U.S. patent application number 14/110422 was filed with the patent office on 2015-02-19 for compositions comprising glucagon analogs and methods of making and using the same.
This patent application is currently assigned to Longevity Biotech, Inc.. The applicant listed for this patent is Samuel H. Gellman, Scott Shandler. Invention is credited to Samuel H. Gellman, Scott Shandler.
Application Number | 20150051141 14/110422 |
Document ID | / |
Family ID | 46969559 |
Filed Date | 2015-02-19 |
United States Patent
Application |
20150051141 |
Kind Code |
A9 |
Shandler; Scott ; et
al. |
February 19, 2015 |
Compositions Comprising Glucagon Analogs And Methods Of Making And
Using The Same
Abstract
This invention relates to novel compositions comprising analogs
of glucagon, 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, including diabetes and other metabolic disorders. 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;
(Philadelphia, PA) ; Gellman; Samuel H.; (Madison,
WI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shandler; Scott
Gellman; Samuel H. |
Philadelphia
Madison |
PA
WI |
US
US |
|
|
Assignee: |
Longevity Biotech, Inc.
Philadelphia
PA
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20140121154 A1 |
May 1, 2014 |
|
|
Family ID: |
46969559 |
Appl. No.: |
14/110422 |
Filed: |
April 5, 2012 |
PCT Filed: |
April 5, 2012 |
PCT NO: |
PCT/US12/32441 PCKC 00 |
371 Date: |
December 23, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61540526 |
Sep 28, 2011 |
|
|
|
61472149 |
Apr 5, 2011 |
|
|
|
Current U.S.
Class: |
514/5.3 ;
514/11.7; 514/6.7; 530/308 |
Current CPC
Class: |
A61P 3/08 20180101; C07K
14/605 20130101; A61K 38/26 20130101 |
Class at
Publication: |
514/5.3 ;
514/6.7; 514/11.7; 530/308 |
International
Class: |
C07K 14/605 20060101
C07K014/605 |
Claims
1. A composition comprising a glucagon analog, wherein said analog
comprises a formula of sequential .alpha.-amino acids (.alpha.) and
at least one .beta.-amino acid (.beta.) chosen from:
.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..alpha..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., wherein the analog
is a fusion polypeptide comprising a first and a second amino acid
sequence, and wherein the first amino acid sequence is derived from
a glucagon amino acid sequence and the second amino acid sequence
is derived from glucagon-like peptide-1 (GLP-1).
2.-16. (canceled)
17. The composition of claim 1, wherein the analog is a fusion
polypeptide comprising a first and a second amino acid sequence,
wherein the first amino acid sequence is derived from a GIP amino
acid sequence and the second amino acid sequence is derived from
GLP-1 amino acid sequence.
18. The composition of claim 17, wherein the analog is a fusion
polypeptide comprising a first, second, and third amino acid
sequence, wherein the first amino acid sequence activates the
glucagon receptor pathway, the second amino acid sequence activates
the GLP-1 receptor pathway, and the third amino acid sequence
activates the GIP receptor pathway.
19. The composition of claim 1, wherein the analog comprises the
sequence: HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein the amino acid sequences
HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA are
modified by a pattern of beta amino acids in the formula chosen
from: .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..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog binds the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor.
20. The composition of claim 1, 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.
21. The composition of claim 1, wherein the analog comprises at
least three cyclic beta amino acids.
22.-25. (canceled)
26. The composition of claim 1, wherein the .beta.-amino acids are
spatially aligned along a longitudinal axis of the analog in order
to constrain the conformation of the analog in an active state.
27.-30. (canceled)
31. A pharmaceutical composition, comprising the composition of
claim 1 or a pharmaceutical salt derived therefrom, and a
pharmaceutically acceptable carrier.
32. The pharmaceutical composition of claim 31, wherein the
composition further comprises one other active agent.
33. A method of manufacturing the composition of claim 1 or a
pharmaceutical salt derived therefrom comprising catalyzing a
reaction between at least one .alpha.-amino acid with at least one
.beta.-amino acid.
34. A method of treating or preventing weight gain, obesity,
elevated insulin levels, hyperglycemia, or metabolic disorders in a
subject in need thereof comprising administering the pharmaceutical
composition of claim 31 to a subject in need thereof.
35. A method of inhibiting secretion of glucagon in a subject in
need thereof comprising administering the pharmaceutical
composition of claim 31 to a subject in need thereof.
36. (canceled)
37. A kit comprising the composition of claim 1.
38. The kit of claim 37, wherein a first container comprises the
composition of claim 1 and a second container comprises a vehicle
for administration of the composition of claim 1.
39.-63. (canceled)
64. The composition of claim 1, wherein the analog comprises the
sequence: YBEGTFTSDY; wherein the C-terminus of the analog is
optionally amidated; and wherein the analog binds the GIP receptor
and/or the GLP-1 receptor and/or the GLP-2 receptor and/or the
glucagon receptor.
65. The composition of claim 64, wherein the analog binds GIP
receptor with an EC50 value less than or equal to 125 nM and binds
GLP-1 receptor with an EC50 value less than or equal to 10 nM.
66. The composition of claim 64, wherein the analog wherein the
analog binds GIP receptor with an EC50 value no more than 3 nM and
binds GLP-1 receptor with an EC50 value no more than 600 pM.
67. The composition of claim 64, wherein the analog comprises at
least 4 cyclic beta amino acids.
68. The composition of claim 67, wherein at least one cyclic beta
amino acid is selected from: APC, ACPC, AHC, or ACHC.
69.-74. (canceled)
75. The composition of claim 64, wherein dipeptidyl peptidase IV
cleaves the analog with at least 10% less effectiveness over a time
period as compared to its rate of cleavage of wild-type glucagon
over the same time period.
Description
[0001] This application claims priority to U.S. Provisional
Application Ser. Nos. 61/472,149, filed Apr. 5, 2011 and
61/540,526, filed Sep. 28, 2011, each of which is incorporated
herein by reference in its entirety. The effectiveness of protein
pharmaceuticals depends heavily on the intrinsic pharmacokinetics
of the natural protein. Because the kidney generally filters out
molecules below 60 kDa, efforts to reduce clearance have focused on
increasing molecular size through protein fusions, glycosylation,
or the addition of polyethylene glycol polymers (i.e. PEG). For
example, fusions to large long-lived proteins such as albumin or
the Fc portion of an IgG, the introduction of glycosylation sites,
and conjugation with PEG (5-7) have been used. Through these
methods, the in vivo exposure of protein therapeutics has been
extended.
BACKGROUND OF THE INVENTION
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.
[0003] Pre-proglucagon is a 158 amino acid precursor polypeptide
that is processed in different tissues to form a number of
different proglucagon-derived peptides, including glucagon,
glucagon-like peptide-1 (GLP-I), glucagon-like peptide-2 (GLP-2)
and oxyntomodulin (OXM), that are involved in a wide variety of
physiological functions, including glucose homeostasis, insulin
secretion, gastric emptying, and intestinal growth, as well as the
regulation of food intake. Glucagon is a 29-amino acid peptide that
corresponds to amino acids 33 through 61 of pre-proglucagon, while
GLP-I is produced as a 37-amino acid peptide that corresponds to
amino acids 72 through 108 of pre-proglucagon.
When blood glucose begins to fall, glucagon, a hormone produced by
the pancreas, signals the liver to break down glycogen and release
glucose, causing blood glucose levels to rise toward a normal
level. GLP-I has different biological activities compared to
glucagon. Its actions include stimulation of insulin synthesis and
secretion, inhibition of glucagon secretion, and inhibition of food
intake. GLP-I has been shown to reduce hyperglycemia (elevated
glucose levels) in diabetics. Exendin-4, a peptide from lizard
venom that shares about 50% amino acid identity with GLP-I,
activates' the GLP-I receptor and likewise has been shown to reduce
hyperglycemia in diabetics.
[0004] Glucose-dependent insulinotropic peptide (GIP) is a 42-amino
acid gastrointestinal regulatory peptide that stimulates insulin
secretion from pancreatic beta-cells in the presence of glucose. It
is derived by proteolytic processing from a 133-amino acid
precursor, preproGIP.
[0005] There is evidence that the combined effect of GLP-1 and GIP
may account for the incretin effect (Keiffer, et al.,
Endocrinology, Vol 136, 3585-3596, 1995). Both proteins are
degraded by dipeptidyl peptidase IV. Both hormones or analogs
thereof have been the subject of recent clinical trials
(NCT00239707; Irwin, et al., Clinical Endocrinology and Metabolism,
Volume 23, Issue 4, Pages 499-512 (August 2009)). GLP-1 (7-36)
amide alone is not very useful for treatment, since it must be
administered by continuous subcutaneous infusion. Several
long-lasting analogs of GLP-1 having insulinotropic activity have
been developed, and two, exenatide (Byetta) and liraglutide
(Victoza), have been approved for use in the U.S. The main
disadvantage of these GLP-1 analogs is they must be administered by
subcutaneous injection.
[0006] WO/2010/011439 describes a GLP-1/GIP chimeric protein with
dual tropism for the GIP receptor and the GLP-1 receptor. The
peptides described in WO/2010/011439, however, are subject to
increased degradation due to their inherent chemical structure and
lack of patterned polypeptide backbone amino acids.
[0007] There is a need to design and manufacture analogs of
glucagon, GIP, and GLP-1 to control, prevent, and treat metabolic
disorders including diabetes and obesity. There is a need to design
and manufacture analogs of glucagon, GIP, and GLP-1 to enhance the
half-life of a bioactive molecules. There is a need for analogs of
glucagon, GIP, and GLP-1 that exhibit increased conformational
constraints or increased conformational flexibility and greater
half-lives. There is a need for analogs of glucagon, GIP, and GLP-1
that are less suspectible to degradation and increase affinity of
pharmaceutical compositions and/or other agents to bind target
molecules in a subject's body, such as GIP receptor. Increased
conformational constraints may lock the active domain of the
polypeptides or chimera into their active state. Increased
conformational flexibility of the polpeptide 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 a pharmaceutical agent unmodified
by the analog. 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
[0008] In some embodiments, the invention relates to compositions
comprising a helical polypeptide synthesized with a repeated
pattern of non natural, .beta.-amino acids at positions along the
entire length of a polypeptide chain. 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, which, when introduced to a subject increase the affinity of
the polypeptide or other co-delivered agent to receptors
responsible for insulin secretion and metaboilism. 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 an analog of GIP and GLP-1, wherein said
analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid. In some embodiments, the composition comprises
an analog of GIP and GLP-1 wherein the analog is a fusion
polypeptide having GIP activity and GLP-1 activity. In some
embodiments, the composition comprises an analog of GIP and GLP-1
wherein the analog is a fusion polypeptide having a GIP-like
sequence and a GLP-1-like sequence, wherein said analog comprises
an .alpha.-amino acid and at least one .beta.-amino acid, and
wherein the fusion polypeptide has increased selectivity for the
GIP receptor and decreased selectivity for the GLP-1 receptor.
[0009] In some embodiments, the composition comprises an analog of
a pharmaceutical agent 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 analog of a pharmaceutical agent
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 an analog of a pharmaceutical agent 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 an analog of
a pharmaceutical agent 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 an analog of a pharmaceutical agent
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 an analog of a pharmaceutical agent 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 an analog of
a pharmaceutical agent wherein the total number of 3-amino acids in
the analog is from about 30 percent to about 50 percent of the
total number of amino acids of the analog.
[0010] In some embodiments, the composition comprises an 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 an 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 an 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 an analog and a
pharmaceutical agent 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 an analog and a
pharmaceutical agent 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 an analog and a pharmaceutical agent 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 an
analog covalently bound to the pharmaceutical agent. In some
embodiments, the composition comprises an analog non-covalently
bound to a pharmaceutical agent.
[0011] In some embodiments, the composition comprises an 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 an 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 an 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 an 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 an
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.
[0012] 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 glucagon,
GLP-1, GLP-2, and GIP. In some embodiments, the amino acid
sequences upon which the analogs are based or derived are fusion
proteins having multiple domains chosen from fragments of
glucaogon, GLP-1, GLP-2, and GIP. In some embodiments, the analogs
have increased selectivity to the naturally occurring receptor of
one of the fusion polypeptide domains and decreased, limited, or
absent selectivity for a naturally occurring receptor of the fusion
polypeptide domain.
[0013] In some embodiments, the composition, pharmaceutical
composition or analog of the present invention includes other
modifications. 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).
[0014] 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.
[0015] 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 mimetic polypeptides and any other analog
sequences are intended to also refer to substitutions, deletions or
additions in corresponding positions in the pharmaceutical agent,
described herein or known in the art and are expressly encompassed
by the present invention.
[0016] 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. In some embodiments,
the composition, pharmaceutical composition, or analog is more
resistant to peptidyl peptidase IV. In some embodiments, the analog
is covalently attached or non-covalently attached to another
pharmaceutical agent or another molecule. In some embodiments, the
analog decreases the rate of degradation of the pharmaceutical
agent while also provided increased stability and/or affinity to
receptors that control glucose metabolism in a subject.
[0017] 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. In some embodiments, the invention
relates to a composition or pharmaceutical composition comprising
at least two biological moieties, wherein the first biological
moiety binds to a GIP receptor and the second biological moiety
binds to a GLP-1 receptor so that its degradation is reduced and/or
its affinity for a GIP receptor or GLP-1 receptor is increased at a
certain concentration. The invention relates to a composition or
pharmaceutical composition comprising at least two biological
moieties, wherein the first biological moiety is a GIP agonist and
the second biological moiety is a GLP-1 agonist, wherein the
degradation of the composition or pharmaceutical composition is
reduced and/or its affinity for GIP and/or GLP-1 receptor is
increased at a certain concentration.
[0018] A "non-naturally encoded amino acid" refers to an amino acid
that is not one of the 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 selenocysteine) 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.
[0019] 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,
immunoglobulin constant region portions such as Fc, poly-glycine or
other moieties that increase half-life of peptides.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] In one aspect, the invention provides a method of treating
obesity in an obese or overweight animal by administering a
therapeutically effective amount of a GIP/GLP-1 co-agonist. In some
embodiments, the invention provides a method of treating or
preventing obesity in an obese or overweight animal by
administering a therapeutically effective amount of a composition
comprising a GIP/GLP-1 co-agonist and a pharmaceutical acceptable
carrier, optionally, in combination with a PYY analog, a PYY
agonist analog east one delivery agent compound and to a animal 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." In some embodiments, 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.
[0025] In some embodiments, the composition or pharmaceutical
compositions of the present invention comprises an analog of the
polypeptides disclosed below, wherein the analog amino acid
sequence is based upon fragments, polypeptides, and functional
deriviatives with 70%, 75%, 85%, 90%, 95%, 98%, or 99% sequence
homology to the following polypeptides disclosed below:
[0026] 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.
[0027] In some embodiments, the composition or pharmaceutical
composition of the claimed invention comprises an analog of a
polypeptide, wherein the analog amino acid sequence is based upon
the fragments, polypeptides, and functional deriviatives disclosed
herein and wherein the analog comprises at least one or a plurality
of non-natural amino acids and/or 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, alkynl, 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.
[0028] 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.
[0029] 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. Non-natural 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, P amino acids such as substituted
.beta.-alanine.
[0030] In some embodiments, the composition or pharmaceutical
composition of the claimed invention comprises an analog of a
polypeptide, wherein the analog amino acid sequence is based upon
the fragments, polypeptides, and functional deriviatives 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
non-natural 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 phenyalanines,
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 .beta.-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.
[0031] The chemical moieties via non-natural 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 deriviatives
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
non-natural amino is a photoreactive non-natural 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.
[0032] 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.
[0033] 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.
[0034] In some embodiments, the composition comprises an analog
with two biological moieties, wherein the first biological moiety
binds a blood serum protein and wherein the second biological
moiety comprise a polypeptide sequence that increases the stability
and/or affinity for a blood serum protein and/or reduces the
degradation of the first biological moiety, 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.
[0035] In some embodiments, the composition comprises an analog
with two biological moieties, wherein the first biological moiety
binds a GIP receptor and wherein the second biological moiety
comprise a polypeptide sequence that binds a GLP-1 receptor,
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 analog with two biological moieties, wherein the first
biological moiety binds a GIP receptor and wherein the second
biological moiety comprises a polypeptide sequence that binds GLP-1
receptor and/or reduces the degradation of the first biological
moiety, 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 an analog with two biological moieties,
wherein the first biological moiety binds a GIP receptor and
wherein the second biological moiety comprises a polypeptide
sequence that binds GLP-1 receptor and/or reduces the degradation
of the first biological moiety, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor and/or reduces the
degradation of the first biological moiety, 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 an
analog with two biological moieties, wherein the first biological
moiety binds a GIP receptor and wherein the second biological
moiety comprises a polypeptide sequence that binds GLP-1 receptor
and/or reduces the degradation of the first biological moiety,
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 an analog with two biological moieties, wherein the first
biological moiety binds a GIP receptor and wherein the second
biological moiety comprises a polypeptide sequence that binds GLP-1
receptor and/or reduces the degradation of the first biological
moiety, 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 an analog with two biological moieties,
wherein the first biological moiety binds a GIP receptor and
wherein the second biological moiety comprises a polypeptide
sequence that binds GLP-1 receptor and/or reduces the degradation
of the first biological moiety, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor and/or reduces the
degradation of the first biological moiety, 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 an analog
with two biological moieties, wherein the first biological moiety
binds a GIP receptor and wherein the second biological moiety
comprises a polypeptide sequence that binds GLP-1 receptor and/or
reduces the degradation of the first biological moiety, 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 an
analog with two biological moieties, wherein the first biological
moiety binds a GIP receptor and wherein the second biological
moiety comprises a polypeptide sequence that binds GLP-1 receptor
and/or reduces the degradation of the first biological moiety,
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 an analog with two biological moieties, wherein the first
biological moiety binds a GIP receptor and wherein the second
biological moiety comprises a polypeptide sequence that binds GLP-1
receptor and/or reduces the degradation of the first biological
moiety, 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 an analog with two biological moieties,
wherein the first biological moiety binds a GIP receptor and
wherein the second biological moiety comprises a polypeptide
sequence that binds GLP-1 receptor and/or reduces the degradation
of the first biological moiety, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor and/or reduces the
degradation of the first biological moiety, 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 an analog
with two biological moieties, wherein the first biological moiety
binds a GIP receptor and wherein the second biological moiety
comprises a polypeptide sequence that binds GLP-1 receptor and/or
reduces the degradation of the first biological moiety, 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 an
analog with two biological moieties, wherein the first biological
moiety binds a GIP receptor and wherein the second biological
moiety comprises a polypeptide sequence that binds GLP-1 receptor
and/or reduces the degradation of the first biological moiety,
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 an analog with two biological moieties, wherein the first
biological moiety binds a GIP receptor and wherein the second
biological moiety comprises a polypeptide sequence that binds GLP-1
receptor and/or reduces the degradation of the first biological
moiety, 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 an analog with two biological moieties,
wherein the first biological moiety binds a GIP receptor and
wherein the second biological moiety comprises a polypeptide
sequence that binds GLP-1 receptor and/or reduces the degradation
of the first biological moiety, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor and/or reduces the
degradation of the first biological moiety, 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.
[0036] In some embodiments, the composition comprises an analog
with at least two biological moieties, wherein a first biological
moiety is a GIP agonist and wherein the second biological moiety
comprises a polypeptide sequence that is a GLP-1 agonist, and
wherein an optional third moiety is a glucogon agonist, wherein the
wherein the total number of .beta.-amino acids in the analog is
from about 5 percent to about 50 percent of the total number of
amino acids of the analog. In some embodiments, the composition
comprises an analog with at least two biological moieties, wherein
a first biological moiety is a GIP agonist and wherein the second
biological moiety comprises a polypeptide sequence that is a GLP-1
agonist, and wherein an optional third moiety is a glucogon
agonist, wherein the wherein the total number of .beta.-amino acids
in the analog is from about 10 percent to about 50 percent of the
total number of amino acids of the analog. In some embodiments, the
composition comprises an analog with at least two biological
moieties, wherein a first biological moiety is a GIP agonist and
wherein the second biological moiety comprises a polypeptide
sequence that is a GLP-1 agonist, and wherein an optional third
moiety is a glucogon agonist, wherein the 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 an analog with at
least two biological moieties, wherein a first biological moiety is
a GIP agonist and wherein the second biological moiety comprises a
polypeptide sequence that is a GLP-1 agonist, and wherein an
optional third moiety is a glucogon agonist, wherein the 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 an
analog with at least two biological moieties, wherein a first
biological moiety is a GIP agonist and wherein the second
biological moiety comprises a polypeptide sequence that is a GLP-1
agonist, and wherein an optional third moiety is a glucogon
agonist, wherein the 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 an analog with at least two biological
moieties, wherein a first biological moiety is a GIP agonist and
wherein the second biological moiety comprises a polypeptide
sequence that is a GLP-1 agonist, and wherein an optional third
moiety is a glucogon agonist, wherein the 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 an analog with at
least two biological moieties, wherein a first biological moiety is
a GIP agonist and wherein the second biological moiety comprises a
polypeptide sequence that is a GLP-1 agonist, and wherein an
optional third moiety is a glucogon agonist, wherein the wherein
the total number of .beta.-amino acids in the analog is from about
10 percent to about 45 percent of the total number of amino acids
of the analog. In some embodiments, the composition comprises an
analog with at least two biological moieties, wherein a first
biological moiety is a GIP agonist and wherein the second
biological moiety comprises a polypeptide sequence that is a GLP-1
agonist, and wherein an optional third moiety is a glucogon
agonist, wherein the wherein the total number of .beta.-amino acids
in the analog is from about 10 percent to about 40 percent of the
total number of amino acids of the analog. In some embodiments, the
composition comprises an analog with at least two biological
moieties, wherein a first biological moiety is a GIP agonist and
wherein the second biological moiety comprises a polypeptide
sequence that is a GLP-1 agonist, and wherein an optional third
moiety is a glucogon agonist, wherein the wherein the total number
of .beta.-amino acids in the analog is from about 10 percent to
about 35 percent of the total number of amino acids of the analog.
In some embodiments, the composition comprises an analog with at
least two biological moieties, wherein a first biological moiety is
a GIP agonist and wherein the second biological moiety comprises a
polypeptide sequence that is a GLP-1 agonist, and wherein an
optional third moiety is a glucogon agonist, wherein the wherein
the total number of .beta.-amino acids in the analog is from about
10 percent to about 30 percent of the total number of amino acids
of the analog. In some embodiments, the composition comprises an
analog with at least two biological moieties, wherein a first
biological moiety is a GIP agonist and wherein the second
biological moiety comprises a polypeptide sequence that is a GLP-1
agonist, and wherein an optional third moiety is a glucogon
agonist, wherein the wherein the total number of .beta.-amino acids
in the analog is from about 15 percent to about 40 percent of the
total number of amino acids of the analog. In some embodiments, the
composition comprises an analog with at least two biological
moieties, wherein a first biological moiety is a GIP agonist and
wherein the second biological moiety comprises a polypeptide
sequence that is a GLP-1 agonist, and wherein an optional third
moiety is a glucogon agonist, wherein the wherein the total number
of .beta.-amino acids in the analog is from about 20 percent to
about 40 percent of the total number of amino acids of the analog.
In some embodiments, the composition comprises an analog with at
least two biological moieties, wherein a first biological moiety is
a GIP agonist and wherein the second biological moiety comprises a
polypeptide sequence that is a GLP-1 agonist, and wherein an
optional third moiety is a glucogon agonist, wherein the wherein
the total number of .beta.-amino acids in the analog is from about
25 percent to about 40 percent of the total number of amino acids
of the analog. In some embodiments, the composition comprises an
analog with at least two biological moieties, wherein a first
biological moiety is a GIP agonist and wherein the second
biological moiety comprises a polypeptide sequence that is a GLP-1
agonist, and wherein an optional third moiety is a glucogon
agonist, wherein the wherein the total number of .beta.-amino acids
in the analog is from about 20 percent to about 35 percent of the
total number of amino acids of the analog. In some embodiments, the
composition comprises an analog with at least two biological
moieties, wherein a first biological moiety is a GIP agonist and
wherein the second biological moiety comprises a polypeptide
sequence that is a GLP-1 agonist, and wherein an optional third
moiety is a glucogon agonist, wherein the 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 an analog with at
least two biological moieties, wherein a first biological moiety is
a GIP agonist and wherein the second biological moiety comprises a
polypeptide sequence that is a GLP-1 agonist, and wherein an
optional third moiety is a glucogon agonist, wherein the wherein
the total number of .beta.-amino acids in the analog is from about
25 percent to about 35 percent of the total number of amino acids
of the analog.
[0037] In some embodiments, the composition comprises an analog
with two biological moieties, wherein the first biological moiety
binds a GIP receptor and wherein the second biological moiety
comprises a polypeptide sequence that binds GLP-1 receptor, wherein
the ratio of total .beta.-amino acids in the analog is from 1 to
.beta.-amino acids for every 7 amino acids of the analog. In some
embodiments, the composition comprises an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor, wherein the ratio
of total p-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 an analog with two biological moieties,
wherein the first biological moiety binds a GIP receptor and
wherein the second biological moiety comprises a polypeptide
sequence that binds GLP-1 receptor, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor, wherein the ratio
of total 3-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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor, 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 an analog with two
biological moieties, wherein the first biological moiety binds a
GIP receptor and wherein the second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor, 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.
[0038] In some embodiments, the composition comprises an analog
with two biological moieties, wherein the first biological moiety
binds a GIP receptor and wherein the second biological moiety
comprises a polypeptide sequence that binds GLP-1 receptor, 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..alpha.,
.beta..alpha..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..
[0039] 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 an analog and one other active agent, wherein
the analog comprises at least one .alpha.-amino acid and at least
one .beta.-amino acid.
[0040] In another embodiment of the invention, the invention
relates to a pharmaceutical composition that comprises an analog
with two biological moieties, wherein the first biological moiety
binds a GIP receptor and wherein the second biological moiety
comprises a polypeptide sequence that binds GLP-1 receptor. In
another embodiment of the invention, the invention relates to a
pharmaceutical composition that comprises an analog with at least
two biological moieties, wherein a first biological moiety binds a
GIP receptor and wherein a second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor. In another
embodiment of the invention, the invention relates to a
pharmaceutical composition that comprises an analog with at least
two biological moieties, wherein a first biological moiety binds a
GIP receptor and wherein a second biological moiety comprises a
polypeptide sequence that binds GLP-1 receptor, and wherein a third
biological moiety binds to a modulator of glucose metabolism.
[0041] In another embodiment of the invention, the invention
relates to a pharmaceutical composition that comprises an analog
with at least two biological moieties, wherein a first biological
moiety binds a GIP receptor and wherein a second biological moiety
comprises a polypeptide sequence that binds GLP-1 receptor, 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..alpha..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 another
embodiment of the invention, the invention relates to a
pharmaceutical composition that comprises an analog or a
pharmaceutical salt thereof with at least two biological moieties,
wherein a first biological moiety binds a GIP receptor and wherein
a second biological moiety comprises a polypeptide sequence that
binds GLP-1 receptor, 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..alpha..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..
[0042] The invention further relates to uses of a composition
comprising an analog in the preparation of a medicament for
treating or preventing a metabolic disorder. The invention further
relates to use of a composition comprising an analog in the
preparation of a medicament for treating or preventing a glucose
metabolism disorder. The invention further relates to use of a
composition comprising an analog in the preparation of a medicament
for treating or preventing obesity. 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.
[0043] The invention also relates to methods of administering to a
subject in need thereof a pharmaceutical composition comprising any
one of the analogs disclosed herein and a pharmaceutical acceptable
carrier, and optionally, another pharmaceutical agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0044] FIG. 1 depicts the association of several beta-amino acid
analogs to GIP receptor over a set of concentrations as compared to
natural ligand and negative controls. The beta-amino acid peptides
can bind GIP-receptor.
[0045] FIG. 2 depicts the association of the same beta-amino acid
analogs to GLP-1 receptor over a set of concentrations as compared
to natural ligand and negative controls. The beta amino acid
peptides can also bind GLP-1 receptor.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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. In some embodiments, the association or
disassociation of the analog of the present invention with another
compound or pharmaceutical agent, macromolecule, or ligand may
propagate or inhibit a biologic signal. In some embodiments, the
association or disassociation of the analog of the present
invention with another compound or pharmaceutical agent,
macromolecule, or ligand may increase the number or proportion of
pharmaceutical agent, macromolecule, or ligand that binds a blood
serum protein. In some embodiments, the association or
disassociation of the analog of the present invention with another
compound or pharmaceutical agent, macromolecule, or ligand may
increase the number or proportion of pharmaceutical agent,
macromolecule, or ligand that binds albumin.
[0050] The term "pharmaceutical agent" means any molecule which
binds to a protein in a subject which modulates any one or more
biological functions in the subject. In sme embodiments, the
pharmaceutical agent may be a chemical compound, a protein, a
polypepetide, an antibody or antibody fragment, or an amino acid
sequence derived from an immunologically active CDR, antibody
fragment, or Fv, or other antibody. In some embodiments, the
pharmaceutical agent is a chaperone. The term "chaperone" or
"chaperone analog" is used herein to describe any analog bound to a
pharmaceutical agent that together functions to bind a molecule
associated with metabolism and, together, have increased resistance
to degradation as compared to the degradation of the pharmaceutical
agent alone. In some embodiments, the analog is bound to the
pharmaceutical agent by any method of ligating a polypeptide to
another polypeptide. In some embodiments, the method includes
creation of a disulfide bridge. In another embodiment, the analog
is bound to the pharmaceutoical agent by methods disclosed in
Constantinou et. al. Biotechnol Lett (2010) 32:609-622, which is
herein incorporated by reference in its entirety.
[0051] 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.
[0052] 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 Table 1. In some embodiments, the analog is about 70%, 75%, 80%,
85%, 90%, 95%, 98%, or 99% homolgous to at least one of the
polypeptides disclosed in Table 1.
[0053] 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.
[0054] 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 imino 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,
--(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 substitutent(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##
An APC residue within an undefined peptide chain, under neutral
aqueous conditions (the ring N is protonated). wherein the NH.sub.2
and/or COOH groups are replaced with functional peptide bonds.
[0055] In some embodiments the term ".beta.-amino acid" refers
to:
##STR00005## [0056] 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; [0057] 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)--(CH.sub.2).sub.m--R.sup.5;
[0058] 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 [0059] 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-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide,
urea; mono-di- or tri-substituted urea, wherein the subsistent(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 [0060] m is an integer of from 2-6 and n
is an integer of from 0-6; [0061] the substituents on heteroatoms
of the ring being independently selected from the group consisting
of
--S(.dbd.O).sup.2CH.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; [0062] 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; [0063]
R.sup.1 is selected from the group consisting hydrogen and an amino
protecting group; [0064] R.sup.2 is selected from the group
consisting of hydrogen and a carboxy protecting group; [0065]
racemic mixtures thereof, isolated or enriched enantiomers thereof;
isolated or enriched diastereomers thereof; [0066] and salts
thereof.
[0067] 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.
[0068] 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, alkyl-halo, arylamido, alkylheterocycle, alkylamino,
alkylguanidino, alkanol, alkylcarboxy, cycloalkyl, heteroaryl,
heteroarylalkyl, heteroarylalkoxy, or heterocyclyl; wherein X is
any substituent.
[0069] 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.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.
[0070] 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, alkyl-halo, 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.
[0071] 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(O)--(CH.sub.2).sub.mR.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(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 substitutent(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. In some embodiments, the beta-amino
acid is
##STR00011##
(also denoted U for purposes of Table 1).
[0072] 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
cycloakyl or cycloalkenyl group; wherein substituents on carbon
atoms of the cycloakyl 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,
--(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(O)--(CH.sub.2).sub.mR.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(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 substitutent(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(--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. In some embodiments the terms beta-3 or
beta-2 amino acid refers to .beta..sup.3-homo .beta..sup.2-homo
amino acids.
[0073] 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.
[0074] 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 an 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).
[0075] 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. In some
embodiments, the terms "derived from" means 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 chemical structure or
amino acid sequence that originating from a particular cell, subset
of cells, organ, tissue, or species of plant or animal.
[0076] As used herein, the term "metabolic disorder" refers to any
disease, condition, or ailment that results from a medical
condition characterized by a subject's abnormal metabolism. In some
embodiments, metabolic disorder refers to Diabetes, type I diabetes
mitellus, type II diabetes mitellus; gestational diabetes; p
Gestational diabetes: phenylketonuria (PKU); Metabolic syndrome;
syndrome X; dysmetabolic syndrome; obesity syndrome; Reaven's
syndrome; In some embodiments, "metabolic disorders" include
diseases, disorders, or conditions associated with aberrant
thermogenesis or aberrant adipose cell (e.g., brown or white
adipose cell) content or function. Metabolic disorders can be
characterized by a misregulation (e.g., downregulation or
upregulation) of 1427-3-activity. Metabolic disorders can
detrimentally affect cellular functions such as cellular
proliferation, growth, differentiation, or migration, cellular
regulation of homeostasis, inter- or intra-cellular communication;
tissue function, such as liver function, muscle function, or
adipocyte function; systemic responses in an organism, such as
hormonal responses (e.g., insulin response). In some embodiments,
metabolic disorders include obesity, diabetes, hyperphagia,
endocrine abnormalities, triglyceride storage disease, Bardet-Biedl
syndrome, Lawrence-Moon syndrome, Prader-Labhart-Willi syndrome,
anorexia, and cachexia. In some embodiments, obesity is defined as
a body mass index (BMI) of 30 kg/2 m or more (National Institute of
Health, Clinical Guidelines on the Identification, Evaluation, and
Treatment of Overweight and Obesity in Adults (1998)). However, in
some embodiments, the present invention is also intended to include
a disease, disorder, or condition that is characterized by a body
mass index (BMI) of 25 kg/2 m or more, 26 kg/2 m or more, 27 kg/2 m
or more, 28 kg/2 m or more, 29 kg/2 m or more, 29.5 kg/2 m or more,
or 29.9 kg/2 m or more, all of which are typically referred to as
overweight (National Institute of Health, Clinical Guidelines on
the Identification, Evaluation, and Treatment of Overweight and
Obesity in Adults (1998)).
[0077] A "non-essential" amino acid residue is a residue that can
be altered from the known sequence from which the analog is derived
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.
[0078] 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 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.
[0079] 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).
[0080] 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.
[0081] In some embodiments, salts of the compositions comprising an
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).
[0082] As used herein, in some embodiments, the term "selectivity"
of a molecule for a first receptor relative to a second receptor
refers to the following ratio: EC50 of the molecule at the second
receptor divided by the EC50 of the molecule at the first receptor.
For example, a molecule that has an EC50 of 1 nM at a first
receptor and an EC50 of 100 nM at a second receptor has 100-fold
selectivity for the first receptor relative to the second
receptor.
[0083] As used herein, "glucagon potency" of a molecule refers to
the ratio of the EC50 of the molecule at glucagon receptor divided
by the EC50 of native glucagon at glucagon receptor. As used
herein, "GIP potency" of a molecule refers to the ratio of the EC50
of the molecule at GIP receptor divided by the EC50 of native GIP
at GIP receptor.
[0084] As used herein, "GLP-1 potency" of a molecule refers to the
ratio of the EC50 of the molecule at GLP-1 receptor divided by the
EC50 of native GLP-1 at GLP-1 receptor.
[0085] 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.
[0086] 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.
[0087] 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. In
some embodiments, the terms "treating" and "to treat" mean to
administer a composition for prophylaxis of a certain condition,
disorder, disease, or ailment.
[0088] "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 tranlated protein
is administered to the same subject.
[0089] 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 GIP
and/or GLP-1 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 GIP
and/or GLP-1, 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 analog is a
fragment of GIP and/or GLP-1 that comprises between 1 to about 27
amino acids and retains binding to the GIP receptor and/or the
GLP-1 receptor. In some embodiments, the analog is a fragment of
GIP and/or GLP-1 is a fragment that comprises between about 1 to
about 20 amino acids of one or both GIP or GLP-1 sequences, and
retains binding to GIP receptor and/or GLP-1 receptor. In some
embodiments, the composition or pharmaceutical composition of
invention comprises His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys
Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn
Thr. In some embodiments, the composition or pharmaceutical
composition of invention comprises
HSQGTFTSDYSKYLDSRRAQDFVQWLMNT
[0090] In some embodiments, the analog is a fragment of glucagon.
In some embodiments, the analog comprises
YBEGTFTSDYSIYLDKQAABEFVNWLLAG (SEQ ID NO: 1), wherein B is Aib. In
some embodiments, the analog comprises
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a fragment thereof, wherein B is
Aib. In some embodiments, the analog comprises between about 1 to
about 30 amino acids and the sequence YBEGTFTSDYSIYLDKQAABEFVNWLLAG
or a functional fragment thereof, wherein B is Aib. In some
embodiments, the analog comprises between 4 to about 30 amino acids
and the sequence YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional
fragment thereof, wherein B is Aib. In some embodiments, the analog
comprises between about 4 to about 29 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 28 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 27 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 26 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 25 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 24 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 23 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 22 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 21 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 20 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 19 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 18 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 4 to about 17 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog comprises between
about 1 to about 16 amino acids and the sequence
YBEGTFTSDYSIYLDKQAABEFVNWLLAG or a functional fragment thereof,
wherein B is Aib. In some embodiments, the analog is modified with
at least one PEG molecule on at least one of the non-natural amino
acids. In some embodiments, the composition or pharmaceutical
composition comprises an analog or and analog and a peptide,
neither of which have been modified with a PEG molecule. the
composition or pharmaceutical composition does not comprise a PEG
molecule.
[0091] The term "halo" or "halogen" refers to fluorine, chlorine,
bromine or iodine or a radical thereof.
[0092] 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.7-C.sub.10,
C.sub.8-C.sub.10C, 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.7, C.sub.1-C.sub.8, or
C.sub.1-C.sub.9,
[0093] The term "alkylene" refers to a divalent alkyl (i.e.,
--R--).
[0094] 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.
[0095] 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.
[0096] 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. I 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.
[0097] "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.
[0098] "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.
[0099] "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.
[0100] "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.
[0101] "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.2
NH.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).
[0102] "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.
[0103] "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.
[0104] 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.
[0105] 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.
[0106] 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.
[0107] 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.
[0108] 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.
[0109] 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. In some embodiments, the
composition or pharmaceutical composition comprises an analog with
a single racemate, single entanitomer, or a single diasteromer.
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.
[0110] 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 deutrated 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.
[0111] 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%.
[0112] 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.
[0113] 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."
[0114] The term "biological activity" encompasses structural and
functional properties of an analog 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.
[0115] 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.
[0116] 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.
[0117] In some embodiments, the analog of the claimed invention is
a pharmaceutically-acceptable acid addition salt or a
pharmaceutically-acceptable base 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.
[0118] 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.
[0119] The invention relates to compositions comprising an analog
of a polypeptide sequence that is a chimeric polypeptide with at
least two amino acid moieties, wherein a first amino acid moiety
comprises a protein sequence that binds the GIP receptor and
wherein a second moiety binds the GLP-1 receptor, and wherein the
chimeric polypeptide comprises at least one alpha amino acid and at
least one beta amino acid. In some embodiments, the moiety that
binds the GIP receptor has an IC50 higher than the IC50 for the
GLP-1 receptor. In some embodiments, the moiety that binds the GIP
receptor has an IC50 lower than the IC50 for the GLP-1 receptor. In
some embodiments, the composition comprises a chimeric polypeptide
with at least two amino acid moieties, wherein a first amino acid
moiety comprises a protein sequence that binds the GIP receptor and
wherein a second moiety binds the GLP-1 receptor, and wherein the
chimeric polypeptide comprises at least one alpha amino acid and at
least one beta amino acid. In some embodiments, the composition
comprises a chimeric polypeptide with at least two amino acid
moieties, wherein a first amino acid moiety comprises a protein
sequence that binds the GIP receptor and wherein a second moiety
binds the GLP-1 receptor, wherein the chimeric polypeptide
comprises at least one alpha amino acid and at least one beta amino
acid; and wherein the first amino acid moiety binds GIP receptor at
a higher affinity than a naturally occurring GIP. In some
embodiments, the composition comprises a chimeric polypeptide with
at least two amino acid moieties, wherein a first amino acid moiety
comprises a protein sequence that binds the GIP receptor and
wherein a second moiety binds the GLP-1 receptor, wherein the
chimeric polypeptide comprises at least one alpha amino acid and at
least one beta amino acid; and wherein the first amino acid moiety
binds GLP-1 receptor at a higher affinity than a naturally
occurring GLP-1. In some embodiments, the composition comprises a
chimeric polypeptide with at least two amino acid moieties, wherein
a first amino acid moiety comprises a protein sequence that binds
the GIP receptor and wherein a second moiety binds the GLP-1
receptor, wherein the chimeric polypeptide comprises at least one
alpha amino acid and at least one beta amino acid; and wherein at
least one of the moieties has a greater selectivity for its
receptor as compared to wild type GIP or GLP-1. In some embodiments
the invention relates to a composition or pharmaceutical
composition comprising an analog of GIP and/or GLP-1 wherein the
analog is from about 80% to 99% homologous to a
YBEGTFTSDYSIYLDKQAABEFVNWLLAG sequence, wherein B=Aib. In some
embodiments the invention relates to a composition or
pharmaceutical composition comprising an analog of a naturally
occurring polypeptide sequence wherein the analog is from about 80%
to 99% homologous to a YBEGTFTSDYSIYLDKQAABEFVNWLLAG sequence,
wherein B=Aib. 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 YBEGTFTSDYSIYLDKQAABEFVNWLLAG sequence, wherein
B=Aib. 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
YBEGTFTSDYSIYLDKQAABEFVNWLLAG sequence, wherein B=Aib. In some
embodiments the invention relates to a composition comprising an
analog of YBEGTFTSDYSIYLDKQAABEFVNWLLAG, wherein B=Aib. 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
YBEGTFTSDYSIYLDKQAABEFVNWLLAG, wherein B=Aib. 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 YBEGTFTSDYSIYLDKQAABEFVNWLLAG,
wherein B=Aib. In some embodiments the invention relates to a
composition comprising an analog wherein the analog is about 80%,
85%, 90%, 95%, 96%, 97%, 98%, or 99% homologous to
YBEGTFTSDYSIYLDKQAABEFVNWLLAG, wherein B=Aib, and wherein the
protein has GIP activity and/or GLP-1 activity. In some embodiments
the invention relates to a composition comprising an analog wherein
the analog is about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%
homologous to YBEGTFTSDYSIYLDKQAABEFVNWLLAG, wherein B=Aib, and
wherein the protein has GIP activity and/or GLP-1 activity. In some
embodiments the composition or pharmaceutical composition comprises
a pharmaceutical agent. In some embodiments, the analog is derived
from the sequence of a GIP and/or GLP-1 protein and has at least
one .beta.-amino acid residue and/or at least one modified amino
acid residue comprising APC or ACPC. In some embodiments, the
analog is derived from the sequence of a GIP and/or GLP-1 protein
and has at least one .beta.-amino acid residue and/or at least one
modified amino acid residue comprising APC or ACPC.
[0120] The invention relates to the manufacturing of a synthetic
polypeptide which is an amino acid sequence or fragment thereof
that acts as a hormone or dual tropic hormone involved in glucose
metabolism. 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. the analog is then covalently or noncovalently
bound to a pharmaceutical agent to increase its stability and alter
its pharmacokinetic profile. Human cells are then contacted with
the pharmaceutical agent ligated to the analog inro der to induce
the biochemical pathway or biological activity ordinarily induced
by the naturally occurring polypeptide upon which the analog is
based.
[0121] 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 Barlos 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.
[0122] 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 800 (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).
[0123] 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.
[0124] 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 analog adopts a helical conformation. In
some embodiments, the analog of the invention comprises the
following 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:
##STR00012##
[0125] In some embodiments, the analog of the invention comprises
the following alignment along a longitudinal axis of the folded
molecular structure from N-terminus to C-terminus:
##STR00013##
[0126] 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..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. 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:
TABLE-US-00001 .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..alpha..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:
TABLE-US-00002
.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:
TABLE-US-00003
.beta..beta..alpha..beta..alpha..alpha..alpha..beta..alpha..alpha..beta..a-
lpha..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..a-
lpha..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..a-
lpha..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:
TABLE-US-00004
.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..
[0127] 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 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..beta.-
.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.
[0128] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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 YBEGTFTSDYSIYLD
KQAABEFVNWLLAG 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.
[0129] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.
[0130] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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; L.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.
[0131] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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-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.
[0132] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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 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.
[0133] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.
[0134] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..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.3=any alpha
amino acid.
[0135] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..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.6=any alpha
amino acid; .alpha.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.
[0136] In some embodiments, the composition comprises a
QRLMEDICLPRWGCLWEDDF 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.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..sub.13, wherein .beta..sub.1=any beta-3 amino acid;
.alpha..sub.1=any alpha amino acid; 2=any alpha amino acid;
.alpha..sub.3=any alpha amino acid; 32=any beta-3 amino acid; 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.
[0137] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..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..sub.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.
[0138] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.alpha..sub.8.beta..-
sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..sub.12.b-
eta..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..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.
[0139] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.
[0140] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.5=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.
[0141] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.5=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.1=any alpha amino acid; .alpha..sub.12=any alpha
amino acid; .alpha..sub.3=any alpha amino acid; and
.beta..sub.6=any beta-3 amino acid.
[0142] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG 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.
[0143] In some embodiments, the composition comprises
YBEGTFTSDYSIYLD KQAABEFVNWLLAG polypeptide, wherein the polypeptide
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; a=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.
[0144] In some embodiments, the composition or pharmaceutical
composition comprises a an analog and a chaperone, wherein the
analog comprises the following repetitive pattern of sequential
.beta.-amino acids from the amino-terminus selected from the
following:
[0145]
.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
[0146]
.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
[0147] wherein the C-terminus is optionally amidated; and
[0148] wherein the N-terminus is optionally acylated;
[0149] or functional fragments thereof.
[0150] In some embodiments, the composition or pharmaceutical
composition comprises a an analog and a chaperone, wherein the
analog comprises the following repetitive pattern of sequential
.beta.-amino acids from the amino-terminus selected from the
following:
[0151]
.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
[0152]
.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;
[0153] .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
[0154] wherein the C-terminus is optionally amidated; and
[0155] wherein the N-terminus is optionally acylated;
[0156] or functional fragments thereof.
[0157] wherein the analog comprises (from N-terminus to C
terminus)YBEGTFTSDYSIYLDKQAABEFVNWLLAGGPSSGAPPPSK; and wherein the
side chain of the C-terminal K is optionally modified with an acyl
group.
[0158] In some embodiments, the composition or pharmaceutical
composition comprises a an analog and a chaperone, wherein the
analog comprises the following repetitive pattern of sequential
.beta.-amino acids from the amino-terminus selected from the
following:
[0159]
.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
[0160]
.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; a=an alpha amino acid; 32=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.5=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; s.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
[0161] wherein the C-terminus is optionally amidated; and
[0162] wherein the N-terminus is optionally acylated;
[0163] or functional fragments thereof.
[0164] wherein the analog comprises (from N-terminus to C
terminus)YBEGTFTSDYSIYLDKQAABEFVNWLLAGGPSSGAPPPSK; and wherein the
side chain of the C-terminal K is optionally modified with
tetradecanoyl (C14), hexadecanoyl (C16), or octadecanoyl (C18)
group.
[0165] In some embodiments, the composition or pharmaceutical
composition comprises a an analog and a chaperone, wherein the
analog comprises the following repetitive pattern of sequential
.beta.-amino acids from the amino-terminus selected from the
following:
[0166]
.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
[0167]
.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; .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
[0168] wherein the C-terminus is optionally amidated; and
[0169] wherein the N-terminus is optionally acylated;
[0170] or functional fragments thereof.
[0171] wherein the analog comprises (from N-terminus to C
terminus)Y.sub.1BEGTFTSDYSIYLDK.sub.16QAABEFVNWLLAGGPSSGAPPPSK.sub.40;
and wherein the side chain of the K.sub.16 is optionally modified
with tetradecanoyl (C14), hexadecanoyl (C16), or octadecanoyl (C18)
group.
[0172] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG analog, wherein the analog comprises
the following repetitive pattern of sequential .beta.-amino acids
from the amino-terminus selected from the following:
[0173]
.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
[0174]
.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.=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
[0175] wherein the C-terminus is optionally amidated; and
[0176] wherein the N-terminus is optionally acylated;
[0177] or functional fragments thereof.
[0178] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG analog, wherein the analog comprises
the following repetitive pattern of sequential .beta.-amino acids
from the amino-terminus selected from the following:
[0179]
.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
[0180]
.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
[0181] wherein the C-terminus is optionally amidated; and
[0182] wherein the N-terminus is optionally acylated;
[0183] or functional fragments thereof.
analog, wherein the analog comprises the following repetitive
pattern of sequential .beta.-amino acids from the amino-terminus
selected from the following:
[0184]
.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; 35=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;
[0185]
.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
[0186]
.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; 3=any beta amino acid;
.alpha..sub.6=any alpha amino acid; .alpha..sub.7=any alpha amino
acid; .alpha..sub.5=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
[0187] wherein the C-terminus is optionally acylated with between 1
and 20 carbon atoms; and wherein the N-terminus is optionally
acylated;
[0188] or functional fragments thereof.
[0189] In some embodiments, the composition comprises a analog and
a chaperone or pharmaceutical agent, wherein the analog comprises
the following repetitive pattern of sequential .beta.-amino acids
from the amino-terminus selected from the following:
[0190]
.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, wherein
.beta..sub.1=any beta amino acid; .alpha..sub.1=any alpha amino
acid; .alpha..sub.2=any alpha amino acid; C.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
[0191]
.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.beta..sub.4.a-
lpha..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=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 amino acid;
[0192]
.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; 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; and
[0193] wherein the C-terminus is optionally amidated; optionally
acylated; or optionally pegylated with 10, 20, 30, 40, 50, 60, 70
80, 90, 100, or more Kdaltons of PEG; and
[0194] wherein the N-terminus is optionally modified.
[0195] In some embodiments, the composition comprises a analog and
a chaperone or pharmaceutical agent, wherein the analog comprises
the following repetitive pattern of sequential .beta.-amino acids
from the amino-terminus selected from the following:
[0196]
.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, wherein 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.s=any beta amino acid
[0197]
.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.beta..sub.4.a-
lpha..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=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 amino acid;
[0198]
.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, 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.5=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; and
[0199] wherein the C-terminus is optionally amidated; optionally
acylated; or optionally pegylated with 10, 20, 30, 40, 50, 60, 70
80, 90, 100, or more Kdaltons of PEG; and
[0200] wherein the N-terminus is optionally modified; and
[0201] wherein the analog comprises SIYLDKQAABEFVNWLLA or fragment
thereof optionally flanked on the N-terminus by YBEGT FTSDY and
optionally flanked on the C terminus by GGPSSGAPPPSK.
[0202] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG analog, wherein the analog comprises
the following repetitive pattern of sequential .beta.-amino acids
from the amino-terminus selected from the following:
[0203]
.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;
[0204]
.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.=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
[0205]
.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 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.=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.
[0206] In some embodiments, the composition comprises a GIP and/or
GLP-1 analog, wherein the analog comprises the following repetitive
pattern of sequential .beta.-amino acids from the amino-terminus
selected from the following:
[0207]
.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;
[0208]
.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
.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.=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 at least one of the beta amino acids
is substituted with a beta amino acid selected from the group
chosen from: a beta-3 homolog, a beta-2 homolog, ACPC, or APC.
[0209] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM.
[0210] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM.
[0211] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least two .beta.-amino acids,
wherein at least two underlined residues of the polypeptide are
replaced with the at least two .beta.-amino acids, and wherein the
analog binds to the GIP receptor with an EC50 of equal to or less
than about 900 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 50 nM.
[0212] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least three .beta.-amino acids,
wherein at least three underlined residues of the polypeptide are
replaced with the at least three .beta.-amino acids, and wherein
the analog binds to the GIP receptor with an EC50 of equal to or
less than about 900 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 50 nM.
[0213] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM.
[0214] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least five .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with four .beta.-amino acids, and wherein the analog binds to the
GIP receptor with an EC50 of equal to or less than about 900 nM,
and wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM.
[0215] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM.
[0216] In some embodiments, the composition comprises an analog of
a polypeptide with a first sequence: QAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM, wherein the analog optionally comprises a second amino acid
sequence that is 70% homologous, 75% homologous, 80% homologous,
85% homologous, 90% homologous, 95% homolgous, 96% homologous, 97%
homologous, 98% homologous, or 99% homolgous to
YBEGTFTSDYSIYLDK
[0217] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM, wherein the analog optionally comprises a second amino acid
sequence that is 70% homologous, 75% homologous, 80% homologous,
85% homologous, 90% homologous, 95% homolgous, 96% homologous, 97%
homologous, 98% homologous, or 99% homolgous YBEGTFTSDYSIYLDK
[0218] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least two .beta.-amino acids,
wherein at least two underlined residues of the polypeptide are
replaced with the at least two .beta.-amino acids, and wherein the
analog binds to the GIP receptor with an EC50 of equal to or less
than about 900 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 50 nM, wherein
the analog optionally comprises a second amino acid sequence that
is 70% homologous, 75% homologous, 80% homologous, 85% homologous,
90% homologous, 95% homolgous, 96% homologous, 97% homologous, 98%
homologous, or 99% homolgous YBEGTFTSDYSIYLDK.
[0219] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least three .beta.-amino acids,
wherein at least three underlined residues of the polypeptide are
replaced with the at least three .beta.-amino acids, and wherein
the analog binds to the GIP receptor with an EC50 of equal to or
less than about 900 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 50 nM, wherein
the analog optionally comprises a second amino acid sequence that
is 70% homolgus, 75% homologous, 80% homologous, 85% homologous,
90% homologous, 95% homolgous, 96% homologous, 97% homologous, 98%
homologous, or 99% homolgous YBEGTFTSDYSIYLDK.
[0220] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM, wherein the
analog optionally comprises a second amino acid sequence that is
70% homologous, 75% homologous, 80% homologous, 85% homologous, 90%
homologous, 95% homolgous, 96% homologous, 97% homologous, 98%
homologous, or 99% homolgous YBEGTFTSDYSIYLDK.
[0221] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least five .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with four .beta.-amino acids, and wherein the analog binds to the
GIP receptor with an EC50 of equal to or less than about 900 nM,
and wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM, wherein the analog optionally
comprises a second amino acid sequence that is 70% homologous, 75%
homologous, 80% homologous, 85% homologous, 90% homologous, 95%
homolgous, 96% homologous, 97% homologous, 98% homologous, or 99%
homolgous YBEGTFTSDYSIYLDK.
[0222] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM, wherein the
analog optionally comprises a second amino acid sequence that is
70% homologous, 75% homologous, 80% homologous, 85% homologous, 90%
homologous, 95% homolgous, 96% homologous, 97% homologous, 98%
homologous, or 99% homolgous to YBEGTFTSDYSIYLDK.
[0223] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 125 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 10
nM.
[0224] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
O-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 125 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 10
nM.
[0225] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least two .beta.-amino acids,
wherein at least two underlined residues of the polypeptide are
replaced with the at least two .beta.-amino acids and wherein the
analog binds to the GIP receptor with an EC50 of equal to or less
than about 125 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 10 nM.
[0226] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least three .beta.-amino acids,
wherein at least three underlined residues of the polypeptide are
replaced with the at least three .beta.-amino acids, and wherein
the analog binds to the GIP receptor with an EC50 of equal to or
less than about 125 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 10 nM.
[0227] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 125 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 10 nM.
[0228] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least five .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with four .beta.-amino acids, and wherein the analog binds to the
GIP receptor with an EC50 of equal to or less than about 125 nM,
and wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 10 nM.
[0229] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 125 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 10 nM.
[0230] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: QAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM.
[0231] In some embodiments, the composition comprises XAAB XFVZW
LLXG; wherein the amino acid B in the
analog=.alpha.-aminoisobutyric acid (Aib); and wherein Z=APC or AHC
or U; X=ACPC or ACHC or U; and wherein the analog binds to the GIP
receptor with an EC50 of equal to or less than about 1 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 1 nM. In some embodiments, the
composition comprises XAAB XFVZW LLXG; wherein the amino acid B in
the analog=.alpha.-aminoisobutyric acid (Aib); and wherein Z=APC or
AHC or U; X=ACPC or ACHC or U; and wherein the analog binds to the
GIP receptor with an EC50 of equal to or less than about 900, 800,
700, 600, 500, 400, 300, 200, 100, or 50 pM, and wherein the analog
binds to the GLP-1 receptor with an EC50 of equal to or less than
about 900, 800, 700, 600, 500, 400, 300, 200, 100, or 50 pM. In
some embodiments, the composition comprises XAAB XFVZW LLXG;
wherein the amino acid B in the analog=.alpha.-aminoisobutyric acid
(Aib); and wherein Z=APC or AHC or U; X=ACPC or ACHC or U; and
wherein the analog binds to the GIP receptor with an EC50 less than
of its wild-type ligand, and wherein the analog binds to the GLP-1
receptor with an EC50 less than it wild-type ligand.
[0232] In some embodiments, the composition comprises an analog
comprising XAAB XFVZW LLXG; wherein the amino acid B in the
analog=.alpha.-aminoisobutyric acid (Aib); and wherein Z=APC or AHC
or U; X=ACPC or ACHC or U; and wherein the analog binds to the GIP
receptor with an EC50 of equal to or less than about 1 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 1 nM; and wherein the analog optionally
comprises an amino acid sequence YBEGTFTSDYSIYLDK on its amino
terminus, wherein at least one of the amino acids in
YBEGTFTSDYSIYLDK is replaced by a beta amino acid. In some
embodiments, the composition comprises XAAB XFVZW LLXG; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib); and
wherein Z=APC or AHC or U; X=ACPC or ACHC or U; and wherein the
analog optionally comprises an amino acid sequence YBEGTFTSDYSIYLDK
on its amino terminus, wherein at least one of the amino acids in
YBEGTFTSDYSIYLDK is replaced by a beta amino acid; and wherein the
analog binds to the GIP receptor with an EC50 of equal to or less
than about 900, 800, 700, 600, 500, 400, 300, 200, 100, or 50 pM,
and wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 900, 800, 700, 600, 500, 400, 300, 200,
100, or 50 pM. In some embodiments, the composition comprises XAAB
XFVZW LLXG; wherein the amino acid B in the
analog=.alpha.-aminoisobutyric acid (Aib); and wherein Z=APC or AHC
or U; X=ACPC or ACHC or U; and wherein the analog optionally
comprises an amino acid sequence YBEGTFTSDYSIYLDK on its amino
terminus, wherein at least one of the amino acids in
YBEGTFTSDYSIYLDK is replaced by a beta amino acid; and wherein the
analog binds to the GIP receptor with an EC50 less than of its
wild-type ligand, and wherein the analog binds to the GLP-1
receptor with an EC50 less than it wild-type ligand.
[0233] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM.
[0234] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least two .beta.-amino acids,
wherein at least two underlined residues of the polypeptide are
replaced with the at least two .beta.-amino acids, and wherein the
analog binds to the GIP receptor with an EC50 of equal to or less
than about 900 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 50 nM.
[0235] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least three .beta.-amino acids,
wherein at least three underlined residues of the polypeptide are
replaced with the at least three .beta.-amino acids, and wherein
the analog binds to the GIP receptor with an EC50 of equal to or
less than about 900 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 50 nM. In some
embodiments, the composition comprises an analog of a polypeptide
with a sequence: LD KQAAB EFVNW LLA; wherein the amino acid B in
the analog=.alpha.-aminoisobutyric acid (Aib), and wherein the
analog comprises at least four .beta.-amino acids, wherein the
underlined residues of the polypeptide are replaced with the at
least four .beta.-amino acids, and wherein the analog binds to the
GIP receptor with an EC50 of equal to or less than about 900 nM,
and wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM.
[0236] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least five .beta.-amino acids,
wherein at least four underlined residues of the polypeptide are
replaced with four .beta.-amino acids, and wherein the analog binds
to the GIP receptor with an EC50 of equal to or less than about 900
nM, and wherein the analog binds to the GLP-1 receptor with an EC50
of equal to or less than about 50 nM.
[0237] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four f.beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM.
[0238] In some embodiments, the composition comprises an analog of
a polypeptide with a first sequence: LD KQAAB EFVNW LLA; wherein
the amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib),
and wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM, wherein the analog optionally comprises a second amino acid
sequence that is 70% homologous, 75% homologous, 80% homologous,
85% homologous, 90% homologous, 95% homolgous, 96% homologous, 97%
homologous, 98% homologous, or 99% homolgous to
YBEGTFTSDYSIYLDK
[0239] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM, wherein the analog optionally comprises a second amino acid
sequence that is 70% homologous, 75% homologous, 80% homologous,
85% homologous, 90% homologous, 95% homolgous, 96% homologous, 97%
homologous, 98% homologous, or 99% homolgous to
YBEGTFTSDYSIYLDK
[0240] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least two .beta.-amino acids,
wherein at least two underlined residues of the polypeptide are
replaced with the at least two .beta.-amino acids, and wherein the
analog binds to the GIP receptor with an EC50 of equal to or less
than about 900 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 50 nM, wherein
the analog optionally comprises a second amino acid sequence that
is 70% homologous, 75% homologous, 80% homologous, 85% homologous,
90% homologous, 95% homolgous, 96% homologous, 97% homologous, 98%
homologous, or 99% homolgous to YBEGTFTSDYSIYLDK.
[0241] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least three .beta.-amino acids,
wherein at least three underlined residues of the polypeptide are
replaced with the at least three .beta.-amino acids, and wherein
the analog binds to the GIP receptor with an EC50 of equal to or
less than about 900 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 50 nM, wherein
the analog optionally comprises a second amino acid sequence that
is 70% homologous, 75% homologous, 80% homologous, 85% homologous,
90% homologous, 95% homolgous, 96% homologous, 97% homologous, 98%
homologous, or 99% homolgous to YBEGTFTSDYSIYLDK.
[0242] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM, wherein the
analog optionally comprises a second amino acid sequence that is
70% homologous, 75% homologous, 80% homologous, 85% homologous, 90%
homologous, 95% homolgous, 96% homologous, 97% homologous, 98%
homologous, or 99% homolgous to YBEGTFTSDYSIYLDK.
[0243] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least five .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with four .beta.-amino acids, and wherein the analog binds to the
GIP receptor with an EC50 of equal to or less than about 900 nM,
and wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM, wherein the analog optionally
comprises a second amino acid sequence that is 70% homologous, 75%
homologous, 80% homologous, 85% homologous, 90% homologous, 95%
homolgous, 96% homologous, 97% homologous, 98% homologous, or 99%
homolgous to YBEGTFTSDYSIYLDK.
[0244] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM, wherein the
analog optionally comprises a second amino acid sequence that is
70% homologous, 75% homologous, 80% homologous, 85% homologous, 90%
homologous, 95% homolgous, 96% homologous, 97% homologous, 98%
homologous, or 99% homolgous to YBEGTFTSDYSIYLDK.
[0245] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 125 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 10
nM.
[0246] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least one, two, three, or four
.beta.-amino acids, wherein at least one underlined residue of the
polypeptide is replaced with the at least one .beta.-amino acid,
and wherein the analog binds to the GIP receptor with an EC50 of
equal to or less than about 125 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 10
nM. In some embodiments, the composition comprises an analog of a
polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the amino
acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least two .beta.-amino acids,
wherein at least two underlined residues of the polypeptide are
replaced with the at least two .beta.-amino acids and wherein the
analog binds to the GIP receptor with an EC50 of equal to or less
than about 125 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 10 nM. In some
embodiments, the composition comprises an analog of a polypeptide
with a sequence: LD KQAAB EFVNW LLA; wherein the amino acid B in
the analog=.alpha.-aminoisobutyric acid (Aib), and wherein the
analog comprises at least three .beta.-amino acids, wherein at
least three underlined residues of the polypeptide are replaced
with the at least three .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 125 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 10 nM.
[0247] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 125 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 10 nM.
[0248] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least five .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with four .beta.-amino acids, and wherein the analog binds to the
GIP receptor with an EC50 of equal to or less than about 125 nM,
and wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 10 nM.
[0249] In some embodiments, the composition comprises an analog of
a polypeptide with a sequence: LD KQAAB EFVNW LLA; wherein the
amino acid B in the analog=.alpha.-aminoisobutyric acid (Aib), and
wherein the analog comprises at least four .beta.-amino acids,
wherein the underlined residues of the polypeptide are replaced
with the at least four .beta.-amino acids, and wherein the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 125 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 10 nM.
[0250] In some embodiments, the analog binds to the GIP receptor
with an EC50 of equal to or less than about 100 nM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 10 nM.
[0251] In some embodiments, the analog binds to the GIP receptor
with an EC50 of equal to or less than about 50 nM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 10 nM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 50 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 1 nM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 20 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 1 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 20 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 800
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 20 nM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 700 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 20 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 600 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 20 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 500 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 20 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 450
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 20 nM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 400 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 20 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 350 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 20 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 300 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 20 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 250
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 20 nM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 200 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 20 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 150 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 20 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 100 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 20 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 75
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 20 nM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 65 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 20 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 55 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 20 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 45 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 20 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 35
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 20 nM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 25 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 20 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 15 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 20 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 10 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 50 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 800
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 50 nM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 50 nM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 25 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 10 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 5 nM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 4 nM, and wherein the analog
binds to the GLP-1 receptor with an EC50 of equal to or less than
about 50 nM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 3 nM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 2 nM, and wherein the analog binds to the GLP-1 receptor with
an EC50 of equal to or less than about 50 nM. In some embodiments,
the analog binds to the GIP receptor with an EC50 of equal to or
less than about 1 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of equal to or less than about 50 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 800 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 50 nM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 700 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 600 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 500 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 400 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 50 nM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 300 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 200 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 100 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 90 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 50 nM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 80 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 70 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 60 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 50 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 50 nM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 40 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 nM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 30 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 50 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 20 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 50
nM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 10 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 50 nM.
[0252] In some embodiments, the analog binds to the GIP receptor
with an EC50 of equal to or less than about 1 nM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 1 nM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 900 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 10 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 20 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 30
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 900 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 40 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 900 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 50 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 60 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 70
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 900 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 80 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 900 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 90 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 100 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 200
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 900 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 300 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 900 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 400 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 500 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 900 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 600
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 900 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 700 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 900 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 800 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 900 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 900 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 10 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 900
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 20 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 900 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 30 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 900 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 40 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 900 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 50 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 900
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 60 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 900 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 70 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 900 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 80 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 900 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 90 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 900
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 100 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 900 pM. In some embodiments, the analog binds to the GIP
receptor with an EC50 of equal to or less than about 200 pM, and
wherein the analog binds to the GLP-1 receptor with an EC50 of
equal to or less than about 900 pM. In some embodiments, the analog
binds to the GIP receptor with an EC50 of equal to or less than
about 300 pM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of equal to or less than about 900 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
equal to or less than about 400 pM, and wherein the analog binds to
the GLP-1 receptor with an EC50 of equal to or less than about 900
pM. In some embodiments, the analog binds to the GIP receptor with
an EC50 of equal to or less than about 10 pM, and wherein the
analog binds to the GLP-1 receptor with an EC50 of equal to or less
than about 900 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 900 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 800 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 700 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 600 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 500 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 400 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 300 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 200 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 100 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 90 pM. In some embodiments, the analog binds to the GIP
receptor and the GLP-1 receptor with an EC50 of equal to or less
than about 80, 70, 60, 50, 40, 30, 20, or 10 pM.
[0253] In some embodiments, the analog or functional fragment
thereof binds to the GIP receptor with an EC50 of no more than
about 500 nM, and wherein the analog binds to the GLP-1 receptor
with an EC50 of no more than about 500 nM. In some embodiments, the
analog or functional fragment thereof binds to the GIP receptor
with an EC50 of no more than about 400 nM, and wherein the analog
binds to the GLP-1 receptor with an EC50 of no more than about 500
nM. In some embodiments, the analog or functional fragment thereof
binds to the GIP receptor with an EC50 of no more than about 300
nM, and wherein the analog binds to the GLP-1 receptor with an EC50
of no more than about 500 nM. In some embodiments, the analog or
functional fragment thereof binds to the GIP receptor with an EC50
of no more than about 200 nM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog or functional fragment thereof binds to the
GIP receptor with an EC50 of no more than about 100 nM, and wherein
the analog binds to the GLP-1 receptor with an EC50 of no more than
about 500 nM. In some embodiments, the analog or functional
fragment thereof binds to the GIP receptor with an EC50 of no more
than about 50 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog or functional fragment thereof binds to the
GIP receptor with an EC50 of no more than about 40 nM, and wherein
the analog binds to the GLP-1 receptor with an EC50 of no more than
about 500 nM. In some embodiments, the analog or functional
fragment thereof binds to the GIP receptor with an EC50 of no more
than about 30 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 20 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 10 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 5 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 1 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 900 pM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 800 pM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 700 pM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 600 pM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 500 pM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 450 pM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 122 nM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 48 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 18 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 3 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 500 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 125 nM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 10 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 125 nM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 7 nM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 125 nM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 575 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 125 nM, and wherein the analog binds to the
GLP-1 receptor with an EC50 of no more than about 445 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 3 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 445 pM. In some
embodiments, the analog binds to the GIP receptor with an EC50 of
no more than about 3 nM, and wherein the analog binds to the GLP-1
receptor with an EC50 of no more than about 575 pM.
[0254] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG analog, wherein B=Aib, and wherein
the analog comprises the following repetitive pattern of sequential
.beta.-amino acids from the amino-terminus selected from the
following: .beta..alpha..alpha..alpha..beta..alpha..alpha. or
.beta..alpha..alpha..beta..alpha..alpha..alpha..
[0255] In some embodiments, the composition comprises a
QAABEFVNWLLA analog, wherein B=Aib, and wherein the analog
comprises the following repetitive pattern of sequential
.beta.-amino acids from the amino-terminus selected from the
following: .beta..alpha..alpha..alpha..beta..alpha..alpha. or
.beta..alpha..alpha..beta..alpha..alpha..alpha. and wherein the
analog optionally comprises YBEGTFTSDYSIYLDK at the N-terminus of
the analog.
[0256] In some embodiments, the composition comprises a
YBEGTFTSDYSIYLD KQAABEFVNWLLAG analog, wherein B=Aib, and wherein
the analog comprises the following repetitive pattern of sequential
.beta.-amino acids from the amino-terminus selected from the
following:
[0257]
.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.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..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;
[0258]
.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; 134=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
[0259]
.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.5=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 at least one of the
beta amino acids is substituted with a beta amino acid selected
from the group chosen from: a beta-3 homolog, a beta-2 homolog,
ACPC, or APC; wherein B=Aib.
[0260] In some embodiments, the composition comprises a GIP and/or
GLP-1analog, wherein the analog comprises the following repetitive
pattern of sequential .beta.-amino acids from the amino-terminus
selected from the following:
[0261]
.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.alpha..sub.8.-
beta..sub.4.alpha..sub.9.alpha..sub.10.beta..sub.5.alpha..sub.11.alpha..su-
b.12.beta..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;
[0262]
.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
[0263]
.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 wherein at least one of the
beta amino acids is substituted with a beta amino acid selected
from the group chosen from: a beta-3 homolog, a beta-2 homolog,
ACPC, or APC.
[0264] In some embodiments, the composition comprises a GIP 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 GIP and/or GLP-1 analog or
functional fragments thereof, 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
[0265] wherein the C-terminus is, optionally, amidated; and
[0266] wherein the N-terminus is, optionally, acylated.
[0267] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a GIP and/or GLP-1
analog, wherein the analog comprises an .alpha.-amino acid and at
least one .beta.-amino acid, and wherein the analog is between
about 75% and 99% homologous to YBEGTFTSDYSIYLDKQAABEFVNWLLAG, and
wherein the analog binds to GIP receptor and/or GLP-1 receptor with
higher selectivity than wild-type GIP and or GLP-1. In some
embodiments, the invention relates to compositions or
pharmaceutical compositions comprising a GIP and/or GLP-1 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 YBEGTFTSDYSIYLDKQAABEFVNWLLAG, and wherein the analog
binds to GIP receptor and/or GLP-1 receptor with higher selectivity
than wild-type GIP and or GLP-1. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
GIP and/or GLP-1 analog, wherein the analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid, and wherein
the analog is between 80% and 99% homologous to
YBEGTFTSDYSIYLDKQAABEFVNWLLAG, and wherein the analog binds to GIP
receptor and/or GLP-1 receptor with higher selectivity than
wild-type GIP and or GLP-1. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
GIP and/or GLP-1 analog, wherein the analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid, and wherein
the analog is between 85% and 99% homologous to
YBEGTFTSDYSIYLDKQAABEFVNWLLAG, and wherein the analog binds to GIP
receptor and/or GLP-1 receptor with higher selectivity than
wild-type GIP and or GLP-1. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
GIP and/or GLP-1 analog, wherein the analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid, and wherein
the analog is between 90% and 99% homologous to
YBEGTFTSDYSIYLDKQAABEFVNWLLAG, and wherein the analog binds to GIP
receptor and/or GLP-1 receptor with higher selectivity than
wild-type GIP and or GLP-1. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
GIP and/or GLP-1 analog, wherein the analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid, and wherein
the analog is between 95% and 99% homologous to
YBEGTFTSDYSIYLDKQAABEFVNWLLAG, and wherein the analog binds to GIP
receptor and/or GLP-1 receptor with higher selectivity than
wild-type GIP and or GLP-1. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
GIP and/or GLP-1 analog, wherein the analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid, and wherein
the analog is between about 75% and about 85% homologous to
YBEGTFTSYSIYLDKQAABEFVNWLLAG, and wherein the analog binds to GIP
receptor and/or GLP-1 receptor with higher selectivity than
wild-type GIP and or GLP-1. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
GIP and/or GLP-1 analog, wherein the analog comprises an
.alpha.-amino acid and at least one .beta.-amino acid, and wherein
the analog is between about 85% and about 95% homologous to
YBEGTFTSDYSIYLDKQAABEFVNWLLAG, and wherein the analog binds to GIP
receptor and/or GLP-1 receptor with higher selectivity than
wild-type GIP and or GLP-1 (in all above-mentioned amino acid
sequences YBEGTFTSDYSIYLDKQAABEFVNWLLAG, B=Aib).
[0268] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a GIP and/or GLP-1
analog, wherein the analog is at least 99% homologus to
YBEGTFTSDYSIYLD KQAABEFVNWLLAG, wherein B=Aib. In some embodiments,
the invention relates to compositions or pharmaceutical
compositions comprising a GIP and/or GLP-1 analog, wherein the
analog is at least 98% homologus to YBEGTFTSDYSIYLD KQAABEFVNWLLAG.
In some embodiments, the invention relates to compositions or
pharmaceutical compositions comprising a GIP and/or GLP-1 analog,
wherein the analog is at least 95% homologus to YBEGTFTSDYSIYLD
KQAABEFVNWLLAG. In some embodiments, the invention relates to
compositions or pharmaceutical compositions comprising a GIP and/or
GLP-1 analog, wherein the analog is at least 90% homologus to
YBEGTFTSDYSIYLDKQAABEFVNWLLAG. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
GIP and/or GLP-1 analog, wherein the analog is at least 85%
homologus to YBEGTFTSDYSIYLDKQAABEFVNWLLAG. In some embodiments,
the invention relates to compositions or pharmaceutical
compositions comprising a GIP and/or GLP-1 analog, wherein the
analog is at least 80% homologus to YBEGTFTSDYSIYLD KQAABEFVNWLLAG.
In some embodiments, the invention relates to compositions or
pharmaceutical compositions comprising a GIP and/or GLP-1 analog,
wherein the analog is at least 75% homologus to YBEGTFTSDYSIYLD
KQAABEFVNWLLAG. In some embodiments, the invention relates to
compositions or pharmaceutical compositions comprising a GIP and/or
GLP-1 analog, wherein the analog is at least 70% homologus to
YBEGTFTSDYSIYLD KQAABEFVNWLLAG. In some embodiments, the invention
relates to compositions or pharmaceutical compositions comprising a
GIP and/or GLP-1 analog, wherein the analog is no more than 75%
homologus to YBEGTFTSDYSIYLD KQAABEFVNWLLAG. In some embodiments,
the invention relates to compositions or pharmaceutical
compositions comprising a GIP and/or GLP-1 analog, wherein the
analog is no more than 70% homologus to YBEGTFTSDYSIYLD
KQAABEFVNWLLAG. In some embodiments, the invention relates to
compositions or pharmaceutical compositions comprising a GIP and/or
GLP-1 analog, wherein the analog is no more than 80% homologus to
YBEGTFTSDYSIYLD KQAABEFVNWLLAG.
[0269] In some embodiments, the invention relates to compositions
or pharmaceutical compositions comprising a GIP and/or GLP-1
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 the GIP and/or GLP-1, and wherein the analog
has decreased susceptibility to degradation of dipeptidyl peptidase
IV (DPP IV). In some embodiments, the invention relates to
compositions or pharmaceutical compositions comprising a GIP and/or
GLP-1 analog, wherein the analog comprises an .alpha.-amino acid
and at least one .beta.-amino acid, and wherein the analog is
between 75% and 85% homologous to the YBEGTFTSDYSIYLD
KQAABEFVNWLLAG, and wherein the analog has decreased susceptibility
to degradation by dipeptidyl peptidase IV (DPP IV). In some
embodiments, the invention relates to compositions or
pharmaceutical compositions comprising a GIP and/or GLP-1 analog,
wherein the analog comprises an .alpha.-amino acid and at least one
.beta.-amino acid, and wherein the analog is between 80% and 85%
homologous to the YBEGTFTSDYSIYLD KQAABEFVNWLLAG, and wherein the
analog has decreased susceptibility to degradation by dipeptidyl
peptidase IV (DPP IV). In some embodiments, the invention relates
to compositions or pharmaceutical compositions comprising a GIP
and/or GLP-1 analog, wherein the analog comprises an .alpha.-amino
acid and at least one .beta.-amino acid, and wherein the analog is
between 75% and 95% homologous to the YBEGTFTSDYSIYLD
KQAABEFVNWLLAG, and wherein the analog has decreased susceptibility
to degradation by dipeptidyl peptidase IV (DPP IV).
[0270] In some embodiments, the glucagon peptides or analogs
described herein exhibit an EC50 for GIP receptor activation
activity of about 100 nM or less, or about 75, 50, 25, 10, 8, 6, 5,
4, 3, 2 or 1 nM or less. In some embodiments, the glucagon peptides
or analogs described herein exhibit an EC50 for GIP receptor
activation activity of about 100 pM or less, or about 75, 50, 25,
10, 8, 6, 5, 4, 3, 2 or 1 pM or less. In some embodiments, the
glucagon peptides described herein exhibit an EC50 at the GIP
receptor that is about 0.001 nM, 0.01 nM, or 0.1 nM. In some
embodiments, the glucagon peptides described herein exhibit an EC50
at the GIP receptor that is no more than about 1 nM, 2 nM, 3 nM, 4
nM, 5 nM, 6 nM, 8 nM, 10 nM, 15 nM, 20 nM, 25 nM, 30 nM, 40 nM, 50
nM, 75 nM, or 100 nM. In some embodiments, the glucagon peptides
exhibit an EC50 for glucagon receptor activation of about 100 nM or
less, or about 75, 50, 25, 10, 8, 6, 5, 4, 3, 2 or 1 nM or less. In
some embodiments, the glucagon peptides described herein exhibit an
EC50 at the glucagon receptor that is about 0.001 nM, 0.01 nM, or
0.1 nM. In some embodiments, the EC50 at the glucagon receptor is
no more than about 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 8 nM, 10 nM,
15 nM, 20 nM, 25 nM, 30 nM, 40 nM, 50 nM, 75 nM, or 100 nM. In some
embodiments, the glucagon peptides exhibit an EC50 for GLP-I
receptor activation of about 100 nM or less, or about 75, 50, 25,
10, 8, 6, 5, 4, 3, 2 or 1 nM or less. In some embodiments, the
glucagon peptides described herein exhibit an EC50 at the GLP-I
receptor that is about 0.001 nM, 0.01 nM, or 0.1 nM. In some
embodiments, the EC50 at the GLP-I receptor is no more than about 1
nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 8 nM, 10 nM, 15 nM, 20 nM, 25 nM,
30 nM, 40 nM, 50 nM, 75 nM, or 100 nM. Receptor activation can be
measured by in vitro assays measuring cAMP induction in HEK293
cells over-expressing the receptor, e.g. assaying HEK293 cells
co-transfected with DNA encoding the receptor and a luciferase gene
linked to cAMP responsive element as described in Example 16.
In some embodiments, glucagon peptides exhibit at least about 0.1%,
0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 5%, 10%, 20%,
30%, 40%, 50%, 60%, 75%, 100%, 125%, 150%, 175% or 200% or higher
activity at the GIP receptor relative to native GIP (GIP potency).
In some embodiments, the glucagon peptides described herein exhibit
no more than 1000%, 10,000%, 100,000%, or 1,000,000% activity at
the GIP receptor relative to native GIP. In some embodiments,
glucagon peptides exhibit at least about 1%, 5%, 10%, 20%, 30%,
40%, 50%, 60%, 75%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%,
400%, 450%, or 500% or higher activity at the glucagon receptor
relative to native glucagon (glucagon potency). In some
embodiments, the glucagon peptides described herein exhibit no more
than 1000%, 10,000%, 100,000%, or 1,000,000% activity at the
glucagon receptor relative to native glucagon. In some embodiments,
glucagon peptides exhibit at least about 0.1%, 0.2%, 0.3%, 0.4%,
0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%,
75%, 100%, 125%, 150%, 175% or 200% or higher activity at the GLP-I
receptor relative to native GLP-I (GLP-I potency). In some
embodiments, the glucagon peptides described herein exhibit no more
than 1000%, 10,000%, 100,000%, or 1,000,000% activity at the GLP-I
receptor relative to native GLP-I. A glucagon peptide's activity at
a receptor relative to a native ligand of the receptor is
calculated as the inverse ratio of EC50s for the glucagon peptide
vs. the native ligand. In some embodiments, the glucagon peptides
or analogs described herein exhibit an EC50 for GLP-1 receptor
activation activity of about 100 nM or less, or about 75, 50, 25,
10, 8, 6, 5, 4, 3, 2 or 1 nM or less. In some embodiments, the
glucagon peptides or analogs described herein exhibit an EC50 for
GLP-1 receptor activation activity of about 100 pM or less, or
about 75, 50, 25, 10, 8, 6, 5, 4, 3, 2 or 1 pM or less.
[0271] Thus, one aspect of the invention provides glucagon peptides
that exhibit activity at both the glucagon receptor and the GIP
receptor ("glucagon/GIP co-agonists"). These glucagon peptides have
lost native glucagon's selectivity for glucagon receptor compared
to GIP receptor. In some embodiments, the EC50 of the glucagon
peptide at the GIP receptor is less than about 50-fold, 40-fold,
30-fold or 20-fold different (higher or lower) from its EC50 at the
glucagon receptor. In some embodiments, the GIP potency of the
glucagon peptide is less than about 500-, 450-, 400-, 350-, 300-,
250-, 200-, 150-, 100-, 75-, 50-, 25-, 20-, 15-, 10-, or 5-fold
different (higher or lower) from its glucagon potency. In some
embodiments, the ratio of the EC50 of the glucagon peptide at the
GIP receptor divided by the EC50 of the glucagon peptide at the
glucagon receptor is less than about 100, 75, 60, 50, 40, 30, 20,
15, 10, or 5. In some embodiments, the ratio of the EC50 at the GIP
receptor divided by the EC50 at the glucagon receptor is about 1 or
less than about 1 (e.g., about 0.01, 0.013, 0.0167, 0.02, 0.025,
0.03, 0.05, 0.067, 0.1, 0.2). In some embodiments, the ratio of the
GIP potency of the glucagon peptide compared to the glucagon
potency of the glucagon peptide is less than about 500, 450, 400,
350, 300, 250, 200, 150, 100, 75, 60, 50, 40, 30, 20, 15, 10, or 5.
In some embodiments, the ratio of the potency at the GIP receptor
divided by the potency at the glucagon receptor is about 1 or less
than about 1 (e.g., about 0.01, 0.013, 0.0167, 0.02, 0.025, 0.03,
0.05, 0.067, 0.1, 0.2). In some embodiments, GLP-I activity has
been significantly reduced or destroyed, e.g., by an amino acid
modification at position 7, a deletion of the amino acid(s)
C-terminal to the amino acid at position 27 or 28, yielding a 27-
or 28-amino acid peptide, or a combination thereof. In some
embodiments, the glucagon analog is a dual agonist of GIP receptor
and GLP-1 receptor, wherein the ratio of EC50 for GIP receptor
versus GLP-1 receptor (EC50 for GIP receptor/EC50 for GLP-1
receptor) is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. In some
embodiments, the glucagon analog is a dual agonist of GIP receptor
and GLP-1 receptor, wherein the ratio of EC50 for GLP-1 receptor
versus GIP receptor (EC50 for GLP-1 receptor/EC50 for GIP receptor)
is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.
[0272] Another aspect of the invention provides glucagon peptides
that exhibit activity at the glucagon, GIP and GLP-I receptors
("glucagon/GIP/GLP-1 tri-agonists"). These glucagon peptides have
lost native glucagon's selectivity for the glucagon receptor
compared to both the GLP-I and GIP receptors. In some embodiments,
the EC50 of the glucagon peptide at the GIP receptor is less than
about 50-fold, 40-fold, 30-fold or 20-fold different (higher or
lower) from its respective EC50s at the glucagon and GLP-I
receptors. In some embodiments, the GIP potency of the glucagon
peptide is less than about 500-, 450-, 400-, 350-, 300-, 250-,
200-, 150-, 100-, 75-, 50-, 25-, 20-, 15-, 10-, or 5-fold different
(higher or lower) from its glucagon and GLP-I potencies. In some
embodiments, the ratio of the EC50 of the tri-agonist at the GIP
receptor divided by the EC50 of the tri-agonist at the GLP-I
receptor is less than about 100, 75, 60, 50, 40, 30, 20, 15, 10, or
5. In some embodiments, the ratio of the EC50 at the GIP receptor
divided by the EC50 at the GLP-I receptor is about 1 or less than
about 1 (e.g., about 0.01, 0.013, 0.0167, 0.02, 0.025, 0.03, 0.05,
0.067, 0.1, 0.2). In some embodiments, the ratio of the GIP potency
of the tri-agonist compared to the GLP-I potency of the tri-agonist
is less than about 100, 75, 60, 50, 40, 30, 20, 15, 10, or 5. In
some embodiments, the ratio of the potency at the GIP receptor
divided by the potency at the GLP-I receptor is about 1 or less
than about 1 (e.g., about 0.01, 0.013, 0.0167, 0.02, 0.025, 0.03,
0.05, 0.067, 0.1, 0.2). In related embodiments, the ratio of the
EC50 of the tri-agonist at the GIP receptor divided by the EC50 of
the tri-agonist at the glucagon receptor is less than about 100,
75, 60, 50, 40, 30, 20, 15, 10, or 5. In some embodiments, the
ratio of the EC50 at the GIP receptor divided by the EC50 at the
glucagon receptor is about 1 or less than about 1 (e.g., about
0.01, 0.013, 0.0167, 0.02, 0.025, 0.03, 0.05, 0.067, 0.1, 0.2). In
some embodiments, the ratio of the GIP potency of the tri-agonist
compared to the glucagon potency of the tri-agonist is less than
about 500, 450, 400, 350, 300, 250, 200, 150, 100, 75, 60, 50, 40,
30, 20, 15, 10, or 5. In some embodiments, the ratio of the potency
at the GIP receptor divided by the potency at the glucagon receptor
is about 1 or less than about 1 (e.g., about 0.01, 0.013, 0.0167,
0.02, 0.025, 0.03, 0.05, 0.067, 0.1, 0.2). In some embodiments, the
ratio of the EC50 of the tri-agonist at the GLP-I receptor divided
by the EC50 of the tri-agonist at the glucagon receptor is less
than about 100, 75, 60, 50, 40, 30, 20, 15, 10, or 5. In some
embodiments, the ratio of the EC50 at the GLP-I receptor divided by
the EC50 at the glucagon receptor is about 1 or less than about 1
(e.g., about 0.01, 0.013, 0.0167, 0.02, 0.025, 0.03, 0.05, 0.067,
0.1, 0.2). In some embodiments, the ratio of the GLP-I potency of
the tri-agonist compared to the glucagon potency of the tri-agonist
is less than about 100, 75, 60, 50, 40, 30, 20, 15, 10, or 5. In
some embodiments, the ratio of the potency at the GLP-I receptor
divided by the potency at the glucagon receptor is about 1 or less
than about 1 (e.g., about 0.01, 0.013, 0.0167, 0.02, 0.025, 0.03,
0.05, 0.067, 0.1, 0.2).
[0273] Yet another aspect of the invention provides glucagon
peptides that exhibit activity at the GLP-I and GIP receptors, but
in which the glucagon activity has been significantly reduced or
destroyed ("GIP/GLP-1 co-agonists"), e.g., by an amino acid
modification at position 3. For example, substitution at this
position with an acidic, basic, or a hydrophobic amino acid
(glutamic acid, ornithine, norleucine) reduces glucagon activity.
In some embodiments, the EC50 of the glucagon peptide at the GIP
receptor is less than about 50-fold, 40-fold, 30-fold or 20-fold
different (higher or lower) from its EC50 at the GLP-I receptor. In
some embodiments, the GIP potency of the glucagon peptide is less
than about 25-, 20-, 15-, 10-, or 5-fold different (higher or
lower) from its GLP-I potency. In some embodiments these glucagon
peptides have about 10% or less of the activity of native glucagon
at the glucagon receptor, e.g. about 1-10%, or about 0.1-10%, or
greater than about 0.1% but less than about 10%. In some
embodiments, the ratio of the EC50 of the glucagon peptide at the
GIP receptor divided by the EC50 of the glucagon peptide at the
GLP-I receptor is less than about 100, 75, 60, 50, 40, 30, 20, 15,
10, or 5, and no less than 1. In some embodiments, the ratio of the
GIP potency of the glucagon peptide compared to the GLP-I potency
of the glucagon peptide is less than about 100, 75, 60, 50, 40, 30,
20, 15, 10, or 5, and no less than 1. A further aspect of the
invention provides glucagon peptides that exhibit activity at the
GIP receptor, in which the glucagon and GLP-I activity have been
significantly reduced or destroyed ("GIP agonist glucagon
peptides"), e.g., by amino acid modifications at positions 3 and 7.
In some embodiments these glucagon peptides have about 10% or less
of the activity of native glucagon at the glucagon receptor, e.g.
about 1-10%, or about 0.1-10%, or greater than about 0.1%, 0.5%, or
1% but less than about 1%, 5%, or 10%. In some embodiments these
glucagon peptides also have about 10% or less of the activity of
native GLP-I at the GLP-I receptor, e.g. about 1-10%, or about
0.1-10%, or greater than about 0.1%, 0.5%, or 1% but less than
about 1%, 5%, or 10%. In accordance with some embodiments of the
invention, the analog of glucagon having GIP agonist activity
comprises SEQ ID NO: 1 with (a) an amino acid modification at
position 1 that confers GIP agonist activity, (b) a modification
which stabilizes the alpha helix structure of the C-terminal
portion (amino acids 12-29) of the analog, and (c) optionally, 1 to
10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) further amino acid
modifications. In some embodiments, the analog exhibits at least
about 1% activity of native GIP at the GIP receptor or any other
activity level at the GIP receptor described herein. In some
embodiments, the modification which stabilizes the alpha helix
structure is a modification selected from the group consisting of:
(i) a lactam bridge between the side chains of amino acids at
positions i and i+4 or between the side chains of amino acids at
positions and j+3, wherein i is 12, 13, 16, 17, 20 or 24, and
wherein j is 17, and (ii) one, two, three, or all of the amino
acids at positions 16, 20, 21, and 24 of the analog is substituted
with an .alpha.,.alpha.-disubstituted amino acid. Such analogs of
glucagon having GIP agonist activity are further described herein.
In some embodiments, the invention provides an analog of glucagon
having GIP agonist activity, with the following modifications
provided herein, wherein the EC50 of the analog for GIP receptor
activation is about 100 nM or less.
[0274] In some aspects, the invention provides a pharmaceutical
composition comprising any of the novel glucagon peptides disclosed
herein, preferably sterile and preferably at a purity level of at
least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, and a
pharmaceutically acceptable diluent, carrier or excipient. Such
compositions may contain a glucagon peptide or analog at a
concentration of at least A, wherein A is 0.001 mg/ml, 0.01 mg/ml,
0.1 mg/ml, 0.5 mg/ml, 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml,
6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 11 mg/ml, 12 mg/ml,
13 mg/ml, 14 mg/ml, 15 mg/ml, 16 mg/ml, 17 mg/ml, 18 mg/ml, 19
mg/ml, 20 mg/ml, 21 mg/ml, 22 mg/ml, 23 mg/ml, 24 mg/ml, 25 mg/ml
or higher. In other embodiments, such compositions may contain a
glucagon peptide at a concentration of at most B, wherein B is 30
mg/ml, 25 mg/ml, 24 mg/ml, 23, mg/ml, 22 mg/ml, 21 mg/ml, 20 mg/ml,
19 mg/ml, 18 mg/ml, 17 mg/ml, 16 mg/ml, 15 mg/ml, 14 mg/ml, 13
mg/ml, 12 mg/ml, 11 mg/ml 10 mg/ml, 9 mg/ml, 8 mg/ml, 7 mg/ml, 6
mg/ml, 5 mg/ml, 4 mg/ml, 3 mg/ml, 2 mg/ml, 1 mg/ml, or 0.1 mg/ml.
In some embodiments, the compositions may contain a glucagon
peptide at a concentration range of A to B mg/ml, for example,
0.001 to 30.0 mg/ml. In one embodiment the pharmaceutical
compositions comprise aqueous solutions that are sterilized and
optionally stored within various containers. The compounds of the
present invention can be used in some embodiments to prepare
pre-formulated solutions ready for injection. In other embodiments
the pharmaceutical compositions comprise a lyophilized powder.
[0275] 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.
[0276] 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.
[0277] 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.
[0278] 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.
[0279] 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.
[0280] 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. In some
embodiments, the invention is directed to an oral transmucosal
solid dosage form comprising an analog described herein, wherein
the concentration of analog is from about 0.01% to about 90% of the
dry matter weight of the composition.
[0281] 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.
[0282] 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.
[0283] 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.
[0284] 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.
[0285] The compositions of the invention can be administered in a
sustained release composition, such as those described in, for
example, U.S. Pat. No. 5,672,659 and U.S. Pat. No. 5,595,760, and
herein incorporate by reference. The use of immediate or sustained
release compositions depends on the type of condition being
treated.
[0286] 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 an increase 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 glucagon
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
effective amount for reducing the severity or frequency of symptoms
associated with a metabolic disorder in a subject in need thereof.
The pharmaceutical compositions of the instant invention or the
pharmaceutical acceptable salts derived therefrom may be in a
dosage amount effective amount for reducing the severity or
frequency of symptoms associated with a metabolic disorder in a
subject. The pharmaceutical compositions of the instant invention
or the pharmaceutical acceptable salts derived therefrom may be in
a dosage amount effective amount for increasing the half-life of
the composition when administered to a human being or other
subject. The pharmaceutical compositions of the instant invention
or the pharmaceutical acceptable salts derived therefrom may be in
a dosage amount effective amount for increasing the half-life of
the composition when administered to a human being or other subject
in need thereof.
[0287] In some embodiments the analog comprises a glucagon analog
comprising HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein the amino acid sequences
HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA are
modified by a pattern of beta amino acids in the formula chosen
from: .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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated. In some
embodiments the analog comprises a glucagon analog comprising HSQGT
FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein
the amino acid sequences HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA are modified by a pattern of beta
amino acids in the formula chosen from:
.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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein one of
the last 5 amino acid residues of the C-terminal region is acylated
with one or more saturated carbons.
[0288] In some embodiments, the invention relates to pharmaceutical
compositions comprising any analog disclosed herein for use in the
treatment or prevention of a metabolic disorder.
[0289] In some embodiments the analog comprises a glucagon analog
comprising HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein the amino acid sequences
HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA are
modified by a pattern of beta amino acids in the formula chosen
from: .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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor.
[0290] In some embodiments the analog comprises a glucagon analog
comprising HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein the amino acid sequences
HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA are
modified by a pattern of beta amino acids in the formula chosen
from: .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..alp-
ha..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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor; and wherein dipeptidyl
peptidase IV cleaves the peptide with at least 40% less effectively
as compared to its rate of cleavage of wild-type glucagon. In some
embodiments the analog comprises a glucagon analog comprising HSQGT
FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein
the amino acid sequences HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA are modified by a pattern of beta
amino acids in the formula chosen from:
.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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor; and wherein dipeptidyl
peptidase IV cleaves the peptide with at least 30% less effectivity
as compared to its rate of cleavage of wild-type glucagon. In some
embodiments the analog comprises a glucagon analog comprising HSQGT
FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein
the amino acid sequences HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA are modified by a pattern of beta
amino acids in the formula chosen from:
.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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor; and wherein dipeptidyl
peptidase IV cleaves the analog with at least 20% less effectivity
as compared to its rate of cleavage of wild-type glucagon. In some
embodiments the analog comprises a glucagon analog comprising HSQGT
FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein
the amino acid sequences HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA are modified by a pattern of beta
amino acids in the formula chosen from:
.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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor; and wherein dipeptidyl
peptidase IV cleaves the analog with at least 10% less effectivity
as compared to its rate of cleavage of wild-type glucagon.
[0291] In some embodiments the analog comprises a glucagon analog
comprising HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein the amino acid sequences
HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA are
modified by a pattern of beta amino acids in the formula chosen
from: .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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor; and wherein dipeptidyl
peptidase IV cleaves the peptide with at least 50% less effectivity
as compared to its rate of cleavage of wild-type glucagon. In some
embodiments the analog comprises a glucagon analog comprising HSQGT
FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein
the amino acid sequences HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA are modified by a pattern of beta
amino acids in the formula chosen from:
.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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor; and wherein dipeptidyl
peptidase IV cleaves the peptide with at least 60% less effectivity
as compared to its rate of cleavage of wild-type glucagon. In some
embodiments the analog comprises a glucagon analog comprising HSQGT
FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein
the amino acid sequences HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA are modified by a pattern of beta
amino acids in the formula chosen from:
.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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor; and wherein dipeptidyl
peptidase IV cleaves the peptide with at least 70% less effectivity
as compared to its rate of cleavage of wild-type glucagon. In some
embodiments the analog comprises a glucagon analog comprising HSQGT
FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein
the amino acid sequences HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA are modified by a pattern of beta
amino acids in the formula chosen from:
.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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor; and wherein dipeptidyl
peptidase IV cleaves the peptide with at least 80% less effectivity
as compared to its rate of cleavage of wild-type glucagon. In some
embodiments the analog comprises a glucagon analog comprising HSQGT
FTSDYSKYLDSRRAQDFVQWLMNT or YBEGTFTSDYSIYLDKQAABEFVNWLLA; wherein
the amino acid sequences HSQGT FTSDYSKYLDSRRAQDFVQWLMNT or
YBEGTFTSDYSIYLDKQAABEFVNWLLA are modified by a pattern of beta
amino acids in the formula chosen from:
.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..alpha.,
.beta..alpha..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.; wherein the
C-terminus of the analog is optionally amidated; and wherein the
analog bind the GIP receptor and/or the GLP-1 receptor and/or the
GLP-2 receptor and or the glucagon receptor; and wherein dipeptidyl
peptidase IV cleaves the peptide with at least 90% less effectivity
as compared to its rate of cleavage of wild-type glucagon.
[0292] The pharmaceutical compositions can be further packaged as
part of a kit that includes a disposable device for administering
the composition to a patient. The containers or kits may be labeled
for storage at ambient room temperature or at refrigerated
temperature.
[0293] The glucagon peptides can be administered to a patient using
any standard route of administration, including parenterally, such
as intravenously, intraperitoneally, subcutaneously or
intramuscularly, intrathecally, transdermally, rectally, orally,
nasally or by inhalation. In one embodiment the composition is
administered subcutaneously or intramuscularly.
[0294] In one embodiment the kit is provided with a device for
administering the glucagon composition to a patient, e.g. syringe
needle, pen device, jet injector or other needle-free injector. The
kit may alternatively or in addition include one or more
containers, e.g., vials, tubes, bottles, single or multi-chambered
pre-filled syringes, cartridges, infusion pumps (external or
implantable), jet injectors, pre-filled pen devices and the like,
optionally containing the glucagon peptide in a lyophilized form or
in an aqueous solution. Preferably, the kits will also include
instructions for use. In some embodiments the device of the kit is
an aerosol dispensing device, wherein the composition is
prepackaged within the aerosol device. In another embodiment the
kit comprises a syringe and a needle, and in one embodiment the
sterile glucagon composition is prepackaged within the syringe.
[0295] In accordance with one embodiment a pharmaceutical
composition is provided wherein the composition comprises a GIP
active glucagon analog of the present disclosure, or
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier. The pharmaceutical composition can comprise any
pharmaceutically acceptable ingredient, including, for example,
acidifying agents, additives, adsorbents, aerosol propellants, air
displacement agents, alkalizing agents, anticaking agents,
anticoagulants, antimicrobial preservatives, antioxidants,
antiseptics, bases, binders, buffering agents, chelating agents,
coating agents, coloring agents, desiccants, detergents, diluents,
disinfectants, disintegrants, dispersing agents, dissolution
enhancing agents, dyes, emollients, emulsifying agents, emulsion
stabilizers, fillers, film forming agents, flavor enhancers,
flavoring agents, flow enhancers, gelling agents, granulating
agents, humectants, lubricants, mucoadhesives, ointment bases,
ointments, oleaginous vehicles, organic bases, pastille bases,
pigments, plasticizers, polishing agents, preservatives,
sequestering agents, skin penetrants, solubilizing agents,
solvents, stabilizing agents, suppository bases, surface active
agents, surfactants, suspending agents, sweetening agents,
therapeutic agents, thickening agents, tonicity agents, toxicity
agents, viscosity-increasing agents, water-absorbing agents,
water-miscible cosolvents, water softeners, or wetting agents.
[0296] In some embodiments, the pharmaceutical composition
comprises any one or a combination of the following components:
acacia, acesulfame potassium, acetyltributyl citrate,
acetyltriethyl citrate, agar, albumin, alcohol, dehydrated alcohol,
denatured alcohol, dilute alcohol, aleuritic acid, alginic acid,
aliphatic polyesters, alumina, aluminum hydroxide, aluminum
stearate, amylopectin, .alpha.-amylose, ascorbic acid, ascorbyl
palmitate, aspartame, bacteriostatic water for injection,
bentonite, bentonite magma, benzalkonium chloride, benzethonium
chloride, benzoic acid, benzyl alcohol, benzyl benzoate, bronopol,
butylated hydroxyanisole, butylated hydroxytoluene, butylparaben,
butylparaben sodium, calcium alginate, calcium ascorbate, calcium
carbonate, calcium cyclamate, dibasic anhydrous calcium phosphate,
dibasic dehydrate calcium phosphate, tribasic calcium phosphate,
calcium propionate, calcium silicate, calcium sorbate, calcium
stearate, calcium sulfate, calcium sulfate hemihydrate, canola oil,
carbomer, carbon dioxide, carboxymethyl cellulose calcium,
carboxymethyl cellulose sodium, .beta.-carotene, carrageenan,
castor oil, hydrogenated castor oil, cationic emulsifying wax,
cellulose acetate, cellulose acetate phthalate, ethyl cellulose,
microcrystalline cellulose, powdered cellulose, silicified
microcrystalline cellulose, sodium carboxymethyl cellulose,
cetostearyl alcohol, cetrimide, cetyl alcohol, chlorhexidine,
chlorobutanol, chlorocresol, cholesterol, chlorhexidine acetate,
chlorhexidine gluconate, chlorhexidine hydrochloride,
chlorodifluoroethane (HCFC), chlorodifluoromethane,
chlorofluorocarbons (CFC)chlorophenoxyethanol, chloroxylenol, corn
syrup solids, anhydrous citric acid, citric acid monohydrate, cocoa
butter, coloring agents, corn oil, cottonseed oil, cresol,
m-cresol, o-cresol, p-cresol, croscarmellose sodium, crospovidone,
cyclamic acid, cyclodextrins, dextrates, dextrin, dextrose,
dextrose anhydrous, diazolidinyl urea, dibutyl phthalate, dibutyl
sebacate, diethanolamine, diethyl phthalate, difluoroethane (HFC),
dimethyl-.beta.-cyclodextrin, cyclodextrin-type compounds such as
Captisol.RTM., dimethyl ether, dimethyl phthalate, dipotassium
edentate, disodium edentate, disodium hydrogen phosphate, docusate
calcium, docusate potassium, docusate sodium, dodecyl gallate,
dodecyltrimethylammonium bromide, edentate calcium disodium, edtic
acid, eglumine, ethyl alcohol, ethylcellulose, ethyl gallate, ethyl
laurate, ethyl maltol, ethyl oleate, ethylparaben, ethylparaben
potassium, ethylparaben sodium, ethyl vanillin, fructose, fructose
liquid, fructose milled, fructose pyrogen-free, powdered fructose,
fumaric acid, gelatin, glucose, liquid glucose, glyceride mixtures
of saturated vegetable fatty acids, glycerin, glyceryl behenate,
glyceryl monooleate, glyceryl monostearate, self-emulsifying
glyceryl monostearate, glyceryl palmitostearate, glycine, glycols,
glycofurol, guar gum, heptafluoropropane (HFC),
hexadecyltrimethylammonium bromide, high fructose syrup, human
serum albumin, hydrocarbons (HC), dilute hydrochloric acid,
hydrogenated vegetable oil, type II, hydroxyethyl cellulose,
2-hydroxyethyl-.beta.-cyclodextrin, hydroxypropyl cellulose,
low-substituted hydroxypropyl cellulose,
2-hydroxypropyl-.beta.-cyclodextrin, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose phthalate, imidurea, indigo carmine,
ion exchangers, iron oxides, isopropyl alcohol, isopropyl
myristate, isopropyl palmitate, isotonic saline, kaolin, lactic
acid, lactitol, lactose, lanolin, lanolin alcohols, anhydrous
lanolin, lecithin, magnesium aluminum silicate, magnesium
carbonate, normal magnesium carbonate, magnesium carbonate
anhydrous, magnesium carbonate hydroxide, magnesium hydroxide,
magnesium lauryl sulfate, magnesium oxide, magnesium silicate,
magnesium stearate, magnesium trisilicate, magnesium trisilicate
anhydrous, malic acid, malt, maltitol, maltitol solution,
maltodextrin, maltol, maltose, mannitol, medium chain
triglycerides, meglumine, menthol, methylcellulose, methyl
methacrylate, methyl oleate, methylparaben, methylparaben
potassium, methylparaben sodium, microcrystalline cellulose and
carboxymethylcellulose sodium, mineral oil, light mineral oil,
mineral oil and lanolin alcohols, oil, olive oil, monoethanolamine,
montmorillonite, octyl gallate, oleic acid, palmitic acid,
paraffin, peanut oil, petrolatum, petrolatum and lanolin alcohols,
pharmaceutical glaze, phenol, liquified phenol, phenoxyethanol,
phenoxypropanol, phenylethyl alcohol, phenylmercuric acetate,
phenylmercuric borate, phenylmercuric nitrate, polacrilin,
polacrilin potassium, poloxamer, polydextrose, polyethylene glycol,
polyethylene oxide, polyacrylates,
polyethylene-polyoxypropylene-block polymers, polymethacrylates,
polyoxyethylene alkyl ethers, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitol fatty acid esters,
polyoxyethylene stearates, polyvinyl alcohol, polyvinyl
pyrrolidone, potassium alginate, potassium benzoate, potassium
bicarbonate, potassium bisulfite, potassium chloride, potassium
citrate, potassium citrate anhydrous, potassium hydrogen phosphate,
potassium metabisulfite, monobasic potassium phosphate, potassium
propionate, potassium sorbate, povidone, propanol, propionic acid,
propylene carbonate, propylene glycol, propylene glycol alginate,
propyl gallate, propylparaben, propylparaben potassium,
propylparaben sodium, protamine sulfate, rapeseed oil, Ringer's
solution, saccharin, saccharin ammonium, saccharin calcium,
saccharin sodium, safflower oil, saponite, serum proteins, sesame
oil, colloidal silica, colloidal silicon dioxide, sodium alginate,
sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium
bisulfite, sodium chloride, anhydrous sodium citrate, sodium
citrate dehydrate, sodium chloride, sodium cyclamate, sodium
edentate, sodium dodecyl sulfate, sodium lauryl sulfate, sodium
metabisulfite, sodium phosphate, dibasic, sodium phosphate,
monobasic, sodium phosphate, tribasic, anhydrous sodium propionate,
sodium propionate, sodium sorbate, sodium starch glycolate, sodium
stearyl fumarate, sodium sulfite, sorbic acid, sorbitan esters
(sorbitan fatty esters), sorbitol, sorbitol solution 70%, soybean
oil, spermaceti wax, starch, corn starch, potato starch,
pregelatinized starch, sterilizable maize starch, stearic acid,
purified stearic acid, stearyl alcohol, sucrose, sugars,
compressible sugar, confectioner's sugar, sugar spheres, invert
sugar, Sugartab, Sunset Yellow FCF, synthetic paraffin, talc,
tartaric acid, tartrazine, tetrafluoroethane (HFC), theobroma oil,
thimerosal, titanium dioxide, alpha tocopherol, tocopheryl acetate,
alpha tocopheryl acid succinate, beta-tocopherol, delta-tocopherol,
gamma-tocopherol, tragacanth, triacetin, tributyl citrate,
triethanolamine, triethyl citrate, trimethyl-.beta.-cyclodextrin,
trimethyltetradecylammonium bromide, tris buffer, trisodium
edentate, vanillin, type I hydrogenated vegetable oil, water, soft
water, hard water, carbon dioxide-free water, pyrogen-free water,
water for injection, sterile water for inhalation, sterile water
for injection, sterile water for irrigation, waxes, anionic
emulsifying wax, carnauba wax, cationic emulsifying wax, cetyl
ester wax, microcrystalline wax, nonionic emulsifying wax,
suppository wax, white wax, yellow wax, white petrolatum, wool fat,
xanthan gum, xylitol, zein, zinc propionate, zinc salts, zinc
stearate, or any excipient in the Handbook of Pharmaceutical
Excipients, Third Edition, A. H. Kibbe (Pharmaceutical Press,
London, UK, 2000), which is incorporated by reference in its
entirety. Remington's Pharmaceutical Sciences, Sixteenth Edition,
E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), which is
incorporated by reference in its entirety, discloses various
components used in formulating pharmaceutically acceptable
compositions and known techniques for the preparation thereof.
Except insofar as any conventional agent is incompatible with the
pharmaceutical compositions, its use in pharmaceutical compositions
is contemplated. Supplementary active ingredients also can be
incorporated into the compositions. The pharmaceutical formulations
disclosed herein may be designed to be short-acting,
fast-releasing, long-acting, or sustained-releasing as described
below. The pharmaceutical formulations may also be formulated for
immediate release, controlled release or for slow release. The
instant compositions may further comprise, for example, micelles or
liposomes, or some other encapsulated form, or may be administered
in an extended release form to provide a prolonged storage and/or
delivery effect. The disclosed pharmaceutical formulations may be
administered according to any regime including, for example, daily
(1 time per day, 2 times per day, 3 times per day, 4 times per day,
5 times per day, 6 times per day), every two days, every three
days, every four days, every five days, every six days, weekly,
bi-weekly, every three weeks, monthly, or bi-monthly. In some
embodiments, the foregoing component(s) may be present in the
pharmaceutical composition at any concentration, such as, for
example, at least A, wherein A is 0.0001% w/v, 0.001% w/v, 0.01%
w/v, 0.1% w/v, 1% w/v, 2% w/v, 5% w/v, 10% w/v, 20% w/v, 30% w/v,
40% w/v, 50% w/v, 60% w/v, 70% w/v, 80% w/v, or 90% w/v. In some
embodiments, the foregoing component(s) may be present in the
pharmaceutical composition at any concentration, such as, for
example, at most B, wherein B is 90% w/v, 80% w/v, 70% w/v, 60%
w/v, 50% w/v, 40% w/v, 30% w/v, 20% w/v, 10% w/v, 5% w/v, 2% w/v,
1% w/v, 0.1% w/v, 0.001% w/v, or 0.0001%. In other embodiments, the
foregoing component(s) may be present in the pharmaceutical
composition at any concentration range, such as, for example from
about A to about B. In some embodiments, A is 0.0001% and B is 90%.
The pharmaceutical compositions may be formulated to achieve a
physiologically compatible pH. In some embodiments, the pH of the
pharmaceutical composition may be at least 5, at least 5.5, at
least 6, at least 6.5, at least 7, at least 7.5, at least 8, at
least 8.5, at least 9, at least 9.5, at least 10, or at least 10.5
up to and including pH 11, depending on the formulation and route
of administration. In certain embodiments, the pharmaceutical
compositions may comprise buffering agents to achieve a
physiological compatible pH. The buffering agents may include any
compounds capable of buffering at the desired pH such as, for
example, phosphate buffers (e.g. PBS), triethanolamine, Tris,
bicine, TAPS, tricine, HEPES, TES, MOPS, PIPES, cacodylate, MES,
and others. In certain embodiments, the strength of the buffer is
at least 0.5 mM, at least 1 mM, at least 5 mM, at least 10 mM, at
least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at
least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at
least 100 mM, at least 120 mM, at least 150 mM, or at least 200 mM.
In some embodiments, the strength of the buffer is no more than 300
mM (e.g. at most 200 mM, at most 100 mM, at most 90 mM, at most 80
mM, at most 70 mM, at most 60 mM, at most 50 mM, at most 40 mM, at
most 30 mM, at most 20 mM, at most 10 mM, at most 5 mM, at most 1
mM). Glucagon peptides that are GIP/GLP-1 co-agonists, glucagon/GIP
co-agonists and glucagon/GIP/GLP-1 tri-agonists may be used in any
indication for which each of their activities has been previously
described as useful. For example, glucagon activity can increase
glucose levels, for insulin buffering, or to decrease gut motility
during radiological examination. GLP-I activity can lower glucose
levels, an activity useful for treating hyperglycemia, e.g.
diabetes. GLP-I activity can also induce weight loss or prevent
weight gain, e.g. through decreasing appetite. GIP activity can
also lower glucose levels, an activity useful for treating
hyperglycemia, e.g. diabetes. GIP/GLP-1 co-agonists and
glucagon/GIP/GLP-1 tri-agonists are particularly advantageous for
inducing weight loss or preventing weight gain, as well as for
treating hyperglycemia, including diabetes. In vivo data disclosed
herein demonstrates that the combination of GIP agonist activity
with GLP-I agonist activity produces a greater effect on weight
reduction than GLP-I alone. This activity is particularly
unexpected in view of teachings in the art that antagonizing GIP is
desirable for reducing daily food intake and body weight, and
increasing insulin sensitivity and energy expenditure. (Irwin et
al., Diabetologia 50: 1532-1540 (2007); and Althage et al., J Biol
Chem, e-publication on Apr. 17, 2008). The GIP and GLP-1 analogs
described herein are expected to be used to reduce or maintain body
weight, or to treat hyperglycemia, or to reduce blood glucose
level, or to normalize and/or stabilize blood glucose level.
[0297] In some embodiments, a method of treating hyperglycemia, or
a method of reducing weight gain or inducing weight loss is
provided, which comprises administering an effective amount of an
aqueous solution comprising any analog disclosed herein. In some
embodiments, a method of treating hyperglycemia, or a method of
reducing weight gain or inducing weight loss is provided, which
comprises administering an effective amount of an aqueous solution
comprising a GIP and/or GLP-1 analog of the invention. In further
embodiments, methods of treating diabetes involving coadministering
a conventional dose or a reduced dose of insulin and a glucagon
peptide of the invention are provided. Methods of treating diabetes
with a glucagon peptide of the invention, without co-administering
insulin are also provided. Such methods for treating hyperglycemia
are expected to be useful for a variety of types of hyperglycemia,
including diabetes, diabetes mellitus type I, diabetes mellitus
type II, or gestational diabetes, either insulin-dependent or
non-insulin-dependent, and reducing complications of diabetes
including nephropathy, retinopathy and vascular disease. Methods
for reducing appetite or promoting loss of body weight are expected
to be useful in reducing body weight, preventing weight gain, or
treating obesity of various causes, including drug-induced obesity,
and reducing complications associated with obesity including
vascular disease (coronary artery disease, stroke, peripheral
vascular disease, ischemia reperfusion, etc.), hypertension, onset
of diabetes type II, hyperlipidemia and musculoskeletal
diseases.
[0298] The invention relates to methods of manufacturing a
composition comprising a GIP and GLP-1 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. 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, wherein the at least one modified amino acid residue is
selected from ACPC or APC. The invention relates to methods of
manufacturing a composition comprising a GIP and/or GLP-1 analog,
wherein the GIP and/or GLP-1 analog comprises an .alpha.-amino acid
and at least one .beta.-amino acid. In some embodiments, the GIP
and/or GLP-1 analog comprises at least one, two, three, four, five,
six, seven or more ACPC or APC residues. In some embodiments, the
GIP and/or GLP-1 analog comprises at least one, two, three, four,
five, six, seven or more U residues as defined in Table 1. 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 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-3-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)-3-Tyr-OH,
(R)-4-(3-pyridyl)-3-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)-J-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.
[0299] In some embodiments, the analog 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 analog 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 a recombinantly produced amino acid
sequence.
[0300] 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.
[0301] 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 GIP and/or GLP-1 analog of the claimed invention
comprises the cyclic amino acid residues. In some embodiments, the
GIP and/or GLP-1 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. In some embodiments, the GIP
and/or GLP-1 analog of the claimed invention comprises at least one
disulfide bridge that forms a chain of atoms to a pharmaceutical
agent. In some embodiments, the GIP and/or GLP-1 analog of the
claimed invention comprises at least one disulfide bridge that
forms a chain of atoms to a pharmaceutical agent.
[0302] In some embodiments, the GIP and/or GLP-1 analog of the
claimed invention comprises at least 17% .beta.-amino acid
residues. In some embodiments, the GIP and/or GLP-1 analog of the
claimed invention comprises from about 15% to about 30%
.beta.-amino acid residues. In some embodiments, the GIP and/or
GLP-1 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 GIP AND/OR GLP-1 analog of the claimed invention
comprises from about 16% to about 29% .beta.-amino acid residues.
In some embodiments, the GIP AND/OR GLP-1 analog of the claimed
invention comprises from about 17% to about 29% .beta.-amino acid
residues. In some embodiments, the GIP AND/OR GLP-1 analog of the
claimed invention comprises from about 18% to about 29%
.beta.-amino acid residues. In some embodiments, the GIP AND/OR
GLP-1 analog of the claimed invention comprises from about 19% to
about 29% .beta.-amino acid residues. In some embodiments, the GIP
AND/OR GLP-1 analog of the claimed invention comprises from about
20% to about 29% .beta.-amino acid residues. In one embodiment, the
GIP AND/OR GLP-1 analog is QRLMEDICLPRWGCLWEDDF or a fragment
thereof.
[0303] In some embodiments, the GIP AND/OR GLP-1 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 GIP AND/OR GLP-1 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 GIP AND/OR GLP-1 analog of
the claimed invention comprises one of the following sequences:
[0304] In some embodiments, the side-chain of any non-naturally
occurring amino acid of the GIP and/or GLP-1 or analog is not
cyclic or bound to any other side chain. In some embodiments, the
GIP and/or GLP-1 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:
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019## ##STR00020## ##STR00021##
[0305] 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:
##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026##
##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031##
[0306] 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: [0307]
L-.beta.-HomohydroxyProline hydrochloride [0308]
(1R,2R)-Boc-2-aminocyclohexane carboxylic acid {(1R,2R)-ACHC}
[0309] (1R,2R)-Fmoc-2-aminocyclohexane carboxyli c acid
{(1R,2R)-ACHC} [0310] (1R,2S)-Boc-2-aminocyclohexane carboxylic
acid {(1R,2S)-ACHC} [0311] (1R,2S)-Fmoc-2-aminocyclohexane
carboxylic acid {(1R,2S)-ACHC} [0312]
(1S,2R)-Boc-2-aminocyclohexane carboxylic acid {(1S,2R)-ACHC}
[0313] (1S,2R)-Fmoc-2-aminocyclohexane carboxylic acid
(1S,2R)-ACHC} [0314] (1S,2S)-Boc-2-aminocyclohexane carboxylic acid
{(1S,2S)-ACHC} [0315] (1S,2S)-Fmoc-2-aminocyclohexane carboxylic
acid {(1S,2S)-ACHC} [0316] (1R,2R)-Boc-2-aminocyclopentane
carboxylic acid {(1R,2R)-ACPC} [0317]
(1R,2R)-Fmoc-2-aminocyclopentane carboxylic acid {(1R,2R)-ACPC}
[0318] (1S,2S)-Boc-2-aminocyclopentane carboxylic acid
{(1S,2S)-ACPC} [0319] (1S,2S)-Fmoc-2-aminocyclopentane carboxylic
acid {(1S,2S)-ACPC} [0320] Boc-cis-2-aminocyclopentane carboxylic
acid, cis-Acpc [0321] Fmoc-cis-2-aminocyclopentane carboxylic acid,
cis-Acpc [0322] (R)-Boc-(2-carboxymethyl)-piperidine,
(R)-(1-piperidin-2-yl)-acetic acid [0323]
(R)-Fmoc-(2-carboxymethyl)-piperidine,
(R)-(1-Fmoc-piperidin-2-yl)-acetic acid [0324]
(S)-Boc-(2-carboxymethyl)-piperidine
(S)-(1-Boc-piperidin-2-yl)-acetic acid [0325]
(S)-Fmoc-(2-carboxymethyl)-piperidine
(S)-(1-Fmoc-piperidin-2-yl)-acetic acid [0326]
(R,S)-Boc-2-carboxymorpholine Boc-Cop [0327]
(R,S)-Boc-2-carboxymorpholine Fmoc-Cop [0328] (R,S)-Boc-nipecotic
acid Boc-Nip [0329] (R,S)-Boc-nipecotic acid Fmoc-Nip [0330]
(R)-Fmoc-nipecotic acid (R)-Fmoc-Nip [0331] (R)-Fmoc-nipecotic acid
(R)-Boc-Nip [0332] (3S)-Boc-1-pyrrolidine-3-carboxylic acid
(3S)-Boc-beta-Pro-OH [0333] (3S)-Fmoc-1-pyrrolidine-3-carboxylic
acid (3S)-Fmoc-beta-Pro-OH
[0334] 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
anaologs 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.
[0335] 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
.alpha., 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.cndot. DCHA,
11-Amino-3,6,9-Trioxaundecanoic Acid .cndot. DCHA. In some
embodiments, the GIP and/or GLP-1 analog does not comprise any PEGs
or mini-PEGs.TM..
[0336] In some embodiments the method of treatment or prevention of
a human disorder depends upon the pharmaceutical agent being linked
to the GIP and/or GLP-1 analog. For instance: pharmaceutical agents
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).
[0337] The present invention also relates to GIP and/or GLP-1
analogs which can be linked to immunomodulatory elements, such as
antibodies, antibody fragments, bivalent or multivalent antibodies
or antibody fragment or antibody analogs.
[0338] In some embodiments, the analogs are linked to IgG
activators, inhibitors analogs, agonist analogs and antagonist
analogs which 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.
[0339] The present invention provides for the use of an analog to
link an antibody or binding composition which specifically binds to
a protein in the blood, liver, or pancreas. In some embodiments the
antibody specifically binds a protein in the blood derived from a
mammalian polypeptide, e.g., a polypeptide derived from a primate,
human, cat, dog, rat, or mouse. Antibodies can be raised proteins
in the blood, 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.
[0340] A number of immunogens may be selected to produce antibodies
specifically reactive with a pharmaceutical agent, or an antibody
linked to an analog. 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 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.
[0341] 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.
[0342] 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.
[0343] 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 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.
[0344] 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.
[0345] 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.
[0346] 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.
[0347] The instant invention is related to pharmaceutical
composition that comprise an analog or chaperon of the instant
invention or the pharmaceutical acceptable salts derived therefrom.
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 comprises 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.
[0348] 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.
[0349] 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.
[0350] 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.
[0351] 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.
[0352] 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.
[0353] 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.
[0354] 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.
[0355] 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.
[0356] The compositions and pharmaceutical compositions of the
invention can be administered via oral transmucosal delivery. 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.
[0357] The compositions of the invention can be administered in a
sustained release composition, such as those described in, for
example, U.S. Pat. No. 5,672,659 and U.S. Pat. No. 5,595,760, and
herein incorporate by reference. The use of immediate or sustained
release compositions depends on the type of condition being
treated.
[0358] 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
biological activity and reducing the degradation of a
pharmaceutical agent. 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
preventing or treating a metabolic disorder. 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 preventing or treating a metabolic disorder,
wherein the pharmaceutical composition has an affinity for the GIP
receptor and/or GLP-1 receptor and/or glucagon receptor. 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
biological activity of the pharmaceutical agent with which the
analog is co-delivered. 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.
[0359] The present invention also encompasses methods of using the
compositions comprising a GIP and/or GLP-1 analog or any analog
derived from the sequences of Table 1.
[0360] The present invention relates to a method of treating any
metabolic disorder disclosed herein comprising the step of
administering a composition or pharmaceutical composition disclosed
herein to a subject in need thereof. In some embodiments, the
composition or pharmaceutical composition comprises a glucogon
analog or a pharmaceutical salt derived therefrom to a subject in
need thereof in an amount sufficient to treat or prevent weight
gain, obesity, elevated insulting levels, hyperglycemia, or
metabolic disorders in a subject. The present invention relates to
a method of inhibiting secretion of glucagon in a subject in need
thereof comprising administrating any one of the compositions,
pharmaceutical compositions, analogs, or pharmaceutical salts
thereof to a subject in need thereof. The present invention relates
to a method of inhibiting secretion of glucagon in a subject in
need thereof comprising administrating any one of the compositions,
pharmaceutical compositions, analogs, or pharmaceutical salts
thereof to a subject in need thereof in an amount sufficient to
treat or prevent weight gain, obesity, elevated insulin levels,
hyperglycemia, or metabolic disorders in a subject.
[0361] Any of these methods may involve the administration of a
pharmaceutical composition comprising an analog wherein the analog
is in a therapeutically effective dose. The composition comprising
an analog of the invention produces a broad range of activities,
depending on the dosage administered. The compositions of the
invention may also be used to prevent or treat any disorder in a
subject in need thereof for which a pharmaceutical agent is bound
to an analog and adminstered. In some embodiments, the method of
prevention comprises administering the composition or
pharmaceutical compositions of the invention to the subject after
the subject is tested for susceptibility or genetic propensity for
developing the disease, indication or disorder. In some
embodiments, the methods of the claimed invention comprise
identifying a subject in need thereof by tested for susceptibility
or genetic propensity for developing the disease, indication or
disorder. In some embodiments, the test for identifying a subject
in need thereof comprises testing for a susceptibility or genetic
propensity for developing a metabolic disorder such as weight gain,
obesity, elevated insulin levels, hyperglycemia, or any type of
diabetes.
[0362] 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.
[0363] 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.
[0364] 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.
[0365] 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.
[0366] 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.
[0367] 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.
[0368] 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.
[0369] 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 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.
[0370] In some embodiments, the subject is administered two, three,
four, or more doses of a pharmaceutical composition per day. In
some embodiments, the subject is administered two, three, four, or
more doses of a pharmaceutical composition per week. In some
embodiments, the subject is administered two, three, four, or more
doses of a pharmaceutical composition per month. In some
embodiments, the subject is administered one dose of a
pharmaceutical composition per month. In some embodiments, the
subject is administered one dose of a pharmaceutical composition
per week.
[0371] In some embodiments, the composition comprising an 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 an 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 an 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 an 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 an 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 an 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 analog administered per day.
[0372] 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. In some embodiments, a subject in need thereof is
administered from about 1 .mu.g to about 2 .mu.g of analog or
pharmaceutically salt thereof per day. In some embodiments, a
subject in need thereof is administered from about 0.1 .mu.g to
about 2 .mu.g of analog or pharmaceutically salt thereof per day.
In some embodiments, a subject in need thereof is administered from
about 0.1 .mu.g to about 1 .mu.g of analog or pharmaceutically salt
thereof per day.
[0373] In some embodiments, a subject in need thereof is
administered from about 0.0001 to about 3000 milligrams of an
analog or pharmaceutically salt there of per day. In some
embodiments, a subject is administered up to about 2000 milligrams
of an analog or pharmaceutically salt thereof day. In some
embodiments, a subject is administered up to about 1800 milligrams
of an analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 1600 milligrams
of an analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 1400 milligrams
of an analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 1200 milligrams
of an analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 1000 milligrams
of an analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered up to about 800 milligrams
of an analog or pharmaceutically salt thereof per day. In some
embodiments, a subject is administered from about 0.0001 milligrams
to about 700 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 700 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 600 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 500 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 400 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 300 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 200 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 100 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 50 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 25 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 15 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 10 milligrams of an analog or pharmaceutically salt
thereof per dose. In some embodiments, a subject is administered up
to about 5 milligrams of an analog or pharmaceutically salt thereof
per dose. In some embodiments, a subject is administered up to
about 2.5 milligrams of an analog or pharmaceutically salt thereof
per dose. In some embodiments, a subject is administered up to
about 1 milligram of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
0.5 milligrams of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
0.1 milligrams of an analog or pharmaceutically salt thereof per
dose.
[0374] In some embodiments, a subject is administered up to about
900 micrograms of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
800 micrograms of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
700 micrograms of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
600 micrograms of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
500 micrograms of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
400 micrograms of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
300 micrograms of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
200 micrograms of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about
100 micrograms of an analog or pharmaceutically salt thereof per
dose.
[0375] In some embodiments, a subject is administered up to about
10 micrograms of an analog or pharmaceutically salt thereof per
dose. In some embodiments, a subject is administered up to about 5
micrograms of an analog or pharmaceutically salt thereof per dose.
In some embodiments, a subject is administered up to about 1
microgram of an analog or pharmaceutically salt thereof per dose.
In some embodiments, a subject is administered up to about 0.1
micrograms of an analog or pharmaceutically salt thereof per dose.
In some embodiments, a subject is administered up to about 0.001
micrograms of an analog or pharmaceutically salt thereof per dose.
In some embodiments, the subject is administered in any one of the
above-identified doses, where the dose is calculated as the sum of
the total mass of the analog and the mass of the pharmaceutical
agent to which the analog is bound or linked.
[0376] The dose administered to the subject can also be measured in
terms of total amount of analog or pharmaceutically salt thereof
administered per ounce of liquid prepared.
In some embodiments, the analog or pharmaceutically salt thereof is
at a concentration of about 2.5 micrograms per ounce of solution.
In some embodiments, the analog or pharmaceutically salt thereof is
at a concentration of about 2.25 grams per ounce of solution. In
some embodiments, the analog or pharmaceutically salt thereof is at
a concentration of about 2.25 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 2.0 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.9 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.8 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.7 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.6 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.5 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.4 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.3 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.2 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.1 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 1.0 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.9 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.8 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.7 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.6 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.5 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.4 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.3 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.2 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.1 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.01 grams per ounce of solution. In some
embodiments, the analog or pharmaceutically salt thereof is at a
concentration of about 0.001 grams per ounce of solution prepared.
In some embodiments, the analog or pharmaceutically salt thereof is
at a concentration of about 0.0001 grams per ounce of solution
prepared. In some embodiments, the analog or pharmaceutically salt
thereof is at a concentration of about 0.00001 grams per ounce of
solution prepared. In some embodiments, the analog or
pharmaceutically salt thereof is at a concentration of about
0.000001 grams per ounce of solution prepared.
[0377] 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.
[0378] 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.
[0379] 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
[0380] 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 (O/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.
[0381] 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.
[0382] According to some embodiments of the invention, the
formulation may be supplied as part of a kit. In some embodiments,
the kit comprises 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.
[0383] 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.
[0384] 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.
[0385] 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.
[0386] In another embodiment, a packaged kit is provided that
contains the pharmaceutical formulation to be administered, i.e., a
pharmaceutical formulation containing an analog disclosed herein, 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.
[0387] 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.
[0388] The invention relates to the use of an analog in the
preparation of a medicament for treatment of a metabolic disorder
of a subject in need of such treatment.
[0389] The invention relates to analogs as well as functional
fragments thereof based upon the polypeptide sequences identified
in WO/2010/011439, which is herein incorporated by reference in its
entirety.
[0390] The invention relates to analogs as well as functional
fragments thereof based upon the polypeptide sequences identified
in Table 1. In some embodiments, the analog comprises a sequence or
fragment of a sequence identified in Table I, wherein the analog
comprises at least 3, 4, 5, 6, or 7 amino acids are replaced with
non-natural amino acids. In some embodiments, the analog comprises
a sequence or fragment of a sequence identified in Table I, wherein
the analog or fragment comprises at least 3, 4, 5, 6, or 7 amino
acids are replaced with beta-amino acids. In some embodiments, the
analog comprises a sequence or fragment of a sequence identified in
Table I, wherein the analog, sequence or fragment of analog
comprises at least 3, 4, 5, 6, or 7 amino acids are replaced with a
beta-3, beta-2, or heterocylic beta-amino acids. In some
embodiments, the analog comprises a sequence or fragment of a
sequence identified in Table I, wherein the analog, sequence or
fragment of analog comprises at least 3, 4, 5, 6, or 7 amino acids
are replaced with a beta-3,3, beta-3, beta-2, or heterocylic
beta-amino acids. In some embodiments, the C-terminus of the analog
is optionally amidated. In some embodiments, the C-terminus of the
analog is acylated. In some embodiments, the C-terminus of the
analog is acylated by between about 2 to about 20 saturated carbon
atoms. In some embodiments, the side chain of the C-terminal amino
acid residue of the analog is acylated. In some embodiments, the
side chain of the C-terminal amino acid residue of the analog is
acylated by between about 2 to about 20 saturated carbon atoms. All
modified and unmodified sequences listed in Table 1 are
contemplated as being part of the invention. The invention relates
to substitutions of any sequence of Table I that contains an X or Z
with a U residue as defined in the legend below. The invention
relates to pharmaceutical compositions comprising any analog of
Table 1 or a functional fragments thereof, pharmaceutical salts
thereof, and a pharmaceutical acceptable carrier. The invention
relates to methods of treating and/or preventing a metabolic
disorder by administration of any pharmaceutical compositions
disclosed herein comprising any analog of Table 1 or a functional
fragments thereof, or pharmaceutical salts thereof, and a
pharmaceutical acceptable carrier.
TABLE-US-00005 TABLE 1 Amino Acid Sequences from which the analogs
are derived YBEGT FTSDY SIYLD KQAAB EFVNW LLAG YBEGT FTSDY SiYLD
KQAAB EFVNW LLAG YBEGT FTSDY SIYLD kQAAB EFVNW LLAG YBEGT FTSDY
SIYLD KQAaB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB EFvNW LLAG YBEGT
FTSDY SIYLD KQAAB EFVNW lLAG YBEGT FTSDY SIYLD KQAAB EFVNW LlAG
YBEGT FTSDY SIYLD KQAAb EFVNW LLAG YBEGT FTSDY SIYLD KqAAB EFVNW
LLAG YBEGT FTSDY SIyLD KQAAB EFVNW LLAG YBEGT FTSDY SIYLd KQAAB
EFVNW LLAG YBEGT FTSDY SIYlD KQAAB EFVNW LLAG YBEGT FTSDY SIYLD
KQaAB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB eFVNW LLAG YBEGT FTSDY
SIYLD KQAAB EfVNW LLAG YBEGT FTSDY SIYLD KQAAB EFvNW LLAG YBEGT
FTSDY SIYLD KQAAB EFVnW LLAG YBEGT FTSDY SIYLD KQAAB EFVNw LLAG
YBEGT FTSDY SIYLD KQAAB EFVNW LLaG YBEGT FTSDY SIYLD KQAAB EFVNW
LLAG YBEGT FTSDY SIYLD KQAAB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB
EFVNW LLAG YBEGT FTSDY SIYLD KQAAB EFVNW LLAG YBEGT FTSDY SIYLD
KQAAB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB EFVNW LLAG YBEGT FTSDY
SIYLD KQAAB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB EFVNW LLAG YBEGT
FTSDY SIYLD KQAAB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB EFVNW LLAG
YBEGT FTSDY SIYLD KQAAB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB EFVNW
LLAG YBEGT FTSDY SXYLD ZQAXB EFXNW XLAG YBEGT FTSDY SIYLD ZQAXB
EFXNW XLAG YBEGT FTSDY SIYXD KXAAB XFVZW LLXG YBEGT FTSDY SIYLD
KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KQAAB EFVNW LLAGG PSSGA PPPSK
YBEGT FTSDY SIYLD KQAAB EFVNW LLAGG PSSGA PPPSK YBEGT FTSDY SIYLD
KQAAB EFVNW LLAGG PSSGA PPPSK YBEGT FTSDY SIYLD KQAAB EFVNW LLAGG
PSSGA PPPSK YBEGT FTSDY SIYLD KQAAB EFVNW LLAGG PSSGA PPPSK YBEGT
FTSDY SIYLD KQAAB EFVNW LLAGG PSSGA PPPSK YBEGT FTSDY SIYLD KQAAB
EFVNW LLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA
PPPSK YBEGT FTSDY SIYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY
SXYLD KQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAAB EFXNW
XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFVNW XLAGG PSSGA PPPSK
YBEGT FTSDY SXYLD ZQAXB EFXNW LLAGG PSSGA PPPSK YBEGT FTSDY SXYLD
ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG
PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT
FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB
EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA
PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY
SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW
XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK
YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD
ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG
PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT
FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB
EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA
PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY
SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW
XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK
YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD
ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG
PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFXNW LLAGG PSSGA PPPSK YBEGT
FTSDY SIYLD KQAAB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB EFVNW LLAG
YBEGT FTSDY SIYLD KQAAB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB EFVNW
LLAG YBEGT FTSDY SIYLD KQAAB EFVNW LLAG YBEGT FTSDY SIYLD KQAAB
EFVNW LLAG YBEGT FTSDY SXYLD ZQAXB EFXNW XLAG YBEGT FTSDY SIYLD
ZQAXB EFXNW XLAG YBEGT FTSDY SIYXD KXAAB XFVZW LLXG YBEGT FTSDY
SIYLD KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KXAAB XFVZW LLXG YBEGT
FTSDY SIYLD KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KXAAB XFVZW LLXG
YBEGT FTSDY SIYLD KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KXAAB XFVZW
LLXG YBEGT FTSDY SIYLD KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KXAAB
XFVZW LLXG YBEGT FTSDY SIYLD KXAAB XFVZW LLXG YBEGT FTSDY SIYLD
KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KXAAB XFVZW LLXG YBEGT FTSDY
SIYLD KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KXAAB XFVZW LLXG YBEGT
FTSDY SIYLD KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KXAAB XFVZW LLXG
YBEGT FTSDY SIYLD KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KXAAB XFVZW
LLXG YBEGT FTSDY SIYLD KXAAB XFVZW LLXG YBXGT FXSDX SIYXD KXAAB
XFVZW LLXG YBXGT FXSDX SIYXD KXAAB XFVZW LLXG YBUGT FXSDX SIYXD
KXAAB XFVZW LLXG YBXGT FUSDX SIYXD KXAAB XFVZW LLXG YBXGT FXSDU
SIYXD KXAAB XFVZW LLXG YBXGT FXSDX SIYXD KXAAB UFVZW LLXG YBUGT
FUSDX SIYXD KXAAB XFVZW LLXG YBUGT FUSDX SIYXD KXAAB UFVZW LLXG
YBXGT FUSDX SIYXD KXAAB UFVZW LLXG YBUGT FUSDX SIYXD KXAAB UFVZW
LLXG YBEGT FTSDY SIYLD KUAAB XFVZW LLXG YBXGT FXSDX SIYXD KUAAB
XFVZW LLXG YBXGT FXSDX SIYXD KUAAB XFVZW LLXG YBUGT FXSDX SIYXD
KUAAB XFVZW LLXG YBXGT FUSDX SIYXD KUAAB XFVZW LLXG YBXGT FXSDU
SIYXD KUAAB XFVZW LLXG YBXGT FXSDX SIYXD KUAAB UFVZW LLXG YBUGT
FUSDX SIYXD KUAAB XFVZW LLXG YBUGT FUSDX SIYXD KUAAB UFVZW LLXG
YBXGT FUSDX SIYXD KUAAB UFVZW LLXG YBUGT FUSDX SIYXD KUAAB UFVZW
LLXG YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK
YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB
EFVNWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK
YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDKQAAB
EFVNWLLAGG PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK
YBQGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB
EFVCWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK
YBEGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB
EFVCWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK
YBEGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB
EFVNWLLAGG PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK
YBEGTFTSDK SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDEQAAK
EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDEQAAK EFVNWLLAGG PSSGAPPPSK
YBQGTFTSDY SIYLDEQAAK EFVNWLLAGG PSSGAPPPSK YBQGTFTSDY SIYLDBQAAK
EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDBQAAQ EFVNWLLAGG PSSGAPPPSC
YBQGTFTSDY SIYLDBQAAK EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDBQAAQ
EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDBQAAB EFVNWLLAGG PSSGAPPPSC
YBQGTFTSDY SIYLDEQAAB EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDKQAAB
EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSC
YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDKQAAB
EFVCWLLAG YBQGTFTSDY SIYLDEQAAB EFVCWLLAG YBQGTFTSDY SIYLDSQAAB
EFVCWLLAG YBQGTFTSDY SIYLDKQAAB EFVNWLLAG YBEGTFTSDY SIYLDKQAAB
EFVKWLLAGG PSSGAPPPS YBEGTFTSDY SIYLDKQAAB EFVKWLLAGG PSSGAPPPS
YBEGTFTSDY SIYLDKQAAB EFVKWLLAGG PSSGAPPPS YBEGTFTSDY SIYLDKQAAB
EFVKWLLAGG PSSGAPPPS YBEGTFTSDK SIYLDKQAAB EFVNWLLAGG PSSGAPPPS
YBEGTFTSDK SIYLDKQAAB EFVNWLLAGG PSSGAPPPS YBEGTFTSDK SIYLDKQAAB
EFVNWLLAGG PSSGAPPPS YBEGTFTSDK SIYLDKQAAB EFVNWLLAGG PSSGAPPPS
YBQGTFTSDY SKYLDEQAAB EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDBQAAB
EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDBQAAB EFVNWLLAGG PSSGAPPPSC
YBQGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB
EFVCWLLAG YBEGTFTSDK SIYLDKQAAB EFVNWLLAG YBEGTFTSDK SIYLDKQAAB
EFVNWLLAG YBEGTFTSDK SIYLDKQAAB EFVNWLLAG YBEGTFTSDK SIYLDKQAAB
EFVNWLLAG YBQGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBQGTFTSDY
SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB EFVCWLLAGG
PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBQGTFTSDY
SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB EFVCWLLAGG
PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBQGTFTSDY
SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDEQAAK EFVNWLLAGG
PSSGAPPPSC YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSC YBEGTFTSDY
SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB EFVCWLMNGG
PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB EFVCWLMNGG PSSGAPPPSK YBEGTFTSDY
SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB EFVCWLLAGG
PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBEGTFTSDY
SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK YBQGTFTSDY SIYLDKQAAB EFVNWLLAGG
PSSGAPPPSK YBQGTFSSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSC YBQGTFBSDY
SIYLDKQAAB EFVNWLLAGG PSSGAPPPSC YBQGTFTSDY SIYLDKQAAB EFVCWLLAGG
PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSK YBEGTFTSDY
SIYLDKQAAB EFVCWLLAGG PSSGAPPPSB YBEGTFTSDY SIYLDKQAAB EFVCWLLAGG
PSSGAPPPSB YBEGTFTSDY SIYLDKQAAB EFVCWLLAGG PSSGAPPPSB YBEGTFTSDY
SIYLDKQAAB EFVCWLLAGG PSSGAPPPSB YBEGTFTSDK SIYLDKQAAB EFVCWLLAGG
PSSGAPPPS YBEGTFTSDK SIYLDKQAAB EFVCWLLAGG PSSGAPPPS YBEGTFTSDY
SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK C YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG
PSSGAPPPSK C YBEGTFTSDK SIYLDKQAAB EFVCWLLAGG PSSGAPPPS YBEGTFTSDY
SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK C YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG
PSSGAPPPSK C HBQGTFTSDY SKYLDEQAAK EFICWLMNGG PSSGAPPPSK YBEGTFTSDY
SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK C YBQGTFTSDY SIYLDKQAAB EFVNWLMNGG
PSSGAPPPSK YBQGTFISDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK YBQGTFISDY
SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG
PSSGAPPPSK C YBEGTFTSDY SIYLDKQAAB EFVNWLLAGG PSSGAPPPSK C
[0391] For purposes of interpreting Table 1, please refer to the
following legend:
[0392] Any bolded and underlined letter=a beta amino acid with the
side chain equivalent in structure to the side chain of the
alpha-amino acid assigned to the one-letter code in bold or a Z or
X, wherein x=ACPC or ACHC; z=APC or AHC
Ac--Acylation
[0393] p-Cl-dF=para-Chlorine, D-Phenylalanine 4cl=Chlorinated
Phenylalaine .sub.dF=para-Chlorine, D-Phenylalanine
.sub.dR=D-Arginine .sub.dY=D-Tyrosine .sub.dA=D-Alanine
.sub.hR=homoarginine pY=Phosphoroylated Tyrosine pS=Phosphoroylated
Serine pE=Pyroglutamic acid
PEG=Polyetheythlene Glycol
[0394] PEG{number kD}=Polyetheythlene Glycol with a molecular
weight near {number} in kilodaltons.
Nle=Noraleucine
N.sub.le=Noraleucine
[0395] Y.sub.m=methoxy-tyrosine. Y.sub.M=methoxy-tyrosine.
K.sub.m=methalyated-lysine. B or Aib=.alpha.-aminoisobutyric
acid
Abu=ALPHA-AMINOBUTYRIC ACID
[0396] Gab=.gamma.-aminobutyric acid;
Dip=.beta.,.beta.-diphenyl-L-alanine; *=indicates cyclization
between residues (lactam ring) dHis=D-His w=D-Tryptophan or
beta-tryptophan Dnp=di-nitro-phenol Mca=methoxycoumarin 4 acetic
acid Sar=sarcosine Sta=statine
Step=Stearyl
[0397] Pyr=pyroglutamic acid Fam=carboxyfluoresceine
LC=--(NH.sub.2--(CH.sub.2).sub.5--C.dbd.O)--
[0398] TAMRA=carboxytetramethylrhodamine T*=N-acetyl galactosamine
labeled Thr NH.sub.2=amidation of carboxy terminus Orn=ornithine
K(W)=Trp residue which is coupled to the side chain of a Lys
Y(OMe)=methylated Tyrosine Cit=citrulline C6=hexanol
##STR00032##
Nva=Norvaline
x or X=ACPC or ACHC
z or Z=APC or AHC
[0399] In some embodiments, analogs of the present invention
(including any polypeptide sequence identified in Tables 1 are
either be N-terminal acylated or an N-terminal free-amine. In some
embodiments, analogs of the present invention are 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.
[0400] 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 GIP/GLP-1 Chimeric Polypeptides
[0401] This prophetic example describes how the polypeptide analogs
may be designed prior to manufacture. The sequence of a
representative glucagon 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 30" of the sequence below is the
C-terminal threonine.
HSQGT FTSDY SKYLD SRRAQ DFVQW LMNT
[0402] A family of analogues were prepared, each containing a
single alpha amino acid replacement to .beta..sup.3 replacement as
identified in the sequences below. Each .beta..sup.3-amino acid
residue will bear the side chain of the .alpha.-amino acid found at
that site in the glucagon-like sequence. Thus, for example,
analogues that contain a 13-residue at position 12 of the sequence
will have .beta..sup.3-homoisoleucine at this position, in place of
the isoleucine at position 12 of sequence. Additional analogues
will be prepared are shown below; the positions indicated with bold
and underlined letters are those at which .alpha.-to-.beta..sup.3,3
replacement has occurred.
[0403] Design Scheme 1. (Prophetic)
[0404] A family of analogues will be prepared, each containing a
single alpha amino acid replacement to .beta..sup.3 replacement as
identified in the sequences below. Each .beta..sup.3-amino acid
residue will bear the side chain of the .alpha.-amino acid found at
that site in the glucagon-like sequence. Thus, for example,
analogues that contain a .beta.-residue at position 12 of the
sequence will have .beta..sup.3-homoisoleucine at this position, in
place of the isoleucine at position 12 of sequence. Additional
analogues will be prepared are shown below; the positions indicated
with bold and underlined letters are those at which
.alpha.-to-.beta..sup.3,3 replacement has occurred.
[0405] Bolded and underlined residues indicate beta amino acid
substitution.
TABLE-US-00006 YBEGT FTSDY SIYLD KQAAB EFVNW LLAGG PSSGA PPPSK
YBEGT FTSDY SIYLD KQAAB EFVNW LLAGG PSSGA PPPSK YBEGT FTSDY SIYLD
KQAAB EFVNW LLAGG PSSGA PPPSK YBEGT FTSDY SIYLD KQAAB EFVNW LLAGG
PSSGA PPPSK YBEGT FTSDY SIYLD KQAAB EFVNW LLAGG PSSGA PPPSK YBEGT
FTSDY SIYLD KQAAB EFVNW LLAGG PSSGA PPPSK
Beta Amino Acids C
[0406] Basic residues replaced by either APC or AHC (z) and/or
other residues replaced with either ACHC or ACPC (x). These
substitutions (from beta homo amino acid to appropriate cyclic
derivative) may or may not be necessary in totality, these
sequences represent the fully-substituted extreme one may choose to
use.
[0407] Bolded and underlined residues indicate beta amino acid
substitution.
TABLE-US-00007 YBEGT FTSDY SXYLD ZQAXB EFXNW XLAGG PSSGA PPPSK
YBEGT FTSDY SIYLD ZQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD
KQAXB EFXNW XLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAAB EFXNW XLAGG
PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB EFVNW XLAGG PSSGA PPPSK YBEGT
FTSDY SXYLD ZQAXB EFXNW LLAGG PSSGA PPPSK YBEGT FTSDY SXYLD ZQAXB
EFXNW XLAG YBEGT FTSDY SIYLD ZQAXB EFXNW XLAG YBEGT FTSDY SIYXD
KXAAB XFVZW LLXG YBEGT FTSDY SIYLD KXAAB XFVZW LLXG
[0408] In each of sequences above, at least one 0-3 residue has
been replaced by a cyclic or heterocyclic residue. In some
embodiments, based upon the above sequences, X=ACPC OR ACHC, Z=APC
OR AHC; uncharged side chains replaced by ACPC OR ACHC, basic side
chains replaced by APC OR AHC, 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.
Design Scheme 2 (not Prophetic):
[0409] A family of analogues were prepared, each containing a
single alpha amino acid replacement to .beta..sup.3 replacement as
identified in the sequences below. Each .beta..sup.3-amino acid
residue will bear the side chain of the .alpha.-amino acid found at
that site in the glucagon-like sequence. Thus, for example,
analogues that contain a .beta.-residue at position 28 of the
sequence will have .beta..sup.3-homoalanine at this position, in
place of the alanine at position 28 of sequence. Additional
analogues prepared are shown below; the positions indicated with
bold and underlined letters are those at which
.alpha.-to-.beta..sup.3,3 replacement has occurred.
TABLE-US-00008 YBEGT FTSDY SIYLD KQAAB EFVNW LLAG (denoted 2000 -
all alpha amino acids) YBEGT FTSDY SIYLD KQAAB EFVNW LLAG (denoted
2001) YBEGT FTSDY SIYLD KQAAB EFVNW LLAG (denoted 2002) YBEGT FTSDY
SIYLD KQAAB EFVNW LLAG (denoted 2003) YBEGT FTSDY SIYLD KQAAB EFVNW
LLAG (denoted 2004) YBEGT FTSDY SIYLD KQAAB EFVNW LLAG (denoted
2005) YBEGT FTSDY SIYLD KQAAB EFVNW LLAG (denoted 2006) YBEGT FTSDY
SXYLD ZQAXB EFXNW XLAG (denoted 2007) YBEGT FTSDY SIYLD ZQAXB EFXNW
XLAG (denoted 2008) YBEGT FTSDY SIYXD KXAAB XFVZW LLXG (denoted
2009) YBEGT FTSDY SIYLD KXAAB XFVZW LLXG (denoted 2010)
Example 2
Structural Analysis of GIP and GLP-1 Polypeptides (Prophetic)
[0410] This prophetic example describes how the polypeptide analogs
of this invention may be characterized after manufacture through
structural conformational assays such as circular dichrosim (CD)
and Nuclear magnetic resonance (NMR).
[0411] 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.
[0412] 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.
[0413] 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 GIP and GLP-1 Polypeptides in Solution
(Prophetic)
[0414] 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.
[0415] 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.
[0416] 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.
[0417] 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.
[0418] 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.
[0419] 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.
[0420] 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.
[0421] 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.
[0422] 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.
[0423] 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.
[0424] 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)).
[0425] 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. Dataanalysis 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 300 .mu.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.n+C.sub.n+1)/2))(t.sub.n+1-t.sub.n)
{in (.mu.g/mL)h} 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.
[0426] 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.
Stability Analysis of GIP and GLP-1 Polypeptides in Solution (not
Prophetic)
[0427] Human liver microsomes were prepared by Absorption Systems.
A reaction mixture, minus NADPH, was prepared as described below.
About 1 milligram of the 2010 test compound originally in powdered
form was suspended in DMSO prior to addition to a reaction mixture.
In parallel, a 2000 alpha test compound The test compound was added
into the reaction mixture (0.5 mg/mL human liver microsomes; 100 mM
potassium phosphate; 5 mM Magnesium chloride) at a final
concentration of 1 .mu.M. An aliquot of the reaction mixture
(without cofactor) was incubated in a shaking water bath at
37.degree. C. for 3 minutes. The control compound, testosterone,
was run simultaneously with the test compound in a separate
reaction. The reaction was initiated by the addition of NADPH
cofactor (1 mM NADPH), and the mixture was then incubated in a
shaking water bath at 37.degree. C. Aliquots (100 .mu.L) were
withdrawn at 0, 10, 20, 30, and 60 minutes for the test compound
and 0, 10, 30, and 60 minutes for testosterone. Test compound and
testosterone samples were immediately combined with 400 .mu.L of
ice-cold 50/50 acetonitrile/dH.sub.2O containing 0.1% formic acid
and internal standard to terminate the reaction. The samples were
then mixed and centrifuged to precipitate microsomal proteins.
Testosterone samples were assayed by LC-MS/MS using electrospray
ionization on a PE SCIEX API 3000 according to the manufacturer's
instructions. A thermo BDS Hypersil C18 column (30.times.2.0 mm; 3
.mu.m) was used for chromatography at 300 .mu.L/minute with an
aqueous reservoir of 90% water and 10% buffer and an organic
reservoir of 90% acetonitrile with 10% buffer (each 25 mM ammonium
formate buffer at pH of 3.5). Test compound samples were analyzed
by orbitrap. The peak area response ratio to internal standard
(PARR) of the compounds at 10, 20, 30, and 60 minutes was compared
to the PARR at time 0 to determine the percent of test compound
remaining at each timepoint. After the final time point,
fluorimetry is used to confirm the addition of NADPH to the
reaction mixture. Half-life was normalized of control using
internal acceptance criteria.
[0428] Below is a table of results that measures the percent of
remaining test compound at various time points when the compound is
in contact with human liver microsomes. The mass spectrometry
measurements of compound were taken at 0, 10, 20, 30, and 60
minutes after incubation of the compound with human liver
microsomes at 5 mg/ml in solution at 37.degree. C.
TABLE-US-00009 Control 2010 2000 peptide Hybridtide (% of mass (%
of mass Time Point remaining in remaining in (mins.) solution)
solution) Testosterone 0 mins. 100 100 100 10 mins. 95 98 53 20
mins. 78 95 30 mins. 72 87 13 60 mins. 50 73 4.8 Half life 58
>60 13.6 (mins) CL.sub.int 0.024 0.011 0.1
Half-life was calculated based upon a t.sub.1/2=0.693/k, where k is
the elimination rate constant based upon the slope of the plot of
natural logarithm percent remaining versus incubation time.
Intrinsic clearance (CL.sub.int) was calculated based upon
CL.sub.int=k/P, where k is the elimination rate constant and P is
the protein concentration in the incubation. The results
demonstrate that the beta amino acid containing peptide sequence
had a half life greater than 60 minutes as compared to the alpha
peptide whose hal-life was calculated to be a total of 58
minutes.
Stability Analysis of GIP and GLP-1 Polypeptides in Human Plasma
(not Prophetic)
[0429] Studies of the 2010 peptide were carried out in human
plasma. All plasma was obtained from Bioreclamation and collected
on sodium heparin. DMSO stocks were first prepared for the test
compounds. Aliquots of the DMSO solutions were dosed into 1 mL of
plasma, which had been pre-warmed to 37.degree. C., at a final test
compound concentration of 1 .mu.M. The vials were kept in a
benchtop Thermomixer.RTM. for the duration of the experiment.
Aliquots (100 .mu.L) were taken at each timepoint (0, 15, 30, 60,
and 120 minutes) and added to 96-well plates which had been
pre-filled with 300 .mu.L of acetonitrile. Samples were stored at
4.degree. C. until the end of the experiment. After the final
timepoint was sampled, the plate was mixed and then centrifuged at
3,000 rpm for 10 minutes. Aliquots of the supernatant were removed,
diluted 1:1 into distilled water, and analyzed by LC-MS/MS.
[0430] Below is a table of data describing the stability of
compounds exposed to human plasma with aliquot of compound
dissolved in DMSO solution at 37.degree. C. The pH of the plasma
solution was adjusted to 7.4 and single replicants of aliquot were
taken at 0, 15, 30, 60 and 120 minutes. LC-MS/MS was used to
determine the percent mass of compound remaining in solution (%
remaining).
TABLE-US-00010 2010 2000 Hybridtide (% of mass (% of mass Time
Point remaining in remaining in (mins.) solution) solution) 0 mins.
100 100 15 mins. 101 96 30 mins. 99 103 60 mins. 95 99 120 mins. 98
97
[0431] The results indicate that both the alpha-containing peptide
and the beta-amino acid containing peptide had serum-half lives
over 120 minutes in length.
Example 4
Functional Analysis
[0432] In Vitro Binding Assay (not prophetic): 5 analogs (compounds
labeled 2001, 2004, 2005, 2008 and 2010 as identified above) in
appropriate phosphate buffer was at pH of 7.5 were exposed to a
functional assay in parallel with wild-type GIP and GLP-1 proteins
as well as positive control ligand for GLP-1 Receptor (exedin 4).
cAMP Hunter cell lines expressing GIP receptor (GIPR) and GLP-1
receptor (GLP1R) 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.
[0433] 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 GIPR1 and GLP1R were exposed to
serial dilutions of wild-type GIP anf GLP-1, respectively, and
separate samples of the same type of cells were exposed to serial
dilutions of glucagon dual agonist analogues (compounds labeled
2001, 2004, 2005, 2008 and 2010) to determine EC.sub.50 values of
the analogue as compared to wild-type ligands (see table below).
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).
TABLE-US-00011 Assay Assay Assay Result Max Compound Name Name
Format Target Type RC50 (uM) Hill Curve Bottom Curve Top Response
GIP cAMP Agonist GIPR EC50 0.00010961 1.23 -4.3 90.9 96.017 2001
cAMP Agonist GIPR EC50 >1 16.467 2004 cAMP Agonist GIPR EC50
0.048441 1.53 -0.8 99.1 99.121 2005 cAMP Agonist GIPR EC50 0.018223
1.05 -2.6 96.3 99.224 2008 cAMP Agonist GIPR EC50 0.12211 2.32 -0.6
82.8 82.156 2010 cAMP Agonist GIPR EC50 0.0030692 1.59 -0.3 85.5
96.948 GLP1 cAMP Agonist GIPR EC50 >1 2.6573 Exedin 4 cAMP
Agonist GLP1R EC50 5.32E-05 4.6 1.6 92.3 96.99 2001 cAMP Agonist
GLP1R EC50 >1 36.704 2004 cAMP Agonist GLP1R EC50 >1 2.6765
2005 cAMP Agonist GLP1R EC50 0.00044512 3.92 1.3 91.1 95.666 2008
cAMP Agonist GLP1R EC50 0.0071748 3.47 0.9 84.4 84.523 2010 cAMP
Agonist GLP1R EC50 0.0005748 2.9 0.4 82.4 82.132 GLP1 cAMP Agonist
GLP1R EC50 4.56E-05 2.71 2 96.5 99.578
Results of the functional data are summarized in FIGS. 1 and 2.
FIG. 1 depicts the relative EC50 calculations for the
beta-containing peptides named above. Relative activities of the
glucagon analogs are depicted by varied concentration versus
luminescence readings in contact with cells expressing the GIP
receptor. The data demonstrate that beta-amino acid containing
analogs of can bind GIP receptor at concentrations similar to the
concentration of native GIP control. FIG. 2 depicts the relative
EC.sub.50 calculations for activity of the beta-containing peptides
named above in contact with the GLP-1 receptor. Relative activities
of the glucagon analogs are depicted by varied concentration via
luminescence readings. The data demonstrate that beta-amino acid
containing analogs of can bind GLP-1 receptor at concentrations
similar to the concentration of native GLP-1 control.
In Vitro Binding Assay 2 (Direct Binding ELISA(Prophetic))
[0434] Mouse, rat, rabbit or human albumin (Sigma) will be
immobilized onto NUNC Maxisorp 96-well plates at 2 mg/ml overnight
at 4 degrees C. The plates will be blocked with binding buffer
(PBS, 0.5% ovalbumin and 0.05% Tween-20) for 1 h at 25 degrees C.
blood protein binding polypeptide variants will be serially diluted
in binding buffer and added at 100 ml per well to the immobilized
albumin for 30 m at 25.degree. C. Unbound blood protein binding
polypeptide variant will be removed by washing wells with 0.05%
PBS/Tween-20 and bound blood protein binding polypeptide variant
will be detected with goat anti-human Fab'2-horseradish peroxidase
(HRP) for 1 h at 25 degrees C. Bound HRP was measured with a
solution of tetramethylbenzidine/H2O2. After 15 m, the reaction
will be quenched by the addition of 1 M phosphoric acid. The
absorbance at 450 nm will be read with a reference wavelength of
650 nm.
Solution Binding ELISA
[0435] A fixed concentration of GIP analog (determined in above
binding ELISA) will be incubated in solution with varying
concentrations of GIP receptor and/or GLP-1 receptor and/or
glucagon receptor. After at least a 2 h incubation at room
temperature, 100 ml of the reaction mixture will be transferred to
a GIP or GLP-1 or glucagon-coated ELISA plate to capture unbound
(free) GIP polypeptide variant. The Direct Binding ELISA, described
above, will then be used to determine the concentration of captured
GIP polypeptide variant.
Pharmacokinetic Studies in Mouse
[0436] In order to determine the in-vivo effects of the candidate
compounds, 1 month placebo-controlled study of 36 db/db mice to
determine obesity/diabetic end-points will be performed. Thirty six
(36) BKS.Cg-m+/+Leprdb/J (stock number 000642) male mice at the age
of 7-8 weeks will be transferred to our in vivo research laboratory
in Sacramento, Calif. The mice will be ear notched for
identification and housed in individually and positively ventilated
polycarbonate cages with HEPA filtered air at a density of 2-3 mice
per cage.
[0437] After 1 week of acclimation, mice will be randomly assigned
into 4 groups (n=9) according to body weights.
[0438] Group 1: Vehicle control
[0439] Group 2: Test 1
[0440] Group 3: Test 2
[0441] Group 4: Test 3
[0442] Mice will receive weekly subcutaneous injections of test
compound or vehicle for 4 weeks. Body weights and food intake will
be measured twice weekly. Mice will undergo DEXA scan to determine
body composition. After each dose, blood will be collected at pre
dose and at 4 hrs after dose. Each time, 50 .mu.l of blood will be
drawn by retro-orbital bleed. Plasma will be analyzed for glucose
or insulin levels.
[0443] Mice will be sacrificed at the end of 4 weeks. Terminal
blood will be collected, and analyzed to identify levels of
glucose, insulin, HbA1c, C-peptide, triglycerides and Cholesterol.
Pancreas will be collected, fixed and sent to a third party for
pancreatic 3-cell mass analysis.
[0444] The results of this study will provide significant insights
into the ability of the analogs to modulate key in-vivo parameters
for obesity and Type2 Diabetes. Typically, patients develop a
progressive form of insulin resistance accompanied by elevated:
blood glucose, weight, blood pressure, triglycerides and
HbA.sub.1c.
[0445] The following journal articles, which are herein
incorporated by reference, disclose sequences upon which the analog
may be designed: 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 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID
NOS: 159 <210> SEQ ID NO 1 <211> LENGTH: 29 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual Agonist 1
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 1 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser
Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp
Leu Leu Ala Gly 20 25 <210> SEQ ID NO 2 <211> LENGTH:
29 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 2 <400> SEQUENCE: 2 His Ser Gln Gly Thr Phe Thr Ser
Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe
Val Gln Trp Leu Met Asn Thr 20 25 <210> SEQ ID NO 3
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 3 <400> SEQUENCE: 3 Gln
Arg Leu Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp 1 5 10
15 Glu Asp Asp Phe 20 <210> SEQ ID NO 4 <211> LENGTH:
40 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 4 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 4 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser
Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp
Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser
Lys 35 40 <210> SEQ ID NO 5 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 5 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa
= AIB <400> SEQUENCE: 5 Ser Ile Tyr Leu Asp Lys Gln Ala Ala
Xaa Glu Phe Val Asn Trp Leu 1 5 10 15 Leu Ala <210> SEQ ID NO
6 <211> LENGTH: 10 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 6 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 6
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr 1 5 10 <210> SEQ ID
NO 7 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 7 <400> SEQUENCE: 7
Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys 1 5 10 <210>
SEQ ID NO 8 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 8 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Xaa = AIB <400>
SEQUENCE: 8 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala 1 5 10
<210> SEQ ID NO 9 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 9 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa = AIB <400>
SEQUENCE: 9 Leu Asp Lys Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu
Ala 1 5 10 15 <210> SEQ ID NO 10 <211> LENGTH: 16
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 10 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <400> SEQUENCE: 10 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 <210> SEQ ID NO 11
<400> SEQUENCE: 11 000 <210> SEQ ID NO 12 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 12 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Iso-leucine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 12
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 13 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 13 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Lysine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 13 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 14 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 14 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (19)..(19) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 14
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Xaa Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 15 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 15 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(23)..(23) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Valine
<400> SEQUENCE: 15 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Xaa Asn
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 16 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 16 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (26)..(26) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE: 16
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Xaa Leu Ala Gly 20 25
<210> SEQ ID NO 17 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 17 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(27)..(27) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Leucine <400> SEQUENCE: 17 Tyr Xaa Glu Gly Thr Phe Thr Ser
Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe
Val Asn Trp Leu Xaa Ala Gly 20 25 <210> SEQ ID NO 18
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 18 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- AIB <400>
SEQUENCE: 18 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr
Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu
Ala Gly 20 25 <210> SEQ ID NO 19 <211> LENGTH: 29
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 19 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Glutamine <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <400> SEQUENCE: 19 Tyr Xaa Glu Gly Thr
Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala
Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO
20 <211> LENGTH: 29 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 20 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 20 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Xaa Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 21 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 21 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Aspartic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 21
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Xaa Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 22 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 22 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Leucine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <400> SEQUENCE: 22 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val
Asn Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 23 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 23 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (18)..(18) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 23
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Xaa Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 24 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 24 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(21)..(21) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Glutamic Acid <400> SEQUENCE: 24 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Xaa
Phe Val Asn Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 25
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 25 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (22)..(22)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Phenylalanine
<400> SEQUENCE: 25 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Xaa Val Asn
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 26 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 26 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (24)..(24) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Asparagine <400> SEQUENCE: 26
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 27 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 27 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(25)..(25) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Tryptophan <400> SEQUENCE: 27 Tyr Xaa Glu Gly Thr Phe Thr Ser
Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe
Val Asn Xaa Leu Leu Ala Gly 20 25 <210> SEQ ID NO 28
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 28 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Alanine
<400> SEQUENCE: 28 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 29 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 29 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Iso-leucine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Lysine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Valine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (26)..(26) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE: 29
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5
10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly 20 25
<210> SEQ ID NO 30 <211> LENGTH: 58 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 30 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Glutamine <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (21)..(21) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Asparagine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (31)..(31) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (41)..(41) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Iso-leucine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (45)..(45) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Lysine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (48)..(48)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Alanine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (49)..(49) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (52)..(52) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Valine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (55)..(55) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE: 30
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5
10 15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly Tyr Xaa
Glu 20 25 30 Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
Gln Ala Xaa 35 40 45 Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly 50 55
<210> SEQ ID NO 31 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 31 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(13)..(13) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Tyrosine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Lysine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Valine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (27)..(27) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 31 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Xaa Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu
Phe Xaa Asn Trp Leu Xaa Ala Gly 20 25 <210> SEQ ID NO 32
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 32 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glutamine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Asparagine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (27)..(27) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 32 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Glu
Phe Val Xaa Trp Leu Xaa Ala Gly 20 25 <210> SEQ ID NO 33
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 33 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Iso-leucine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Aspartic Acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (19)..(19) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (22)..(22)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Phenylalanine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (29)..(29) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glycine <400> SEQUENCE: 33
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Xaa Lys 1 5
10 15 Gln Ala Xaa Xaa Glu Xaa Val Asn Trp Xaa Leu Ala Xaa 20 25
<210> SEQ ID NO 34 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 34 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Glutamine <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (21)..(21) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Asparagine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <400> SEQUENCE: 34 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa
Phe Val Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 35
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 35 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Leucine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (18)..(18) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Glutamic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (25)..(25) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Tryptophan <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(28)..(28) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Alanine <400> SEQUENCE: 35 Tyr Xaa Glu Gly Thr Phe Thr Ser
Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Gln Xaa Ala Xaa Xaa Phe
Val Asn Xaa Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 36
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 36 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Aspartic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (18)..(18) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (22)..(22) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Phenylalanine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (25)..(25) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Tryptophan <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(29)..(29) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Glycine <400> SEQUENCE: 36 Tyr Xaa Glu Gly Thr Phe Thr Ser
Asp Tyr Ser Ile Tyr Leu Xaa Lys 1 5 10 15 Gln Xaa Ala Xaa Glu Xaa
Val Asn Xaa Leu Leu Ala Xaa 20 25 <210> SEQ ID NO 37
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 37 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Aspartic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (18)..(18) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (22)..(22) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Phenylalanine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (25)..(25) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Tryptophan <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(29)..(29) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Glycine <400> SEQUENCE: 37 Tyr Xaa Glu Gly Thr Phe Thr Ser
Asp Tyr Ser Ile Tyr Leu Xaa Lys 1 5 10 15 Gln Xaa Ala Xaa Glu Xaa
Val Asn Xaa Leu Leu Ala Xaa 20 25 <210> SEQ ID NO 38
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 38 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 38 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly 20 25 <210> SEQ ID NO 39 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 39 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (16)..(16) <223> OTHER
INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 39 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly 20 25
<210> SEQ ID NO 40 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 40 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 40 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 41 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 41 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 41 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 42 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 42 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Iso-leucine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Lysine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Valine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (26)..(26) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE: 42
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5
10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 43 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 43 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Lysine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Valine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (27)..(27) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 43 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Xaa Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu
Phe Xaa Asn Trp Leu Xaa Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 44 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 44 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tyrosine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = Beta-3
homo- AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Asparagine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (27)..(27) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE:
44 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys
1 5 10 15 Xaa Ala Ala Xaa Glu Phe Val Xaa Trp Leu Xaa Ala Gly Gly
Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 45 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 45 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Iso-leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Aspartic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (22)..(22)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Phenylalanine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 45 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Xaa Tyr Leu Xaa Lys 1 5 10 15 Gln Ala Xaa Xaa Glu
Xaa Val Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 46 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 46 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glutamic Acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (24)..(24) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Asparagine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Alanine
<400> SEQUENCE: 46 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val Xaa
Trp Leu Leu Xaa Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 47 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 47 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Aspartic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (18)..(18) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (22)..(22)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Phenylalanine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (25)..(25) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Tryptophan <400> SEQUENCE: 47 Tyr Xaa Glu Gly Thr Phe
Thr Ser Asp Tyr Ser Ile Tyr Leu Xaa Lys 1 5 10 15 Gln Xaa Ala Xaa
Glu Xaa Val Asn Xaa Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly
Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 48 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 48 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (18)..(18)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Alanine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glutamic Acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (25)..(25) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tryptophan <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Alanine
<400> SEQUENCE: 48 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Gln Xaa Ala Xaa Xaa Phe Val Asn
Xaa Leu Leu Xaa Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 49 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 49 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 49 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 50 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 50 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Iso-leucine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 50 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
51 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 51 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Lysine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (19)..(19) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 51 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 52 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 52 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Alanine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 52 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 53 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 53 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Valine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (26)..(26) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <400>
SEQUENCE: 53 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr
Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu
Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40
<210> SEQ ID NO 54 <211> LENGTH: 40 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 54 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 54 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 55 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 55 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tyrosine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 55 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 56 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 56 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Aspartic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 56 Tyr Xaa Glu Gly Thr Phe Thr Ser Xaa Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 57 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 57 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Serine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 57 Tyr Xaa Glu Gly Thr Phe Thr Xaa Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 58 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 58 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 58 Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 59 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 59 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Phenylalanine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 59 Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 60 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 60 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 60 Tyr Xaa Glu Gly Xaa Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 61 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 61 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Glycine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 61 Tyr Xaa Glu Xaa Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 62 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 62 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Glutamic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 62 Tyr Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 63 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 63 <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 63 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 64 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 64 <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Tyrosine <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 64 Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 65 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 65 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Glutamic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Threonine <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 65 Tyr Xaa
Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
66 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 66 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <400> SEQUENCE: 66 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Xaa Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 67 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 67 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (29)..(29) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Glycine <400> SEQUENCE:
67 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Xaa Gly
Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 68 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 68 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (30)..(30) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glycine <400> SEQUENCE: 68 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Xaa Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 69 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 69 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (31)..(31) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Proline <400> SEQUENCE:
69 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly
Xaa Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 70 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 70 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (32)..(32) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Serine <400> SEQUENCE: 70 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Xaa 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 71 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 71 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (33)..(33) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Serine <400> SEQUENCE:
71 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly
Pro Ser 20 25 30 Xaa Gly Ala Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 72 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 72 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (34)..(34) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glycine <400> SEQUENCE: 72 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Xaa Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 73 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 73 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (35)..(35) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Alanine <400> SEQUENCE:
73 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly
Pro Ser 20 25 30 Ser Gly Xaa Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 74 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 74 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (36)..(36) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Proline <400> SEQUENCE: 74 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Xaa Pro Pro Ser Lys 35 40 <210> SEQ ID NO 75 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 75 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (37)..(37) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Proline <400> SEQUENCE:
75 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly
Pro Ser 20 25 30 Ser Gly Ala Pro Xaa Pro Ser Lys 35 40 <210>
SEQ ID NO 76 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 76 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (38)..(38) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Proline <400> SEQUENCE: 76 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Xaa Ser Lys 35 40 <210> SEQ ID NO 77 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 77 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (39)..(39) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Serine <400> SEQUENCE:
77 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly
Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Xaa Lys 35 40 <210>
SEQ ID NO 78 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 78 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (40)..(40) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Lysine <400> SEQUENCE: 78 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Xaa 35 40 <210> SEQ ID NO 79 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 79 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Threonine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Serine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 79 Tyr Xaa Glu Gly Xaa Phe Thr
Xaa Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 80 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 80 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Iso-leucine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Aspartic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (22)..(22) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Phenylalanine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE:
80 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Xaa Lys
1 5 10 15 Gln Ala Xaa Xaa Glu Xaa Val Asn Trp Xaa Leu Ala Gly 20 25
<210> SEQ ID NO 81 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 81 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Lysine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 81 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 82 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 82 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Aspartic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 82 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Xaa Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 83 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 83 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 83 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 84 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 84 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tyrosine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 84 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 85 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 85 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Iso-leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 85 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Xaa Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 86 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 86 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Serine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 86 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Xaa Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 87 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 87 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(10)..(10) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Tyrosine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 87 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Xaa Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 88 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 88 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Aspartic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 88 Tyr Xaa
Glu Gly Thr Phe Thr Ser Xaa Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 89 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 89 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Serine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 89 Tyr Xaa Glu Gly Thr Phe Thr Xaa Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 90 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 90 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Threonine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 90 Tyr Xaa
Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 91 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 91 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(6)..(6) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Phenylalanine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (17)..(17) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 91 Tyr Xaa
Glu Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 92 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 92 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Threonine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 92 Tyr Xaa Glu Gly Xaa Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 93 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 93 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glycine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 93 Tyr Xaa
Glu Xaa Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 94 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 94 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 94 Tyr Xaa Xaa Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 95 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 95 <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 95 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 96 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 96 <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(1)..(1) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 96 Xaa Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 97 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 97 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Tyrosine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 97 Tyr Xaa
Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 98 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 98 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 98 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 99 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 99 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 99 Tyr Xaa
Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 100 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 100
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 100 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 101 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 101
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 101 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 102 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 102
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 102 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 103 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 103
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 103 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 104 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 104
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 104 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 105 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 105 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 105 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 106 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 106 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 106 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 107 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 107
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glutamic Acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Threonine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (17)..(17) <223> OTHER
INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 107 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 108 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 108 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 108 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 109 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 109 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 109 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 110 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 110 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 110 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 111 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 111
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 111 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 112 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 112 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 112 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 113 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 113
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 113 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 114 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 114 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 114 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 115 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 115 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 115 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 116 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 116
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 116 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 117 <211> LENGTH: 40 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 117
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 117 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Cys 35 40 <210> SEQ ID NO 118 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 118 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 118 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 119 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 119 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 119 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 120 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 120 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 120 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 121 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 121 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 121 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 122 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 122 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 122 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 123 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 123 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <400> SEQUENCE: 123 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val
Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro
Pro Ser Cys 35 40 <210> SEQ ID NO 124 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 124 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <400> SEQUENCE: 124 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val
Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro
Pro Ser Lys 35 40 <210> SEQ ID NO 125 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 125 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <400> SEQUENCE: 125 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val
Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro
Pro Ser Lys 35 40 <210> SEQ ID NO 126 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 126 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 126 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Cys 35 40 <210> SEQ ID NO 127 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 127 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 127 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Gln Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Cys 35 40 <210> SEQ ID NO 128 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 128 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 128 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Cys 35 40 <210> SEQ ID NO 129 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 129 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 129 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Cys 35 40 <210> SEQ ID NO 130 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 130 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 130 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Cys 35 40 <210> SEQ ID NO 131 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 131 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 131 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Cys 35 40 <210> SEQ ID NO 132 <211> LENGTH: 29
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 132 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 132 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 133 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 133 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <400> SEQUENCE: 133 Tyr Xaa Gln Gly
Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala
Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25 <210> SEQ
ID NO 134 <211> LENGTH: 29 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 134 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 134
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 135 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 135
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 135 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 136 <211>
LENGTH: 39 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 136 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <400> SEQUENCE: 136 Tyr Xaa Glu Gly
Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala
Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30
Ser Gly Ala Pro Pro Pro Ser 35 <210> SEQ ID NO 137
<211> LENGTH: 39 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 137 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 137
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> SEQ ID NO
138 <211> LENGTH: 39 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 138 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 138
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> SEQ ID NO
139 <211> LENGTH: 39 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 139 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 139
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> SEQ ID NO
140 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 140 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 140
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 141 <211> LENGTH: 29 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 141 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 141
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 142 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 142
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 142 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 143 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 143 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <400> SEQUENCE: 143 Tyr Xaa Gln Gly
Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala
Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30
Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 144
<211> LENGTH: 40 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 144 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 144
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 145 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 145 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 145
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 146 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 146 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 146
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 147 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 147 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 147
Tyr Xaa Gln Gly Thr Phe Ser Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 148 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 148 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 148
Tyr Xaa Gln Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 149 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 149 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (40)..(40)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 149
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 <210> SEQ
ID NO 150 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 150 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (40)..(40)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 150
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 <210> SEQ
ID NO 151 <211> LENGTH: 39 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 151 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 151
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> SEQ ID NO
152 <211> LENGTH: 39 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 152 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 152
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 <210> SEQ ID NO
153 <211> LENGTH: 41 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 153 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 153
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys Cys 35 40 <210>
SEQ ID NO 154 <211> LENGTH: 41 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 154
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 154 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys Cys 35 40 <210> SEQ ID NO 155 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 155 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <400> SEQUENCE: 155 His Xaa Gln Gly Thr Phe Thr Ser Asp
Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile
Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro
Pro Ser Lys 35 40 <210> SEQ ID NO 156 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 156 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 156 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 157 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 157 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 157 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 158 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 158 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 158 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 159 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: agonist analog
159 <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: X =
ACPC or ACHC or
4-Amino-1-(3-carboxypropanoyl)pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (4)..(4) <223> OTHER INFORMATION: Aib <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: X = ACPC or AHC or
4-Amino-1-(3-carboxypropanoyl)pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (8)..(8) <223> OTHER INFORMATION: X = APC or AHC or
(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: X = ACPC or ACHC or
(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid <400>
SEQUENCE: 159 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 1
5 10
1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 159
<210> SEQ ID NO 1 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 1 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <400>
SEQUENCE: 1 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu
Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala
Gly 20 25 <210> SEQ ID NO 2 <211> LENGTH: 29
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 2 <400> SEQUENCE: 2 His Ser Gln Gly Thr Phe Thr Ser
Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe
Val Gln Trp Leu Met Asn Thr 20 25 <210> SEQ ID NO 3
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 3 <400> SEQUENCE: 3 Gln
Arg Leu Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp 1 5 10
15 Glu Asp Asp Phe 20 <210> SEQ ID NO 4 <211> LENGTH:
40 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 4 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 4 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser
Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp
Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser
Lys 35 40 <210> SEQ ID NO 5 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 5 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa
= AIB <400> SEQUENCE: 5 Ser Ile Tyr Leu Asp Lys Gln Ala Ala
Xaa Glu Phe Val Asn Trp Leu 1 5 10 15 Leu Ala <210> SEQ ID NO
6 <211> LENGTH: 10 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 6 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 6
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr 1 5 10 <210> SEQ ID
NO 7 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 7 <400> SEQUENCE: 7
Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys 1 5 10 <210>
SEQ ID NO 8 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 8 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Xaa = AIB <400>
SEQUENCE: 8 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala 1 5 10
<210> SEQ ID NO 9 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 9 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa = AIB <400>
SEQUENCE: 9 Leu Asp Lys Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu
Ala 1 5 10 15 <210> SEQ ID NO 10 <211> LENGTH: 16
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 10 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <400> SEQUENCE: 10 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 <210> SEQ ID NO 11
<400> SEQUENCE: 11 000 <210> SEQ ID NO 12 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 12 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Iso-leucine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 12
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 13 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 13 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Lysine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 13 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 14 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 14 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(19)..(19) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <400> SEQUENCE: 14 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Val
Asn Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 15 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 15 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (23)..(23) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Valine <400> SEQUENCE: 15 Tyr
Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10
15 Gln Ala Ala Xaa Glu Phe Xaa Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 16 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 16 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Leucine <400> SEQUENCE: 16 Tyr Xaa Glu Gly Thr Phe Thr Ser
Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe
Val Asn Trp Xaa Leu Ala Gly 20 25 <210> SEQ ID NO 17
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 17 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (27)..(27)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Leucine
<400> SEQUENCE: 17 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Xaa Ala Gly 20 25 <210> SEQ ID NO 18 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 18 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- AIB <400> SEQUENCE: 18 Tyr
Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10
15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 19 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 19 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(17)..(17) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Glutamine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <400> SEQUENCE: 19 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Glu Phe Val
Asn Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 20 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 20 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tyrosine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 20
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 21 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 21 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(15)..(15) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Aspartic Acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <400> SEQUENCE: 21 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Xaa Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val
Asn Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 22 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 22 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 22
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 23
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 23 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (18)..(18)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Alanine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 23 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Xaa Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 24 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 24 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (21)..(21) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <400> SEQUENCE:
24 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys
1 5 10 15 Gln Ala Ala Xaa Xaa Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 25 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 25 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(22)..(22) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Phenylalanine <400> SEQUENCE: 25 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu
Xaa Val Asn Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 26
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 26 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Asparagine
<400> SEQUENCE: 26 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 27 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 27 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (25)..(25) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tryptophan <400> SEQUENCE: 27
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Xaa Leu Leu Ala Gly 20 25
<210> SEQ ID NO 28 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 28 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(28)..(28) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Alanine <400> SEQUENCE: 28 Tyr Xaa Glu Gly Thr Phe Thr Ser
Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe
Val Asn Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 29
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 29 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Iso-leucine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Lysine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (19)..(19) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Valine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 29 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly 20 25 <210> SEQ ID NO 30
<211> LENGTH: 58 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 30 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Leucine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glutamine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Glutamic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Asparagine <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(28)..(28) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (31)..(31) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (41)..(41) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Iso-leucine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (45)..(45) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Lysine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (48)..(48)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Alanine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (49)..(49) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (52)..(52) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Valine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (55)..(55) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE: 30
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5
10 15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly Tyr Xaa
Glu 20 25 30 Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
Gln Ala Xaa 35 40 45 Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly 50 55
<210> SEQ ID NO 31 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 31 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(13)..(13) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Tyrosine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Lysine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Valine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (27)..(27) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 31 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Xaa Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu
Phe Xaa Asn Trp Leu Xaa Ala Gly 20 25 <210> SEQ ID NO 32
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 32 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glutamine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Asparagine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (27)..(27) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 32 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Glu
Phe Val Xaa Trp Leu Xaa Ala Gly 20 25 <210> SEQ ID NO 33
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 33 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Iso-leucine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Aspartic Acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (19)..(19) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (22)..(22)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Phenylalanine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (29)..(29) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glycine <400> SEQUENCE: 33
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Xaa Lys 1 5
10 15 Gln Ala Xaa Xaa Glu Xaa Val Asn Trp Xaa Leu Ala Xaa 20 25
<210> SEQ ID NO 34 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 34 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Glutamine <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (21)..(21) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Asparagine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <400> SEQUENCE: 34 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa
Phe Val Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 35
<211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 35 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Leucine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (18)..(18) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Glutamic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (25)..(25) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Tryptophan <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(28)..(28) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Alanine <400> SEQUENCE: 35 Tyr Xaa Glu Gly Thr Phe Thr Ser
Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Gln Xaa Ala Xaa Xaa Phe
Val Asn Xaa Leu Leu Xaa Gly
20 25 <210> SEQ ID NO 36 <211> LENGTH: 29 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual Agonist 36
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Aspartic Acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (18)..(18) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (22)..(22)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Phenylalanine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (25)..(25) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Tryptophan <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (29)..(29) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glycine <400> SEQUENCE: 36
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Xaa Lys 1 5
10 15 Gln Xaa Ala Xaa Glu Xaa Val Asn Xaa Leu Leu Ala Xaa 20 25
<210> SEQ ID NO 37 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 37 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(15)..(15) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Aspartic Acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (18)..(18) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (22)..(22)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Phenylalanine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (25)..(25) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Tryptophan <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (29)..(29) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glycine <400> SEQUENCE: 37
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Xaa Lys 1 5
10 15 Gln Xaa Ala Xaa Glu Xaa Val Asn Xaa Leu Leu Ala Xaa 20 25
<210> SEQ ID NO 38 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 38 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 38 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly 20 25
<210> SEQ ID NO 39 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 39 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 39 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly 20 25 <210> SEQ ID NO 40 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 40 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 40 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 41 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 41 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (17)..(17) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 41
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 42 <211> LENGTH: 40 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 42 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Iso-leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Lysine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (19)..(19) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Valine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 42 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 43 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 43 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tyrosine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Lysine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = Beta-3
homo- AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Valine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (27)..(27) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE: 43
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Xaa 1 5
10 15 Gln Ala Ala Xaa Glu Phe Xaa Asn Trp Leu Xaa Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 44 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 44 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glutamine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Asparagine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (27)..(27) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 44 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Glu
Phe Val Xaa Trp Leu Xaa Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 45 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 45 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Iso-leucine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Aspartic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (22)..(22) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Phenylalanine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE:
45 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Xaa Lys
1 5 10 15 Gln Ala Xaa Xaa Glu Xaa Val Asn Trp Xaa Leu Ala Gly Gly
Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 46 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 46 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Glutamine <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (21)..(21) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Asparagine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <400> SEQUENCE: 46 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa
Phe Val Xaa Trp Leu Leu Xaa Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 47 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 47 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Aspartic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (18)..(18) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Alanine <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (22)..(22) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Phenylalanine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (25)..(25)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Tryptophan
<400> SEQUENCE: 47 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Xaa Lys 1 5 10 15 Gln Xaa Ala Xaa Glu Xaa Val Asn
Xaa Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 48 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 48 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Leucine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (18)..(18) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (25)..(25) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Tryptophan <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (28)..(28) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Alanine <400> SEQUENCE: 48
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Xaa Asp Lys 1 5
10 15 Gln Xaa Ala Xaa Xaa Phe Val Asn Xaa Leu Leu Xaa Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 49 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 49 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 49 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 50 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 50 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Iso-leucine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 50 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
51 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 51 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Lysine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (19)..(19) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(20)..(20) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 51 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 52 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 52 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Alanine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 52
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5
10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 53 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 53 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Valine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (26)..(26) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <400>
SEQUENCE: 53 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr
Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu
Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40
<210> SEQ ID NO 54 <211> LENGTH: 40 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 54 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 54 Tyr Xaa Glu Gly Thr Phe Thr
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 55 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 55 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tyrosine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 55 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 56 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 56 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Aspartic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 56 Tyr Xaa Glu Gly Thr Phe Thr Ser Xaa Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 57 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 57 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Serine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 57 Tyr Xaa Glu Gly Thr Phe Thr Xaa Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
58 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 58 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 58 Tyr Xaa
Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
59 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 59 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Phenylalanine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 59 Tyr Xaa
Glu Gly Thr Xaa Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
60 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 60 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 60 Tyr Xaa
Glu Gly Xaa Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
61 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 61 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Glycine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 61 Tyr Xaa
Glu Xaa Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
62 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 62 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 62
Tyr Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5
10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 63 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 63 <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 63 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
64 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 64 <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 64 Xaa Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15
Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20
25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO
65 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 65 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<400> SEQUENCE: 65 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 66 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 66 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Glutamic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Threonine <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Alanine <400> SEQUENCE:
66 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Xaa Gly Gly
Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 67 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 67 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (29)..(29)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Glycine
<400> SEQUENCE: 67 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Xaa Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 68 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 68 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Glutamic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Threonine <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (30)..(30) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Glycine <400> SEQUENCE:
68 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Xaa
Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 69 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 69 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (31)..(31) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Proline <400> SEQUENCE: 69 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Xaa Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 70 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 70 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (32)..(32) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Serine <400> SEQUENCE:
70 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly
Pro Xaa 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 71 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 71 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (33)..(33)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Serine
<400> SEQUENCE: 71 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr
Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn
Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Xaa Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 72 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 72 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Glutamic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Threonine <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (34)..(34) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Glycine <400> SEQUENCE:
72 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly
Pro Ser 20 25 30 Ser Xaa Ala Pro Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 73 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 73 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (35)..(35) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <400> SEQUENCE: 73 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Xaa
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 74 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 74 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (36)..(36) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Proline <400> SEQUENCE:
74 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly
Pro Ser 20 25 30 Ser Gly Ala Xaa Pro Pro Ser Lys 35 40 <210>
SEQ ID NO 75 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 75 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (37)..(37) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Proline <400> SEQUENCE: 75 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Xaa Pro Ser Lys 35 40
<210> SEQ ID NO 76 <211> LENGTH: 40 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 76 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (38)..(38) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Proline <400> SEQUENCE: 76 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Xaa Ser Lys 35 40 <210> SEQ ID NO 77 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 77 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (39)..(39) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Serine <400> SEQUENCE:
77 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa
1 5 10 15 Gln Ala Xaa Xaa Glu Phe Xaa Asn Trp Xaa Leu Ala Gly Gly
Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Xaa Lys 35 40 <210>
SEQ ID NO 78 <211> LENGTH: 40 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 78 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
Beta-3 homo- Threonine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (19)..(19)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (40)..(40) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Lysine <400> SEQUENCE: 78 Tyr Xaa Xaa Gly Thr Phe Xaa
Ser Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Xaa 35 40 <210> SEQ ID NO 79 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 79 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Threonine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Serine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <400> SEQUENCE: 79 Tyr Xaa Glu Gly Xaa Phe Thr
Xaa Asp Tyr Ser Xaa Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Xaa Xaa Glu
Phe Xaa Asn Trp Xaa Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 80 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 80 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Iso-leucine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Aspartic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (19)..(19) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa
= AIB <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (22)..(22) <223> OTHER INFORMATION: Xaa
= Beta-3 homo- Phenylalanine <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa = Beta-3 homo- Leucine <400> SEQUENCE:
80 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Xaa Lys
1 5 10 15 Gln Ala Xaa Xaa Glu Xaa Val Asn Trp Xaa Leu Ala Gly 20 25
<210> SEQ ID NO 81 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 81 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Lysine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 81 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 82 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 82 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Aspartic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 82 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Xaa Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 83 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 83 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 83 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 84 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 84 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tyrosine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 84 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 85 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 85 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Iso-leucine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 85 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Xaa Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 86 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 86 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(11)..(11) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Serine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 86 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Xaa Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 87 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 87 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Tyrosine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 87 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Xaa Ser Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 88 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 88 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(9)..(9) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Aspartic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 88 Tyr Xaa Glu Gly Thr Phe Thr Ser Xaa
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 89 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 89 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Serine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 89 Tyr Xaa
Glu Gly Thr Phe Thr Xaa Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 90 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 90 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Threonine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 90 Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 91 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 91 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Phenylalanine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 91
Tyr Xaa Glu Gly Thr Xaa Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 92 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 92 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: Xaa = Beta-3 homo-
Threonine <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 92 Tyr Xaa Glu Gly Xaa Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 93 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 93 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glycine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 93 Tyr Xaa
Glu Xaa Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 94 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 94 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Glutamic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa
= 3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 94 Tyr Xaa Xaa Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 95 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 95 <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- AIB <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 95 Tyr Xaa
Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 96 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 96 <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(1)..(1) <223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 96 Xaa Xaa Glu Gly Thr Phe Thr Ser Asp
Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 97 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 97 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Glutamic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Threonine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Tyrosine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Leucine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 97 Tyr Xaa
Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 98 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 98 <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Xaa = AIB <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 98 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 99 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 99 <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 99 Tyr Xaa
Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 100 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 100
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 100 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 101 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 101
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 101 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15
Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 102 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 102
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 102 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 103 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 103
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 103 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 104 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 104
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 104 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 105 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 105 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 105 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 106 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 106 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 106 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 107 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 107
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Glutamic Acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Xaa = Beta-3 homo- Threonine <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Xaa = Beta-3 homo- Tyrosine
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa = Beta-3
homo- Leucine <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (17)..(17) <223> OTHER
INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 107 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 108 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 108 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 108 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 109 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 109 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 109 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 110 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 110 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa
= 2-aminocyclopentanecarboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24)
<223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 110 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 111 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 111 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 111 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 112 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 112
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 112 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 113 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 113 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (20)..(20) <223>
OTHER INFORMATION: Xaa = AIB <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (21)..(21) <223>
OTHER INFORMATION: Xaa = 4-Amino-1-(3-carboxypropanoyl)
pyrrolidine-3-carboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 113 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 114 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 114
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (24)..(24) <223>
OTHER INFORMATION: Xaa = 3-Aminopyrrolidine-4-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (28)..(28) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <400> SEQUENCE: 114 Tyr
Xaa Xaa Gly Thr Phe Xaa Ser Asp Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10
15 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 20 25
<210> SEQ ID NO 115 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 115
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 115 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 116 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 116 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa =
2-aminocyclopentanecarboxylic Acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (21)..(21) <223> OTHER INFORMATION: Xaa =
4-Amino-1-(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (24)..(24) <223> OTHER INFORMATION: Xaa =
3-Aminopyrrolidine-4-carboxylic Acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (28)..(28)
<223> OTHER INFORMATION: Xaa = 2-aminocyclopentanecarboxylic
Acid <400> SEQUENCE: 116 Tyr Xaa Xaa Gly Thr Phe Xaa Ser Asp
Xaa Ser Ile Tyr Xaa Asp Lys 1 5 10 15 Xaa Ala Ala Xaa Xaa Phe Val
Xaa Trp Leu Leu Xaa Gly 20 25 <210> SEQ ID NO 117 <211>
LENGTH: 40 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 117 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <400> SEQUENCE: 117 Tyr Xaa Glu Gly
Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala
Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30
Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ ID NO 118
<211> LENGTH: 40 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 118 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 118
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 119 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 119 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 119
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 120 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 120 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 120
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 121 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 121 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 121
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30
Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ ID NO 122
<211> LENGTH: 40 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: GLP1/GIP dual Agonist 122 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 122
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 123 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 123 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 123
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5
10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 124 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 124 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 124
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5
10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 125 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 125 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 125
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5
10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 126 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 126 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 126
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5
10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 127 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 127 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 127
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5
10 15 Gln Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 128 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 128 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 128
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 129 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 129 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 129
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 130 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 130 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 130
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 131 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 131 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 131
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 132 <211> LENGTH: 29 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 132 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 132
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 133 <211> LENGTH: 29 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 133
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 133 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 134 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 134 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <400> SEQUENCE: 134 Tyr Xaa Gln Gly
Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser 1 5 10 15 Gln Ala
Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25 <210> SEQ
ID NO 135 <211> LENGTH: 29 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 135 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 135
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25
<210> SEQ ID NO 136 <211> LENGTH: 39 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: GLP1/GIP dual Agonist 136
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 136 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Lys
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser 35 <210> SEQ ID NO 137 <211> LENGTH: 39 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual Agonist 137
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 137 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Lys
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser 35 <210> SEQ ID NO 138 <211> LENGTH: 39 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual Agonist 138
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 138 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser 35 <210> SEQ ID NO 139 <211> LENGTH: 39 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual Agonist 139
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 139 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser 35 <210> SEQ ID NO 140 <211> LENGTH: 40 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual Agonist 140
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 140 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Cys 35 40 <210> SEQ ID NO 141 <211> LENGTH: 29
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 141 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 141 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly 20 25 <210> SEQ ID NO 142 <211>
LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
GLP1/GIP dual Agonist 142 <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Xaa = AIB <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (20)..(20) <223> OTHER
INFORMATION: Xaa = AIB <400> SEQUENCE: 142 Tyr Xaa Glu Gly
Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala
Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 <210> SEQ
ID NO 143 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 143 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 143
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 144 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 144 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 144
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 145 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 145 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 145
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 146 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 146 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 146
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> SEQ
ID NO 147 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 147 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 147
Tyr Xaa Gln Gly Thr Phe Ser Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 148 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 148 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 148
Tyr Xaa Gln Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> SEQ
ID NO 149 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 149 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (20)..(20)
<223> OTHER INFORMATION: Xaa = AIB <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (40)..(40)
<223> OTHER INFORMATION: Xaa = AIB <400> SEQUENCE: 149
Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5
10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 <210> SEQ
ID NO 150 <211> LENGTH: 40 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: GLP1/GIP dual Agonist 150 <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (40)..(40) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 150 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Xaa 35 40 <210> SEQ ID NO 151 <211> LENGTH: 39
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 151 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 151 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser 35 <210> SEQ ID NO 152 <211> LENGTH: 39 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual Agonist 152
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 152 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser 35 <210> SEQ ID NO 153 <211> LENGTH: 41 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual Agonist 153
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa = AIB
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 153 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys Cys 35 40 <210> SEQ ID NO 154 <211> LENGTH: 41
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 154 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 154 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys Cys 35 40 <210> SEQ ID NO 155 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 155 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <400> SEQUENCE: 155 His Xaa Gln Gly Thr Phe Thr Ser Asp
Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile
Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro
Pro Ser Lys 35 40 <210> SEQ ID NO 156 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 156 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 156 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 157 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 157 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 157 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 158 <211> LENGTH: 40
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: GLP1/GIP dual
Agonist 158 <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa =
AIB <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (20)..(20) <223> OTHER INFORMATION: Xaa = AIB
<400> SEQUENCE: 158 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr
Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn
Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro
Ser Lys 35 40 <210> SEQ ID NO 159 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: agonist analog
159 <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: X =
ACPC or ACHC or
4-Amino-1-(3-carboxypropanoyl)pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (4)..(4) <223> OTHER INFORMATION: Aib <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(5)..(5)
<223> OTHER INFORMATION: X = ACPC or AHC or
4-Amino-1-(3-carboxypropanoyl)pyrrolidine-3-carboxylic Acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (8)..(8) <223> OTHER INFORMATION: X = APC or AHC or
(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: X = ACPC or ACHC or
(3-carboxypropanoyl) pyrrolidine-3-carboxylic Acid <400>
SEQUENCE: 159 Xaa Ala Ala Xaa Xaa Phe Val Xaa Trp Leu Leu Xaa Gly 1
5 10
* * * * *