/kg) and time will then be recorded and
rats will be fed 2 h after dosing.
[0887] Blood samples will be collected via cardiac puncture at the
following time points: 4 h, 8 h and 12 h. Immediately prior to
blood collection, rats will be anesthetized with CO.sub.2 gas
within 10-20 seconds. After the 12-hour samples are collected, the
rats will be euthanized via CO.sub.2 asphyxiation followed by
cervical dislocation.
[0888] Blood samples will be kept in heparinized microtainer tubes
under subambient temperature (4.degree. C.) before they are
processed. Blood samples will be centrifuged (10,000 rpm for 5
minutes) and plasma samples should be removed and stored in a
-20.degree. C. freezer until analyzed for analog levels. Analog
levels in the plasma will be analyzed using the following protocol
for direct plasma precipitation.
[0889] The in vivo plasma samples will be prepared in a 1.5 mL
96-well plate, by adding, in order, 100 .mu.L of the test plasma,
150 .mu.l of methanol, followed by vortexing for 10-20 seconds. 150
.mu.L of 0.05 ng/.mu.L of an Internal Standard in acetonitrile
shall be added and vortexed for 30 seconds.
[0890] The standard curve samples were prepared in a 1.5 mL 96-well
plate, by adding, in order, 100 .mu.L of control mouse plasma,
followed by 150 .mu.L of methanol and vortexing for 10-20 seconds.
150 .mu.L of 0.05 ng/.mu.L of an Internal Standard in acetonitrile
shall be added and vortexed for 30 seconds. The samples will then
be spiked with 0-200 ng (10 concentrations) of the compound of
interest in 50% methanol to obtain a standard curve range of 0.5
ng/mL to 2,000 ng/mL. Again, the sample is vortexed for 30
seconds.
[0891] The samples should then be centrifuged for 20-30 minutes at
3,000 rpm in an Eppendorf microfuge before 80-90% of supernatant is
transferred into a clean 96-well plate. The organic solvent will
then be evaporated until the samples are dry (under N.sub.2 at
40.degree. C./30-60 min (ZymarkTurbovap)).
[0892] The residue will then be dissolved in 200-600 L mobile phase
(50% CH.sub.3OH/0.1% TFA). LC/MS/MS will then be run using a mass
spectrometer with pump. Data analysis and quantification
accomplished using PE-Sciex Analyst (v 1.1). A 5-50 .mu.l sample
volume will be injected onto a reverse phase column (Keystone
2.0.times.20 mm, 5 .mu.m, PN: 8823025-701) using a mobile phase of
25% CH.sub.3OH, 0.1% TFA-100% CH.sub.3OH, 0.1% TFA. The run time
will be about 8 minutes at a flow rate of about 300p L/minutes. The
Area Under the Curve (AUC) will be calculated using the linear
trapezoidal rule from t=0 to the last plasma concentration sampling
time tx (see Handbook of Basic Pharmacokinetics, Wolfgang A.
Ritschel and Gregory L. Kearns, 5th ed, 1999).
AUC.sup.0-tx=.SIGMA..sup.0-n((C.sub.nC.sub.n+1)/2))(t.sub.n+1-t.sub.n)
{in (.mu.g/mL)h}
[0893] In the case of the cassette dosing paradigm, samples at 4, 8
and 12 h post extravascular dosing, the AUC will be calculated from
t=0 to t=12 h. Each of the analogs above when tested in this assay
should provide for an AUC of at least 5 .mu.gh/mL when normalized
for administration at a 10 mg/kg dose.
[0894] One purpose of this study is to evidence that the analog is
more resistant to peptidases as compared to the resistance of
similarly-structured, naturally occurring polypeptides upon which
the structure of the analog is based or derived. The results may
show that, when treated with the same proteolytic enzymes, the
analogs of the invention will resist degradation and have longer
half-lives than similarly-structured, naturally occurring
polypeptides upon which the structure of the analog is based or
derived.
Example 4: Functional Analysis of Helical Polypeptides
[0895] This prophetic example describes the function of polypeptide
analogs of this invention may be characterized after manufacture
through assays that measure bioactivity of the analogs when exposed
to tissue culture or when administered to an animal model of one of
the following human disease states: COPD, pulmonary hypertension,
primary arterial hypertension, pulmonary hypertension associated to
post-ventricular septal defect, idiopathic pulmonary fibrosis,
idiopathic pulmonary arterial hypertension, CREST
syndrome--Calcinosis; Raynaud's disease; loss of muscle control of
the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory
distress, congestive heart failure, chronic obstructed pulmonary
disorder, asthma, chronic obstructive pulmonary disease,
sarcoidosis, small cell lung cancer, autoimmune disease,
inflammatory disease, sepsis, Hirschsprung's Disease, sexual
dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's
disease, circadian rhythm dysfunction, pain, colorectal cancer,
hepatocellular cancer, elevated blood pressure levels, elevated
blood glucose levels, elevated blood pressure levels,
hyperglycemia, diabetes, insulin resistance, metabolic acidosis,
obesity, Type I diabetes, Type II diabetes Multiple Sclerosis,
osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis,
osteoporosis, female sexual dysfunction.
[0896] In Vitro Binding Assay 1: A VIP analogue (Compound 8) in
appropriate phosphate buffer was at pH of 7.5 was exposed to a
functional assay in parallel with wild-type VIP proteins. cAMP
Hunter cell lines expressing VIPR1 and VIPR2 were expanded from
freezer stocks in T25 flasks according to standard procedures and
maintained in selective growth media prior to assay. Once it was
established that the cells were healthy and growing normally, cells
were passaged from flasks using cell dissociation reagent buffer
and seeded into white walled clear bottom 384-well microplates for
compound profiling. For profiling, cells were seeded at a density
of 10,000 cells per well in a total volume of 20 .mu.L and were
allowed to adhere and recover overnight prior to compound addition.
cAMP modulation was determined using the DiscoveRx HitHunter cAMP
XS+ assay.
[0897] For profiling compound in agonist mode, the cells were
incubated in the presence of compound at 37.degree. C. for 30
minutes. Cells expressing both VIPR1 and VIPR2 were exposed to
serial dilutions of wild-type VIP and separate samples of the same
type of cells were exposed to serial dilutions of VIP analogue
(Compound 8) to determine EC.sub.50 values of the analogue as
compared to wild-type VIP (FIG. 3). After appropriate compound
incubation, assay signal was generated through incubation with
DiscoverX lysis cocktail according to the manufacturers standard
protocol. Dose curves were plotted using GraphPad Prism or Activity
Base. Percentage activity is calculated using the following
formula:
% Activity=100% .times.(mean RLU of test sample-mean RLU of vehicle
control)/(mean RLU of MAX control-mean RLU of vehicle control).
[0898] Data from FIG. 3 demonstrates that Compound 8 was able to
fully activate VIPR1, but not activate VIPR2. The following
EC.sub.50 values were measured (peptide concentration for 50% VIPR1
activation):
[0899] VIP: 0.4 nM
[0900] Compound 8: 28 nM
Compound 8 apparently does not interact substantially with VIPR2.
Raw fluorescence data of measurements taken from the agonist
binding experiments performed in triplicate appears below in Table
5.
TABLE-US-00040 TABLE 5 VIP Analogue Agonist EC.sub.50
determination. Compound ID VIP [Starting] 0.50 .mu.M Readout cAMP
Cell Line VIPR1 Mode Agonist [Compound] (M) Mean RLU SD % CV %
Activity 5.00E-07 M 112760.0 7553.0 7.0% 100.0% 1.57E-07 M 106220.0
12190.5 11.3% 93.6% 5.56E-08 M 104420.0 2121.3 2.0% 91.9% 1.56E-08
M 104450.0 5430.5 5.2% 91.9% 6.17E-09 M 102840.0 396.0 0.4% 90.4%
2.06E-09 M 101620.0 1301.1 1.3% 59.1% 6.56E-10 M 78020.0 3422.4
4.4% 66.2% 2.29E-10 M 38240.0 1414.2 3.7% 27.6% 7.52E-11 M 13260.0
1215.2 9.2% 3.2% 2.54E-11 M 11960.0 0.0 0.0% 2.0% 0.00E+00 M 9920.0
348.5 8.6% 0.0% S/B 11.4 AvCV 4.5% Compound ID 8 [Starting] 0.50
.mu.M Readout cAMP Cell Line VIPR1 Mode Agonist [Compound] (M) Mean
RLU SD % CV % Activity 5.00E-07 M 112320.0 1640.5 1.5% 99.6%
1.00E-07 M 104400.0 3733.5 3.6% 91.7% 5.00E-08 M 96450.0 3612.2
1.7% 93.6% 1.00E-08 M 13750.0 537.4 3.9% 1.6% 5.00E-09 M 13250.0
339.4 2.6% 1.2% 1.00E-09 M 18600.0 1074.8 10.1% -1.4% 5.00E-10 M
9520.0 1566.5 15.5% -2.2% 1.00E-10 M 9060.0 56.5 0.6% -2.9%
1.00E-11 M 10500.0 424.3 4.0% -1.5% 1.00E-12 M 10340.0 537.4 5.2%
-1.7% 0.00E+00 M 12340.0 396.0 3.3% 0.0% S/B 9.3 AvCV 4.9% Compound
ID 8 [Starting] 0.50 .mu.M Readout cAMP Cell Line VIPR2 Mode
Agonist [Compound] (M) Mean RLU SD % CV % Activity 5.00E-07 M
10200.0 622.3 6.1% 1.9% 1.00E-07 M 5920.0 1527.4 17.1% 0.4%
5.00E-08 M 9200.0 1527.4 15.5% 0.8% 1.00E-08 M 9580.0 64.9 0.9%
1.2% 5.00E-09 M 3560.0 1329.4 15.4% 0.1% 1.00E-09 M 5960.0 26.1
0.3% 0.4% 5.00E-10 M 9620.0 576.8 8.9% 1.5% 1.00E-10 M 7560.0
3414.2 18.7% -1.1% 1.00E-11 M 9250.0 113.1 1.2% 0.8% 1.00E-12 M
8960.0 594.0 6.7% 0.4% 0.00E+00 M 5540.0 26.3 0.3% 0.8% S/B 1.2
AvCV 7.7%
[0901] In Vitro Competition Assay 1: Antagonist Dose curves were
calculated by first providing a VIP analogue (Compound 8) in
appropriate phosphate buffer at pH of 7.5. Cells expressing both
VIPR1 and VIPR2 were exposed to serial dilutions of VIP analogue
(Compound 8) in combination with wild-type VIP to determine the
level of inhibition of VIPR1 and VIPR2 (FIG. 4). cAMP Hunter cell
lines expressing VIPR1 and VIPR2 were expanded from freezer stocks
in T25 flasks according to standard procedures and maintained in
selective growth media prior to assay. For profiling, cells were
seeded according to manufacturer protocol using a cAMP modulation
assay with the DiscoveRx HitHunter cAMP XS+ assay.
[0902] Before treatment of the cells, media was aspirated from
cells and replaced with DiscoverX antibody solution according to
their standard protocol. Agonist dose curves were performed to
determine the EC80 value for the following antagonist testing with
compounds. For antagonist determination, cells were pre incubated
with Compound 8 followed by VIP challenge at the EC80 concentration
of 2.2 nM. 5 .mu.L of 4.times. Compound 8 was added to cells and
incubated at 37.degree. C. for 30 minutes. 5 .mu.L of 4.times. EC80
VIP agonist was added to cells and incubated at 37.degree. C. for
30 minutes.
[0903] After appropriate compound incubation, assay signal was
generated through incubation with DiscoverX lysis cocktail
according to the manufacturers standard protocol. Dose curves were
plotted using GraphPad Prism or Activity Base. Dose curves were
plotted using GraphPad Prism or Activity Base. FIG. 4, Panel A,
shows a percent inhibition of VIPR1 by Compound 8. For antagonist
mode assays, percentage inhibition is calculated using the
following formula:
% Inhibition=100% .times.(1 (mean RLU of test sample-mean RLU of
vehicle control)/(mean RLU of EC80 control-mean RLU of vehicle
control)).
Data shown in FIG. 4 was normalized to the maximal and minimal
response observed in the presence of EC80 ligand and vehicle
respectively. The decrease in inhibition observed in FIG. 4, Panel
A, is related to agonist activity and receptor selectivity of
VIPR1. FIG. 4, Panel B, shows a percent inhibition of VIPR2 by
Compound 8. Raw fluorescence data from the binding experiments
performed in duplicate appears below in Table 6.
TABLE-US-00041 TABLE 6 VIP Analogue Antagonist Activity Compound ID
8 [Starting] 0.50 .mu.M Readout cAMP Cell Line VIPR1 Mode
Antagonist [Compound] (M) Mean RLU SD % CV % Inhibition Basal
Activity 9920.0 548.5 6.5% 100.0% 5.00E-07 M 124380.0 4497.2 3.6%
-30.5% 1.00E-07 M 123820.0 196.0 0.2% -29.5% 5.00E-08 M 123150.0
2286.2 1.8% -29.1% 1.00E-08 M 117128.6 1527.4 1.3% -22.2% 5.00E-09
M 106740.0 2530.4 2.8% -10.4% 1.00E-09 M 92540.0 2573.9 2.8% 5.6%
5.00E-10 M 87920.0 0.0 0.8% 11.1% 1.00E-10 M 90150.0 5317.4 5.9%
8.3% 1.00E-11 M 88720.0 3224.4 3.8% 10.2% 1.00E-12 M 92720.0 4468.9
4.8% 5.6% 0.00E+00 M 97640.0 2148.6 2.2% 0.0% S/B 9.6 AvCV 3.1%
Compound ID 8 [Starting] 0.50 .mu.M Readout cAMP Cell Line VIPR2
Mode Antagonist [Compound] (M) Mean RLU SD % CV % Inhibition Basal
Activity 9300.0 198.0 2.1% 100.0% 5.00E-07 M 64220.0 12077.4 14.3%
0.4% 1.00E-07 M 79580.0 3705.2 4.7% 6.6% 5.00E-08 M 79840.0 10634.9
13.3% 6.2% 1.00E-08 M 77460.0 14566.4 16.5% 9.4% 5.00E-09 M 76320.0
7071.1 9.3% 10.9% 1.00E-09 M 79620.0 7495.3 9.4% 6.5% 5.00E-10 M
74980.0 6081.1 8.1% 12.7% 1.00E-10 M 81340.0 6081.1 7.5% 4.2%
1.00E-11 M 76000.0 6616.5 8.5% 8.7% 1.00E-12 M 81720.0 11144.0
13.6% 3.7% 0.00E+00 M 84520.0 7523.6 8.9% 0.0% S/B 9.1 AvCV
9.9%
[0904] In Vitro Binding Assay 2: The analogs of the present
invention will be serially diluted into aqueous solutions with
appropriate buffer. The various concentrations of analogs will be
administered to a plurality of cells in culture that expresses
relevant naturally occurring receptor family for the naturally
occurring polypeptide upon which the analog is derived. In one
method of detection, VPAC.sub.1 CHO-K1 Division Arrested (DA) cells
or VPAC.sub.1-CRE-.beta.-lactamase CHO-K1 cells (10,000 cells/well)
are plated in a 384-well format and incubated for 16-20 hours.
Cells can then be stimulated with a dilution series of each
Secretin analog in the presence of 0.5% DMOS for 5 hours. Cells can
then be loaded with an engineered fluorescent substrate containing
two fluoroprobes, coumarin and fluorescein (2 uM final
concentration if CCF4AM and 1 mM solution D) for two hours. In the
absence of .beta.-lactamase expression, the substrate molecule
remains intact. In this state, excitation of the coumarin results
in fluorescence resonance energy transfer to the fluorescein moiety
and emission of green light (530 nm). However, in the presence of
.beta.-lactamase expression, the substrate is cleaved, thereby
separating the fluorophores, and disrupting energy transfer.
Excitation of the coumarin in the presence of enzyme
.beta.-lactamase activity results in a blue fluorescence signal
(460 nm). Fluorescence emission values at 460 nm and 530 nm can be
obtained using a standard fluorescence plate reader and plotted for
each replicate against the concentration of analog present. The
resulting blue:green ratio provides a normalized reporter response.
The degree of .beta.-lactamase expression is directly correlated to
the stimulation of the specific receptor being interrogated. The
particular receptor construct is covalently linked to a
.beta.-lactamase transcription factor, which is released upon
receptor stimulation. Serially diluted analogs in the appropriate
concentration of buffered solution (or medium alone as a control)
will be added to individual wells together with cells expressing a
specific receptor that is capable of .beta.-lactamase production. A
polypeptide that engages in competitive binding to the analog
receptor, or medium only as a background control, will also be
added to each well. After sufficient time, the wells will be
inspected by light spectrometry to determine the relative light
units, which serve a readout for receptor activation. Another
mechanism for determining binding values is through the monitoring
of a second messenger readout. For the intended receptor class, the
detection of cAMP can be a direct indicator for receptor
activation. Through the detection of cAMP (using known protocols)
across a range of analog concentrations, the specific degree of
receptor binding for each analog and concentration can be
determined. The binding of the analog to receptor will be monitored
by calculating the IC.sub.50 values in media. The signal of test
wells will be normalized to that of control wells without inhibitor
after background subtraction from both. The percent inhibition of
activity will be expressed as a function of the log 10
concentration of any competitive inhibitor added to the system. A
four-parameter sigmoid function will be fitted to the data in
Prism. The R.sup.2 values for the fits will be determined Finally,
the means.+-.S.E.M. of the IC.sub.50 values from the individual
fits of the three repeat experiments will be calculated.
[0905] In Vitro Binding Assay 3: The analogs of the present
invention will be serially diluted into aqueous solutions with
appropriate buffer. The various concentrations of analogs will be
administered to a plurality of cells in culture that expresses
relevant naturally occurring receptor family for the naturally
occurring polypeptide upon which the analog is derived. The analogs
will be administered to the cAMP Hunter.TM. eXpress CHO-K1 VIPR2
(DiscoveRx) cells according to the manufacturers suggested
protocol. cAMP Hunter.TM. Detection Reagents will be used to detect
the concentration of analog bound on the surface of the cells as a
function of signal strength in the absence and presence of
wild-type VIP provided as a control. Various EC.sub.50 values for
the VIP analogs will be calculated per the manufacturer's
recommended instructions.
[0906] In Vitro Selectivity Binding Assay: Binding assays:
Membranes prepared from a stable VPAC2 cell line (such as a CHO--S
cell line stably expressing human VPAC2 receptor or from cells
transiently transfected with human VPAC1 or PAC1) are used. A
filter binding assay is performed using .sup.125I-labeled VIP for
VPAC1 and VPAC2 and .sup.125I-labeled PACAP-27 for PAC as the
tracers. For this assay, the solutions and equipment include:
[0907] Presoak solution: 0.5% Polyethyleneamine in Aqua dest [0908]
Buffer for flushing filter plates: 25 mM HEPES pH 7.4 [0909]
Blocking buffer: 25 mM HEPES pH 7.4; 0.2% protease free BSA [0910]
Assay buffer: 25 mM HEPES pH 7.4; 0.5% protease free BSA [0911]
Dilution and assay plate: PS-Microplate, U form [0912] Filtration
Plate Multiscreen FB Opaque Plate; 1.0 mM Type B Glasfiber filter
In order to prepare the filter plates, the presoak solution will be
aspirated by vacuum filtration. The plates will be flushed twice
with 200 .mu.L flush buffer. 200 .mu.L blocking buffer will be
added to the filter plate. The filter plate will then be incubated
with 200 .mu.L presoak solution for 1 hour at room temperature. The
assay plate will be filled with 25 .mu.L assay buffer, 25 .mu.L
membranes (2.5 pg) suspended in assay buffer, 25 .mu.L agonist in
assay buffer, and 25 .mu.L tracer (about 40000 cpm) in assay
buffer. The filled plate will be incubated for 1 hour with shaking.
The transfer from assay plate to filter plate will be conducted.
The blocking buffer will be aspirated by vacuum filtration and
washed two times with flush buffer. 90 .mu.L will be transferred
from the assay plate to the filter plate. The 90 .mu.L transferred
from assay plate will be aspirated and washed three times with 200
.mu.L flush buffer. The plastic support is removed. It is dried for
1 hour at 60.degree. C. 30 .mu.L Microscint will beaded. The count
will be performed based upon analog affinity to VPAC1, VPAC2, or
PAC1 receptors. IC.sub.50 and EC.sub.50 calculations will be
performed based upon affinity scoring.
[0913] In Vivo Efficacy in Animal Models: To determine the activity
of analogs of the invention in vivo as compared to the naturally
occurring polypeptides upon which the analogs are derived, the
analogs will be administered alone (IP, IV, SC, PO, by inhalation
or nasal routes) or in combination with known active agent to
monitor the above-mentioned disease states. Secretin family analogs
alone or in combination with sub-optimal doses of relevant active
agents for specific indications or disease states will be, for
example, administered to an appropriate animal model mice (8-10
days after injection/day 1 of experiment) by tail vein or IP routes
at doses ranging from 0.0001 mg/kg to 50 mg/kg for 1 to 21 days.
Optionally, the mice will be assayed throughout the experiment with
a selection marker relevant to the particular studies disease state
every other day and survival monitored daily for the duration of
the experiment. Expired mice will be optionally subjected to
necropsy at the end of the experiment. These in vivo tests
optionally generate preliminary pharmacokinetic, pharmacodynamic
and toxicology data.
[0914] Adjuvant-Induced Arthritis in Rats: Adjuvant induced
arthritis ("AIA") is an animal model useful in the study of
rheumatoid arthritis ("RA"), which is induced by injecting M.
tuberculosis in the base of the tail of Lewis rats. Between 10 and
15 days following injection, animals develop a severe, progressive
arthritis.
[0915] Generally, analogs will be tested for their ability to alter
hind paw swelling and bone damage resulting from adjuvant induced
edema in rats. To quantitate the inhibition of hind paw swelling
resulting from AIA, two phases of inflammation have been defined:
(1) the primary and secondary injected hind paw, and (2) the
secondary uninjected hind paw, which generally begins developing
about eleven days from the induction of inflammation in the
injected paw. Reduction of the latter type of inflammation is an
indication of immunosuppressive activity. Cf. Chang, Arth. Rheum.,
20, 1135-1141 (1977).
[0916] Using an animal model of RA, such as AIA, enables one to
study the cellular events involved in the early stages of the
disease. CD44 expression on macrophages and lymphocytes is up
regulated during the early development of adjuvant arthritis,
whereas LFA 1 expression is up regulated later in the development
of the disease. Understanding the interactions between adhesion
molecules and endothelium at the earliest stages of adjuvant
arthritis could lead to significant advances in the methods used in
the treatment of RA.
[0917] Collagen Induced Arthritis in Rats: To determine the
efficacy of a representative analog of this invention administered
by po bid dosing (Days (-1)-20) for inhibition of the inflammation,
cartilage destruction and bone resorption that occurs in developing
type II collagen arthritis in rats.
[0918] Animals: Female Lewis rats (Harlan), weighing 125-150 g on
arrival. (inject subtotal of rats with collagen to get responders
on days 10, 11, 12 for 6 groups of 10). The animals (a group for
arthritis, a group for normal control), housed 4-5/cage, will be
acclimated for 4-8 days. The animals will be dosed from about po1
mg/kg bid to po100 mg/kg bid.
[0919] Materials: Peptides or analogs in vehicle, Type II collagen,
Freund's incomplete adjuvant, methotrexate (Sigma)
[0920] General Study Design: Dosing initiated on day minus 1. The
acclimated animals will be anesthetized with isoflurane and given
collagen injections (D0). On day 6 they will be anesthetized again
for the second collagen injection. Collagen is prepared by making a
4 mg/mL solution in 0.01 N acetic acid. Equal volumes of collagen
and Freund's incomplete adjuvant, will be emulsified by hand mixing
until a bead of this material held its form when placed in water.
Each animal will receive 300 uL of the mixture each time spread
over 3 sites on back. Calipering of normal (pre-disease) right and
left ankle joints are to be done approximately one day prior to the
expected days on onset of disease.
[0921] Rats will be weighed on days (-) 1, 6, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, and 20 of the study and caliper
measurements of ankles taken every day beginning on day 9. Final
body weights will be taken on day 20. After final body weight
measurement, animals are to be anesthetized for terminal plasma
collection and then euthanization. Both hind paws and knees will be
removed. Hind paws will be weighed, placed (with knees) in formalin
and then processed for microscopy.
[0922] Processing of Joints: Following 1-2 days in fixative and
then 4-5 days in decalcifier, the ankle joints will be cut in half
longitudinally, knees will be cut in half in the frontal plane,
processed, embedded, sectioned and stained with toluidine blue.
[0923] Induction of Colitis in HLA-B27 Rats: The efficacy of the
analogs of the present invention in reversing colitis can be
determined in HLA-B27 transgenic rats. HLA-B27 transgenic rats have
been utilized as an animal model of Inflammatory Bowel Disease
which mimics Crohn's Disease in humans The rats overexpress the
human MHC class I HLA-B27 heavy chain and beta-2 microglobulin
proteins, which induces a variety of autoimmune diseases that
include inflammation of the colon.
[0924] The therapeutic effect of the analogs described in this
invention in terms of resolving colitis can be evaluated in HLA-B27
transgenic rats. Diseased rats will be dosed subcutaneously with
0.001-100 mg/kg of a single analog of this invention once or twice
a day for 16 days or once per week for two weeks.
[0925] Disease Activity Index (DAI) scores will be used to
determine the efficacy of each analog as compared to rats dosed
with vehicle. In addition, fecal consistency and FOB scores for
both rats dosed with analogs will be statistically compared to the
vehicle group.
[0926] Induction of Colitis: 1-20 HLA-B27 (6-9 weeks old)
transgenic rats will be acclimated in animal facility for 10 weeks.
Animal bedding will be mixed from different cages once a week to
control for a "dirty" environmental flora.
[0927] Treatments: Rats are to be enrolled and randomized into four
groups (n=5) based on weight and DAI scores (FC.gtoreq.3,
FOB.gtoreq.2). The experimental groups will be dosed subcutaneously
with an analog 0.001-100 mg/kg once or twice a day for 16 days or
once per week for two weeks and terminated at trough. The control
groups include a vehicle-treated group and a GG5/3 (mouse anti-rat
alpha-4 integrin antibody) positive control group dosed
subcutaneously at 10 mg/kg (5 mL/kg) on d0, d3, and d6 and
terminated at trough on d8. Fresh analog and vehicle treatments are
to be formulated in advance of treatment.
[0928] Endpoint Read-outs: Disease Activity Index scores, Fecal
Consistency test and Fecal Occult Blood test, are to be taken 4
times a week to generate in-life clinical scores. The primary
read-out for the study is a histopathological analysis of cecum,
proximal colon, mid-colon, and distal colon. An IBD scoring system
was applied (Table H2). TABLE H2 IBD Scoring System Multiple
Endpoints A Destruction of epithelium and glands B Dilatation of
glandular crypts C Depletion and loss of goblet cells D
Inflammatory cell infiltrates E Edema F Vascular congestion G Crypt
Abscesses H Atrophia
[0929] Primary Arterial Hypertension animal model: 36 adult male
Sprague-Dawley rats (300-350 g in body weight were randomized for
treatment 22 days after a s.c. injection of saline or 60 mg/kg MCT
(Sigma-Aldrich) to induce pulmonary hypertension. In addition to a
group of untreated rats, the experimental groups included rats that
received either daily, weekly or monthly delivery of a secretin
analog at an appropriate dose of (0.001-50 mg/kg or the delivery
vehicle alone. On Day 22 a carotid/femoral artery will be accessed
for arterial blood gases (systemic blood pressure can be monitored
as well). Thoracotomy performed and right ventricle catheterized
with a Millar catheter (or other appropriate catheter) which will
be advanced to the pulmonary artery. Animals will have anesthesia
induced and maintained on isoflurane through out the experiment.
Rats will be intubated prior to surgical procedures. Hemodynamic
measurements such as Pulmonary arterial pressure, systemic blood
pressure (SAP, DAP, MAP) and heart rate are to be collected
continuously via a Gould-Ponemah physiograph. Statistical analysis
will be performed on all hemodynamic data. Arterial blood samples
collected at protocol specified time points (up to 8 time points)
for analysis of drug concentration and/or arterial blood gases.
Animals euthanized after 30 minutes and lungs collected and snap
frozen for shipment to the Sponsor. Lungs analyzed for levels of
drug.
[0930] Animals are to be clinically observed once daily with body
weight measured weekly. While some embodiments of the invention
have been illustrated and described, it will be appreciated that
various changes can be made therein without departing from the
spirit and scope of the invention.
[0931] Small Cell Lung Cancer Model: Female athymic BALByc nude
mice, 4-5 weeks old, will be housed in filter-top cages in a
pathogenfree, temperature-controlled, laminar-flow, filtered-air,
isolated room and will be exposed to light from 7:00 a.m. to 7:00
p.m. NCI-H69 cells will be injected subcutaneously into the right
flank of each mouse. There were four experimental groups, of four
mice each, three of which will receive VIP and/or an analog of VIP
(1.0, 5.0, or 10 mg/day) in PBS; as a control, the fourth will
receive only PBS. All solutions will be infused for 8 weeks,
beginning 1 week after injection of the cells, and delivered by
i.v., i.p., subc., i.m. injection or osmotic pumps placed
aseptically under the skin of the back of the mice. The pump will
release its contents at a rate of 0.5 ml/h for a duration of 2
weeks. The spent pumps will be removed every 2 weeks, and new
pumps, containing fresh solutions, will be implanted with known
techniques; this procedure will be repeated three times. After
treatment, The tumors will be measured with calipers, and the mice
will be weighed weekly for 8 weeks. Tumor volume will be calculated
for an ellipsoid as (maximal length).times.(maximal
height).times.(maximal width).times.(.pi./6). On the last day of
the experiment, blood will be sampled from the retroorbital plexus
into chilled heparin-containing tubes rinsed with 0.05% NaEDTA and
containing three protease inhibitors, 10 mg/ml soybean trypsin
inhibitor, 100 TIU/ml aprotinin, and 10 mg/ml phosphamidon), as
well as 0.1 mM IBMX for measurement of plasma VIP and cAMP levels.
The mice will then euthanized The tumors will be excised, weighed,
and frozen in liquid nitrogen for subsequent extraction (in
methanol) and for measurement of protein content by known
techniques; a portion of the tumor will be fixed in 10% neutral
buffered formalin for morphologic examination.
[0932] One purpose of these studies is to evidence that the analogs
are capable of producing the desired biological, biochemical,
diagnostic, medicinal and/or therapeutic outcome in a living
animal.
Example 5
DPPIV Protease Assay (Prophetic)
[0933] Digest buffer {100 mM Tris-HCl (pH 8)} containing 15 .mu.M
peptide and 1 .mu.g porcine kidney DPPIV (Sigma-Aldrich) will be
incubated at 37 C. The reaction will be terminated at the specified
time point by adding 10 .mu.l 10% TFA, followed by reverse-phase
HPLC on a Gemini C18 column (Phenomenex, Macclesfield, UK). The
column will be eluted with a linear gradient of 27-31% AcN over 50
min at 1 ml/min. Peptides and their degradation products will be
monitored by their absorbance at 214 nm. Percent degradation will
be quantified by integration of peak areas related to undigested
peptide peaks and corrected for degradation in the absence of
enzyme.
Example 6
Method for Measuring Triglyceride Levels
[0934] hApoA1 mice (obtained from Jackson Laboratories, Bar Harbor,
Me.) are bled (by either eye or tail vein) and grouped according to
equivalent mean serum triglyceride levels. They are dosed orally
(by gavage in a pharmaceutically acceptable vehicle) with the test
polypeptide once daily for 8 days. The animals are then bled again
by eye or tail vein, and serum triglyceride levels are determined.
In each case, triglyceride levels are measured using a Technicon
Axon Autoanalyzer (Bayer Corporation, Tarrytown, N.Y.).
Method for Measuring HDL-Cholesterol Levels
[0935] To determine plasma HDL-cholesterol levels, hApoA1 mice are
bled and grouped with equivalent mean plasma HDL-cholesterol
levels. The mice are orally dosed once daily with vehicle or test
polypeptide for 7 days, and then bled again on day 8. Plasma is
analyzed for HDL-cholesterol using the Synchron Clinical System
(CX4) (Beckman Coulter, Fullerton, Calif.).
[0936] Method for Measuring Total Cholesterol, HDL-Cholesterol,
Triglycerides, and Glucose Levels. In another in vivo assay, obese
monkeys are bled, then orally dosed once daily with vehicle or test
polypeptide for 4 weeks, and then bled again. Serum is analyzed for
total cholesterol, HDL-cholesterol, triglycerides, and glucose
using the Synchron Clinical System (CX4) (Beckman Coulter,
Fullerton, Calif.). Lipoprotein subclass analysis is performed by
NMR spectroscopy as described by Oliver, et al., (Proc. Natl. Aced.
Sci. USA 98:5306-5311, 2001).
[0937] The following journal articles, which are herein
incorporated by reference, disclose secretin family analogs
contemplated to be a polypeptide backbone for the secretin family
analogs of the invention. The journal articles also disclose a
series of methods of administering secretin family analogs as part
of pharmaceutical compositions: [0938] 1. Gozes, et. al., Current
Pharmaceutical Design, 2003, Vol. 9, No. 6 [0939] 2. Delgado, et.
al., Brain Behav Immun. 2008 November; 22(8): 1146-1151.
doi:10.1016/j.bbi.2008.06.001. [0940] 3. L. Dickson, K.
Finlayson/Pharmacology & Therapeutics 121 (2009) 294-316.
[0941] 4. Gonzales-Rey, et. al., TRENDS in Pharmacological Sciences
Vol. 28 No. 9. [0942] 5. Varela, et. al., Expert Opin. Biol. Ther.
(2007) 7(4):461-478 [0943] 6. Brenneman, Peptides 28 (2007) 1720
1726; [0944] 7. Onoue, et. al., Naunyn-Schmiedeberg's Arch
Pharmacol (2008) 377:579-590
[0945] Any journal article, patent application, issued patent or
other publication referenced in this application is herein
incorporated by reference. The embodiments listed herein are not
meant to be restrictive, but rather illustrative of the invention.
Sequence CWU 0 SQTB SEQUENCE LISTING The patent application
contains a lengthy "Sequence Listing" section. A copy of the
"Sequence Listing" is available in electronic form from the USPTO
web site
(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20210205415A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
0 SQTB SEQUENCE LISTING The patent application contains a lengthy
"Sequence Listing" section. A copy of the "Sequence Listing" is
available in electronic form from the USPTO web site
(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20210205415A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
* * * * *
References