U.S. patent application number 15/453369 was filed with the patent office on 2018-03-01 for compositions and methods for the treatment of cast nephropathy and related conditions.
The applicant listed for this patent is Thrasos Therapeutics Inc.. Invention is credited to Marie-Elaine Caruso, Gilles Dube, Roger Leger, Jerome Rossert.
Application Number | 20180057534 15/453369 |
Document ID | / |
Family ID | 58419069 |
Filed Date | 2018-03-01 |
United States Patent
Application |
20180057534 |
Kind Code |
A1 |
Leger; Roger ; et
al. |
March 1, 2018 |
COMPOSITIONS AND METHODS FOR THE TREATMENT OF CAST NEPHROPATHY AND
RELATED CONDITIONS
Abstract
Provided are novel peptides of Formula SEQ ID No. 1:
TABLE-US-00001 (SEQ ID No. 1)
J.sup.1CysX.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6ProX.sup.7ThrCysJ.sup-
.2J.sup.3(J.sup.4).sub.s(J.sup.5).sub.t; pharmaceutically
acceptable salts thereof, and pharmaceutical compositions thereof,
which are which are effective inhibitors of light chains to
uromodulin.
Inventors: |
Leger; Roger;
(Saint-Lambert, CA) ; Dube; Gilles; (Beaconsfield,
CA) ; Caruso; Marie-Elaine; (Montreal, CA) ;
Rossert; Jerome; (Nahant, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Thrasos Therapeutics Inc. |
Montreal |
|
CA |
|
|
Family ID: |
58419069 |
Appl. No.: |
15/453369 |
Filed: |
March 8, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15368260 |
Dec 2, 2016 |
9611297 |
|
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15453369 |
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62380068 |
Aug 26, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 7/08 20130101; A61K
38/00 20130101; A61P 25/00 20180101 |
International
Class: |
C07K 7/08 20060101
C07K007/08 |
Claims
1. A peptide of the Formula SEQ ID No. 1: TABLE-US-00009 (SEQ ID
No. 1)
J.sup.1CysX.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6ProX.sup.7ThrCysJ.sup-
.2J.sup.3(J.sup.4).sub.s(J.sup.5).sub.t;
or a pharmaceutically acceptable salt thereof, wherein J.sup.1 is
Aha or Arg; X.sup.1 to X.sup.7 are each independently a natural or
non-natural amino acid; s, and t are each independently 0 or 1;
J.sup.2 and J.sup.3 are each independently Lys or Arg; J.sup.4, if
present is Lys or Arg; and J.sup.5, if present is Lys or Arg.
2. The peptide of claim 1, wherein X.sup.1 is selected from Arg,
Lys, His, Pro, Cys, Thr, Ser, Gln, Glu, Leu, Ile, Met, Ala, Val,
Gly, n-Leu, Met, Asp, and Ile.
3. The peptide of claim 1, wherein X.sup.1 is selected from Arg,
Gln, Glu, Leu, n-Leu, Met, Asp, and Ile.
4. The peptide of claim 1, wherein X.sup.1 is selected from Gln,
Leu, and n-Leu.
5. The peptide of claim 1, wherein X.sup.2 is selected from a
natural amino acid.
6. The peptide of claim 1, wherein X.sup.2 is selected from Ser,
Thr, Cys, Met, Asn, Lys, Gln, His, Arg, Glu, and Asp.
7. The peptide of claim 1, wherein X.sup.2 is selected from Ser,
Gln, His, Arg, Glu, and Asp.
8. The peptide of claim 1, wherein X.sup.2 is selected from Gln and
His.
9. The peptide of claim 1, wherein X.sup.3 is selected from a
natural amino acid.
10. The peptide of claim 1, wherein X.sup.3 is selected from Tyr,
Trp, Phe, Ser, Thr, Cys, Met, Asn, Ala, Lys, His, Glu, Arg, and
Asp.
11. The peptide of claim 1, wherein X.sup.3 is selected from Tyr,
Ser, Ala, Glu, Arg, and Asp.
12. The peptide of claim 1, wherein X.sup.3 is selected from Tyr,
Ser, Arg, and Asp.
13. The peptide of claim 1, wherein X.sup.4 is selected from a
natural amino acid.
14. The peptide of claim 1, wherein X.sup.4 is selected from Gly,
Ala, Val, Leu, Ile, Pro, Phe, Tyr, Trp, Asp, Glu, Lys, Arg, and
His.
15. The peptide of claim 1, wherein X.sup.4 is selected from Leu,
Asp, Gly, Tyr, Glu, and Arg.
16. The peptide of claim 1, wherein X.sup.4 is selected from Leu,
Asp, Tyr, and Arg.
17. The peptide of claim 1, wherein X.sup.5 is selected from a
natural amino acid.
18. The peptide of claim 1, wherein X.sup.5 is selected from Ser,
Thr, Cys, Met, Asn, Gln, Asp, Glu, Lys, Arg, and His.
19. The peptide of claim 1, wherein X.sup.5 is selected from Tyr,
Ser, Arg, Glu, and Asp.
20. The peptide of claim 1, wherein X.sup.6 is selected from Gly,
Ala, Val, Leu, Ile, Pro, Phe, Tyr, Trp, Ser, Cys, Met, Gln, Lys,
Arg, and His.
21. The peptide of claim 1, wherein X.sup.6 is selected from Ile,
Leu, Pro, Val, Ala, Gly, His, Lys, and Arg.
22. The peptide of claim 1, wherein X.sup.6 is selected from Ile,
Leu, and Arg.
23. The peptide of claim 1, wherein X.sup.6 is selected from Ile
and Leu.
24. The peptide of claim 1, wherein X.sup.7 is selected from Gly,
Ala, Val, Leu, Ile, Pro, Phe, Tyr, Trp, Ser, Thr, Cys, Met, Asn,
Gln, Lys, Arg, and His.
25. The peptide of claim 1, wherein X.sup.7 is selected from Tyr,
Phe, His, Lys, Arg, and Trp.
26. The peptide of claim 1, wherein X.sup.7 is selected from Tyr,
Arg, and Trp.
27. The peptide of claim 1, wherein X.sup.7 is Tyr.
28. The peptide of claim 1, wherein s and t are each 0.
29. The peptide of claim 1, wherein s and t are each 1.
30. The peptide of claim 1, where J.sup.1 is Aha.
31. The peptide of claim 1, wherein the peptide is selected from
TABLE-US-00010 AhaCQQSYSIPWTCKK; AhaCQQSYSIPYTCKK;
AhaCQQYDSLPLTCKK; AhaCQQYSYLPITCK*K*; AhaCQQYSTAPWTCKK;
AhaCQQYYSAPPTCKK; AhaCQQYKNYPWTCKK; AhaCQHYDYLPITCK*K*;
AhaCQQSYSIPWTCK*K*; AhaCQQSYSIPYTCK*K*; AhaCQQ*SYSIPWTCK*K*;
AhaCQQS*YSIPWTCK*K*; AhaCQQSY*SIPWTCK*K*; AhaCQQ*SYSIPYTCK*K*;
AhaCQQS*YSIPYTCK*K*; AhaCEQSYSIPYTCKK; AhaCQESYSIPYTCKK;
AhaCQQEYSIPYTCKK; AhaCQQSESIPYTCKK; AhaCQQSYEIPYTCKK;
AhaCQQSYSEPYTCKK; AhaCQQSYSIEYTCKK; AhaCQQSYSIPETCKK;
AhaCQQSYSIPYECKK; AhaCRQSYSIPYTCKK; AhaCQRSYSIPYTCKK;
AhaCQQRYSIPYTCKK; AhaCQQSRSIPYTCKK; AhaCQQSYRIPYTCKK;
AhaCQQSYSRPYTCKK; AhaCQQSYSIRYTCKK; AhaCQQSYSIPRTCKK;
AhaCQQSYSIPYRCKK; AhaCQQSY*SIPYTCK*K*K*K*; AhaCQQYSYLPITCK*K*;
AhaCQQYSYLPITCR*R*; AhaCQQSYLPITCK*K*; AhaCQQYSLPITCK*K*;
AhaCQQYDLPITCK*K*; and AhaCQQSYSIPYTCR*R*;
or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition comprising a peptide of claim 1,
or a pharmaceutically acceptable salt thereof; and a
pharmaceutically acceptable carrier.
33. A method of treating cast neuropathy in a subject in need
thereof, comprising administering to the subject a therapeutically
effective amount of a peptide of claim 1, or a pharmaceutically
acceptable salt thereof.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/368,260, filed Dec. 2, 2016, which claims
priority to U.S. Provisional Application No. 62/380,068 filed Aug.
26, 2016, the entire contents of each of which are incorporated
herein by reference.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which
has been submitted electronically in ASCII format and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Dec. 21, 2016, is named 119562-03502_SL.txt and is 20,665 bytes
in size.
BACKGROUND
[0003] Multiple myeloma is a neoplastic disorder characterized by a
clonal proliferation of malignant plasma cells, which produce
monoclonal immunoglobulins (i.e., antibodies). Acute kidney injury
(AKI) is a well-known complication of multiple myeloma with high
tumor burden and high amounts of light chains (which are fragments
of immunoglobulins) in the urine. AKI affects up to 50% of patients
with multiple myeloma, and has important consequences: it exposes
patients to the risk of permanent kidney damage (including end
stage kidney failure), is associated with a decrease in overall
survival, and impacts the treatment of the underlying myeloma.
[0004] In the vast majority of cases, AKI is due to myeloma cast
nephropathy that results from the precipitation of complexes
(called myeloma casts) formed by light chains and uromodulin (a
protein normally present in urine) in the distal part of the
nephron. See Leung et al., Adv Chronic Kidney Dis, 21: 36-47. These
casts obstruct the nephrons, leading to AKI and induce an
inflammatory reaction that leads to fibrosis and irreversible
chronic kidney damage. The events leading to cast formation have
been dissected. See Huang, et al., J Clin Invest, 92: 2975-83,
1993; Huang, et al., J Clin Invest, 99: 732-6, 1997. In particular,
different light chains were found to bind to the same peptidic
segment of uromodulin (later identified as D8C) and interacted with
uromodulin through their CDJ3 (for complementarity-determining
region 3). This finding led to the indentation of a CDJ3 sequence
derived peptide that blocked the interaction between monoclonal
light chains and uromodulin, and inhibited cast formation in vivo.
See e.g., Ying, et al., Am J Pathol, 158: 1859-66, 2012.
[0005] Recognizing this result, peptides that inhibit the binding
of light chains to uromodulin represent are are an attractive
targets for combating myeloma cast nephropathy and related
conditions.
SUMMARY OF THE INVENTION
[0006] Provided herein are peptides and compositions thereof which
are effective binding inhibitors of light chains to uromodulin.
(See e.g., Table 3). Such peptides include those of Formula SEQ ID
No. 1:
TABLE-US-00002 (SEQ ID No. 1)
J.sup.1CysX.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6ProX.sup.7ThrCysJ2J.s-
up.3(J.sup.4).sub.s(J.sup.5).sub.t;
or a pharmaceutically acceptable salt thereof, wherein each of
X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.6, X.sup.7,
J.sup.1, J.sup.2 J.sup.3, J.sup.4, J.sup.5, s, and t are as defined
and described herein.
[0007] Also provided are methods of treating myeloma cast
nephropathy in e.g., patient populations with severe renal
impairment, comprising administering one or more of the peptides or
compositions described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 illustrates the plasma pharmacokinetics following
intravenous bolus injection of a peptide of Formula SEQ ID No. 1 in
rat.
[0009] FIG. 2 illustrates the plasma pharmacokinetics following 2
hour intravenous infusion of a peptide of Formula SEQ ID No. 1 in
rat.
[0010] FIG. 3 compares the plasma pharmacokinetics of two peptides
of Formula SEQ ID No. 1 after intraperitoneal injection in rat,
where a.) shows a plot of peptide vs time at various
concentrations; b.) shows a plot of steady state concentration
(Css) as a function of. dose; and c.) shows a plot of the Area
Under the Cure (AUC) as a function of dose.
[0011] FIG. 4 illustrates the urine recovery of a peptide of
Formula SEQ ID No. 1.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
1. General Description of Peptides
[0012] In one aspect, provided herein are peptides of Formula SEQ
ID No. 1:
TABLE-US-00003 (SEQ ID No. 1)
J.sup.1CysX.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6ProX.sup.7ThrCysJ.sup-
.2J.sup.3(J.sup.4).sub.s(J.sup.5).sub.t;
or a pharmaceutically acceptable salt thereof, wherein [0013]
J.sup.1 is Aha or Arg; [0014] X.sup.1 to X.sup.7 are each
independently a natural or non-natural amino acid; [0015] s, and t
are each independently 0 or 1; [0016] J.sup.2 and J.sup.3 are each
independently Lys or Arg; [0017] J.sup.4, if present is Lys or Arg;
and [0018] J.sup.5, if present is Lys or Arg.
2. Peptides and Definitions
[0019] "Amino acid" refers to an organic compound containing an
amine (--NH.sub.2) and a carboxylic acid (--COOH) functional group,
usually along with a side-chain specific to each amino acid. Amino
acids can be classified according to the core structural functional
groups' locations as alpha- (.alpha.-), beta- (.beta.-), gamma-
(.gamma.-) or delta- (.delta.-) amino acids; other categories
relate to polarity, pH level, and side-chain group type (aliphatic,
acyclic, aromatic, containing hydroxyl or sulfur, etc.). In one
embodiment, amino acid includes
[0020] "Natural amino acid" is used interchangeably with
proteinogenic amino acid and refers to the 20 standard amino acids
encoded by the universal genetic code along with selenocysteine and
pyrrolysine. The 20 standard amino acids encoded by the universal
genetic code include glycine, alanine, valine, leucine, isoleucine,
proline, phenylalanine, tyrosine, tryptophan, serine, threonine,
cysteine, methionine, asparagine, glutamine, aspartate, glutamate,
lysine, arginine, and histidine. Unless otherwise specified, when a
natural amino acid is defined without indicating the
stereochemistry it will be understood that the defined amino acid
is present as the L-enantiomer. Thus, when used as part of a
formula, the letter A or Ala means L-alanine.
[0021] The full name of a natural amino acid and its corresponding
three-letter or one-letter code are used interchangeably. For
example, glycine is interchangeable with three letter abbreviation
Gly or the one letter abbreviation G; alanine is interchangeable
with three letter abbreviation Ala or the one letter abbreviation
A, valine is interchangeable with three letter abbreviation Val or
the one letter abbreviation V, leucine is interchangeable with
three letter abbreviation Leu or the one letter abbreviation L,
isoleucine is interchangeable with three letter abbreviation Ile or
the one letter abbreviation I, proline is interchangeable with
three letter abbreviation Pro or the one letter abbreviation P,
phenylalanine is interchangeable with three letter abbreviation Phe
or the one letter abbreviation F, tyrosine is interchangeable with
three letter abbreviation Tyr or the one letter abbreviation Y,
tryptophan is interchangeable with three letter abbreviation Trp or
the one letter abbreviation W, serine is interchangeable with three
letter abbreviation Ser or the one letter abbreviation S, threonine
is interchangeable with three letter abbreviation Thr or the one
letter abbreviation T, cysteine is interchangeable with three
letter abbreviation Cys or the one letter abbreviation C,
methionine is interchangeable with three letter abbreviation Met or
the one letter abbreviation M, asparagine is interchangeable with
three letter abbreviation Asn or the one letter abbreviation N,
glutamine is interchangeable with three letter abbreviation Gln or
the one letter abbreviation Q, aspartate is interchangeable with
three letter abbreviation Asp or the one letter abbreviation D,
glutamate is interchangeable with three letter abbreviation Glu or
the one letter abbreviation E, lysine is interchangeable with three
letter abbreviation Lys or the one letter abbreviation K, arginine
is interchangeable with three letter abbreviation Arg or the one
letter abbreviation R, histidine is interchangeable with three
letter abbreviation His or the one letter abbreviation H,
selenocysteine is interchangeable with three letter abbreviation
Sec or the one letter abbreviation U, and pyrrolysine is
interchangeable with three letter abbreviation Pyl or the one
letter abbreviation O. In one embodiment, the term "natural amino
acid" or proteinogenic amino acid refers only to the 20 standard
amino acids encoded by the universal genetic code, i.e., G, A, V,
L, I, P, F, Y, W, S, T, C, M, N, Q, D, E, K, R, and H.
[0022] "Non-natural amino acid" refers to a non-proteinogenic amino
acid that is not found in proteins (e.g., carnitine,
gamma-aminobutyric acid, and D-forms of natural amino acids except
glycine) or not produced directly and in isolation by standard
cellular machinery (e.g., hydroxyproline and selenomethionine).
Other examples include, but are not limited to, .beta.-amino acids
(.beta.3 and .beta.2), homo-amino acids, alanine derivatives,
alicyclic amino acids, arginine derivatives, asparagine
derivatives, aspartic acid derivatives, cysteine derivatives,
2,4-diaminobutyric acid, glycine derivatives, isoleucine
derivatives, leucine derivatives, lysine derivatives (such as
6-aminohexanoic acid abbreviated herein as Aha), methionine
derivatives, norleucine (nL) and norleucine derivatives,
phenylalanine derivatives, phenylglycine derivatives, proline and
pyruvic acid derivatives, pyroglutamine derivatives, serine
derivatives, threonine derivatives, tryptophan derivatives,
norvaline derivatives, 2,3-diaminopropionic acid, ornithine
derivatives, valine derivatives, linear core amino acids, and
N-methyl amino acids. In one embodiment, the term "non-natural
amino acid" refers only to D-forms of the 20 standard amino acids
encoded by the universal genetic code. These forms include D-Ala,
D-Val, D-Leu, D-Ile, D-Pro, D-Phe, D-Tyr, D-Trp, D-Ser, D-Thr,
D-Cys, D-Met, D-Asn, D-Gln, D-Asp, D-Glu, D-Lys, D-Arg, and
D-His.
[0023] The abbreviation "oxC" means a compound of the structure
##STR00001##
[0024] The abbreviation "Pen" means a compound of the structure
##STR00002##
[0025] A "D-amino acid" or D-form of an amino acid means that the
indicated amino acid is present as the D-enantiomer. Shorthand
notation for the D-enantiomer of an amino acid can be represented
by an asterisk (*). For example, I* or I*le, wherein * represents a
D-amino acid, refers to the D-enantiomer of Ile (isoleucine).
[0026] The peptides described herein may be present in the form of
pharmaceutically acceptable salts. Pharmaceutically acceptable
salts are art-recognized and include e.g., relatively non-toxic
inorganic and organic acid addition salts, or inorganic or organic
base addition salts that are suitable for human consumption.
Examples of such salts include, but are not limited to, sodium,
potassium, calcium, magnesium, acetate, benzoate, bicarbonate,
carbonate, citrate, dihydrochloride, gluconate, glutamate,
hydrochloride, and tartrate.
[0027] The term "pharmaceutically acceptable carrier" refers to a
non-toxic carrier, adjuvant, or vehicle that does not adversely
affect the pharmacological activity of the peptide with which it is
formulated, and which is also safe for human use. Pharmaceutically
acceptable carriers that may be used include, but are not limited
to, ion exchangers, alumina, aluminum stearate, magnesium stearate,
lecithin, serum proteins, such as human serum albumin, buffer
substances such as phosphates, glycine, sorbic acid, potassium
sorbate, partial glyceride mixtures of saturated vegetable fatty
acids, water, salts or electrolytes, such as protamine sulfate,
disodium hydrogen phosphate, dicalcium phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone,
polyvinylpyrrolidone-vinyl acetate, cellulose-based substances
(e.g., microcrystalline cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose acetate succinate, hydroxypropyl
methylcellulose Phthalate), starch, lactose monohydrate, mannitol,
trehalose sodium lauryl sulfate, and crosscarmellose sodium,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
polymethacrylate, waxes, polyethylene-polyoxypropylene-block
polymers, polyethylene glycol and wool fat.
[0028] The terms "subject" and "patient" may be used
interchangeably, and mean a mammal in need of treatment, e.g.,
companion animals (e.g., dogs, cats, and the like), farm animals
(e.g., cows, pigs, horses, sheep, goats and the like) and
laboratory animals (e.g., rats, mice, guinea pigs and the like).
Typically, the subject is a human in need of treatment.
[0029] The terms "treatment," "treat," and "treating" refer to
reversing, alleviating, or inhibiting the progress of a disease or
disorder, or one or more symptoms thereof, as described herein. In
some embodiments, treatment may be administered after one or more
symptoms have developed, i.e., therapeutic treatment. In other
embodiments, treatment may be administered in the absence of
symptoms. For example, treatment may be administered to a
susceptible individual prior to the onset of symptoms (e.g., in
light of a history of symptoms and/or in light of genetic or other
susceptibility factors), i.e., prophylactic treatment. Treatment
may also be continued after symptoms have resolved, for example to
prevent or delay their recurrence.
[0030] An "effective amount" or "therapeutically effective amount"
is a quantity sufficient to achieve a desired therapeutic and/or
prophylactic effect, for example, an amount which results in the
prevention of or a decrease in the symptoms associated with a
condition that is being treated, e.g., the conditions described
herein.
3. Description of Exemplary Peptides
[0031] In a first embodiment, provided herein are peptides of the
Formula SEQ ID No. 1:
TABLE-US-00004 (SEQ ID No. 1)
J.sup.1CysX.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6ProX.sup.7ThrCysJ.sup-
.2J.sup.3(J.sup.4).sub.s(J.sup.5).sub.t;
or a pharmaceutically acceptable salt thereof, wherein the
variables are as described above.
[0032] In a second embodiment, X.sup.6 in the peptide of Formula
SEQ ID No. 1 is not Glu, Thr, Asn, or Asp; and X.sup.7 is not Glu
or Asp, wherein the remaining variables in SEQ ID No. 1 are as
described above.
[0033] In a third embodiment, X.sup.1 in the peptide of Formula SEQ
ID No. 1 is selected from Arg, Lys, His, Pro, Cys, Thr, Ser, Gln,
Glu, Leu, Ile, Met, Ala, Val, Gly, n-Leu, Met, Asp, and Ile,
wherein the remaining variables in SEQ ID No. 1 are as described
above for SEQ ID No. 1 or the second embodiment. Alternatively,
X.sup.1 in the peptide of Formula SEQ ID No. 1 is selected from
Arg, Gln, Glu, Leu, n-Leu, Met, Asp, and Ile, wherein the remaining
variables in SEQ ID No. 1 are as described above for SEQ ID No. 1
or the second embodiment. In another alternative, X.sup.1 in the
peptide of Formula SEQ ID No. 1 is selected from Gln, Leu, and
n-Leu, wherein the remaining variables in SEQ ID No. 1 are as
described above for SEQ ID No. 1 or the second embodiment.
[0034] In a forth embodiment, X.sup.2 in the peptide of Formula SEQ
ID No. 1 is selected from a natural amino acid, wherein the
remaining variables in SEQ ID No. 1 are as described above for SEQ
ID No. 1 or the second or third embodiment. Alternatively, X.sup.2
in the peptide of Formula SEQ ID No. 1 is selected from Ser, Thr,
Cys, Met, Asn, Lys, Gln, His, Arg, Glu, and Asp, wherein the
remaining variables in SEQ ID No. 1 are as described above for SEQ
ID No. 1 or the second or third embodiment. In another alternative,
X.sup.2 in the peptide of Formula SEQ ID No. 1 is selected from
Ser, Gln, His, Arg, Glu, and Asp, wherein the remaining variables
in SEQ ID No. 1 are as described above for SEQ ID No. 1 or the
second or third embodiment. In yet another alternative, X.sup.2 in
the peptide of Formula SEQ ID No. 1 is selected from Gln and His,
wherein the remaining variables in SEQ ID No. 1 are as described
above for SEQ ID No. 1 or the second or third embodiment.
[0035] In a fifth embodiment, X.sup.3 in the peptide of Formula SEQ
ID No. 1 is selected from a natural amino acid, wherein the
remaining variables in SEQ ID No. 1 are as described above for SEQ
ID No. 1 or the second, third, or forth embodiment. Alternatively,
X.sup.3 in the peptide of Formula SEQ ID No. 1 is selected from
Tyr, Trp, Phe, Ser, Thr, Cys, Met, Asn, Ala, Lys, His, Glu, Arg,
and Asp, wherein the remaining variables in SEQ ID No. 1 are as
described above for SEQ ID No. 1 or the second, third, or forth
embodiment. In another alternative, X.sup.3 in the peptide of
Formula SEQ ID No. 1 is selected from Tyr, Ser, Ala, Glu, Arg, and
Asp, wherein the remaining variables in SEQ ID No. 1 are as
described above for SEQ ID No. 1 or the second, third, or forth
embodiment. In yet another alternative, X.sup.3 is selected from
Tyr, Ser, Arg, and Asp, wherein the remaining variables in SEQ ID
No. 1 are as described above for SEQ ID No. 1 or the second, third,
or forth embodiment.
[0036] In a sixth embodiment, X.sup.4 in the peptide of Formula SEQ
ID No. 1 is selected from a natural amino acid, wherein the
remaining variables in SEQ ID No. 1 are as described above for SEQ
ID No. 1 or the second, third, fourth, or fifth embodiment.
Alternatively, X.sup.4 in the peptide of Formula SEQ ID No. 1 is
selected from Gly, Ala, Val, Leu, Ile, Pro, Phe, Tyr, Trp, Asp,
Glu, Lys, Arg, and His, wherein the remaining variables in SEQ ID
No. 1 are as described above for SEQ ID No. 1 or the second, third,
fourth, or fifth embodiment. In another alternative, X.sup.4 in the
peptide of Formula SEQ ID No. 1 is selected from Leu, Asp, Gly,
Tyr, Glu, and Arg, wherein the remaining variables in SEQ ID No. 1
are as described above for SEQ ID No. 1 or the second, third,
fourth, or fifth embodiment. In yet another alternative X.sup.4 in
the peptide of Formula SEQ ID No. 1 is selected from Leu, Asp, Tyr,
and Arg, wherein the remaining variables in SEQ ID No. 1 are as
described above for SEQ ID No. 1 or the second, third, fourth, or
fifth embodiment.
[0037] In a seventh embodiment, X.sup.5 in the peptide of Formula
SEQ ID No. 1 is selected from a natural amino acid, wherein the
remaining variables in SEQ ID No. 1 are as described above for SEQ
ID No. 1 or the second, third, fourth, fifth, or sixth embodiment.
Alternatively, X.sup.5 in the peptide of Formula SEQ ID No. 1 is
selected from Ser, Thr, Cys, Met, Asn, Gln, Asp, Glu, Lys, Arg, and
His, wherein the remaining variables in SEQ ID No. 1 are as
described above for SEQ ID No. 1 or the second, third, fourth,
fifth, or sixth embodiment. In another alternative, X.sup.5 in the
peptide of Formula SEQ ID No. 1 is selected from Tyr, Ser, Arg,
Glu, and Asp, wherein the remaining variables in SEQ ID No. 1 are
as described above for SEQ ID No. 1 or the second, third, fourth,
fifth, or sixth embodiment.
[0038] In an eighth embodiment, X.sup.6 in the peptide of Formula
SEQ ID No. 1 is selected from Gly, Ala, Val, Leu, Ile, Pro, Phe,
Tyr, Trp, Ser, Cys, Met, Gln, Lys, Arg, and His, wherein the
remaining variables in SEQ ID No. 1 are as described above for SEQ
ID No. 1 or the second, third, fourth, fifth, sixth, or seventh
embodiment. Alternatively, X.sup.6 in the peptide of Formula SEQ ID
No. 1 is selected from Ile, Leu, Pro, Val, Ala, Gly, His, Lys, and
Arg, wherein the remaining variables in SEQ ID No. 1 are as
described above for SEQ ID No. 1 or the second, third, fourth,
fifth, sixth, or seventh embodiment. In another alternative,
X.sup.6 in the peptide of Formula SEQ ID No. 1 is selected from
Ile, Leu, and Arg, wherein the remaining variables in SEQ ID No. 1
are as described above for SEQ ID No. 1 or the second, third,
fourth, fifth, sixth, or seventh embodiment. In yet another
alternative, X.sup.6 in the peptide of Formula SEQ ID No. 1 is
selected from Ile and Leu, wherein the remaining variables in SEQ
ID No. 1 are as described above for SEQ ID No. 1 or the second,
third, fourth, fifth, sixth, or seventh embodiment.
[0039] In a ninth embodiment, X.sup.7 in the peptide of Formula SEQ
ID No. 1 is selected from Gly, Ala, Val, Leu, Ile, Pro, Phe, Tyr,
Trp, Ser, Thr, Cys, Met, Asn, Gln, Lys, Arg, and His, wherein the
remaining variables in SEQ ID No. 1 are as described above for SEQ
ID No. 1 or the second, third, fourth, fifth, sixth, seventh, or
eighth embodiment. Alternatively, X.sup.7 in the peptide of Formula
SEQ ID No. 1 is selected from Tyr, Phe, His, Lys, Arg, and Trp,
wherein the remaining variables in SEQ ID No. 1 are as described
above for SEQ ID No. 1 or the second, third, fourth, fifth, sixth,
seventh, or eighth embodiment. In another alternative, X.sup.7 in
the peptide of Formula SEQ ID No. 1 is selected from Tyr, Arg, and
Trp, wherein the remaining variables in SEQ ID No. 1 are as
described above for SEQ ID No. 1 or the second, third, fourth,
fifth, sixth, seventh, or eighth embodiment. In yet another
alternative, X.sup.7 in the peptide of Formula SEQ ID No. 1 is Tyr,
wherein the remaining variables in SEQ ID No. 1 are as described
above for SEQ ID No. 1 or the second, third, fourth, fifth, sixth,
seventh, or eighth embodiment.
[0040] In a tenth embodiment, s and t are each 0 in the peptide of
Formula SEQ ID No. 1, wherein the remaining variables in SEQ ID No.
1 are as described above for SEQ ID No. 1 or the second, third,
fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
[0041] In an eleventh embodiment, s and t are each 1 in the peptide
of Formula SEQ ID No. 1, wherein the remaining variables in SEQ ID
No. 1 are as described above for SEQ ID No. 1 or the second, third,
fourth, fifth, sixth, seventh, eighth, ninth, or tenth
embodiment.
[0042] In a thirteenth embodiment, J.sup.1 in the peptide of
Formula SEQ ID No. 1 is Aha, wherein the remaining variables in SEQ
ID No. 1 are as described above for SEQ ID No. 1 or the second,
third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or
eleventh embodiment.
[0043] Specific examples of the disclosed peptides are provided in
Table 1 and Table 2 below as well as in the EXEMPLIFICATION
sections. Pharmaceutically acceptable salts as well as the neutral
forms of these peptides are included in the present disclosure.
TABLE-US-00005 TABLE 1 SEQ ID No. Sequence 11 AhaCQQSYSIPWTCKK 12
AhaCQQSYSIPYTCKK 13 AhaCQQYDSLPLTCKK 14 AhaCQQYSYLPITCK*K* 15
AhaCQQYSTAPWTCKK 16 AhaCQQYYSAPPTCKK 17 AhaCQQYKNYPWTCKK 18
AhaCQHYDYLPITCK*K* 20 AhaCQQSYSIPWTCK*K* 21 AhaCQQSYSIPYTCK*K* 22
AhaCQQ*SYSIPWTCK*K* 23 AhaCQQS*YSIPWTCK*K* 24 AhaCQQSY*SIPWTCK*K*
25 AhaCQQ*SYSIPYTCK*K* 26 AhaCQQS*YSIPYTCK*K* 27
AhaCQQSY*SIPYTCK*K* 28 AhaCEQSYSIPYTCKK 29 AhaCQESYSIPYTCKK 30
AhaCQQEYSIPYTCKK 31 AhaCQQSESIPYTCKK 32 AhaCQQSYEIPYTCKK 33
AhaCQQSYSEPYTCKK 34 AhaCQQSYSIEYTCKK 35 AhaCQQSYSIPETCKK 36
AhaCQQSYSIPYECKK 37 AhaCRQSYSIPYTCKK 38 AhaCQRSYSIPYTCKK 39
AhaCQQRYSIPYTCKK 40 AhaCQQSRSIPYTCKK 41 AhaCQQSYRIPYTCKK 42
AhaCQQSYSRPYTCKK 43 AhaCQQSYSIRYTCKK 44 AhaCQQSYSIPRTCKK 45
AhaCQQSYSIPYRCKK 46 AhaCQQSY*SIPYTCK*K*K*K* 50 AhaCQQYSYLPITCK*K*
51 AhaCQQYSYLPITCR*R* 52 AhaCQQSYLPITCK*K* 53 AhaCQQYSLPITCK*K* 54
AhaCQQYDLPITCK*K* 55 AhaCQQSYSIPYTCR*R*
TABLE-US-00006 TABLE 2 SEQ ID No. Sequence 2 AhaCAAWDDSLNGPVCKK 3
AhaCnLQALRTPLYTCKK 4 AhaCLSADSSGSYLYVCKK 5 AhaCQVWDNSVGVCKK 6
AhaCQSYDNTLSGSYVCKK 7 AhaCQSYDNTLSGSLCKK 8 AhaCQSYDARNV 9
AhaCQSYDHNNQ 10 AhaCQSYDSTNEGVCKK 19 AhaCQHYGSSALTCKK 47
K*K*CQQSY*SIPYTCK*K* 48 AhaPenQQSY*SIPYTPenK*K* 49
oxCCQQSY*SIPYTCK*K*
4. Uses, Formulation, and Administration
[0044] In certain embodiments, the present disclosure provides a
method of treating a subject (e.g., a human) suffering from myeloma
cast nephropathy, comprising administering to the subject a
therapeutically effective amount of a peptide of Formula SEQ ID No.
1, or a pharmaceutically acceptable salt thereof. In certain
embodiments, the amount of peptide of SEQ ID No. 1 is such that it
is an effective binding inhibitor of light chains to uromodulin. In
certain embodiments, a provided composition is formulated for
administration to a subject in need of such composition.
[0045] Pharmaceutically acceptable compositions are included and
can be administered to humans and other animals by other methods
such as e.g., orally, rectally, parenterally, intracisternally,
intraperitoneally, topically (as by powders, creams, ointments, or
drops), bucally, as an oral or nasal spray, or the like. In certain
embodiments, the disclosed peptides may be administered
parenterally (e.g., intravenous).
[0046] In certain embodiments, the present disclosure also provides
a method of treating a subject (e.g., a human) suffering from
myeloma cast nephropathy, comprising administering to the subject a
therapeutically effective amount of composition comprising a
peptide of Formula SEQ ID No. 1, or a pharmaceutically acceptable
salt thereof; and a pharmaceutically acceptable carrier. adjuvant,
or vehicle. In certain embodiments, the amount of peptide of SEQ ID
No. 1 in a provided composition is such that it is an effective
binding inhibitor of light chains to uromodulin.
[0047] It will be understood that a specific dosage for any
particular subject will depend upon a variety of factors, including
age, body weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, the judgment
of the treating physician, and the severity of the particular
disease being treated. The amount of a provided peptide in the
composition will also depend upon the particular peptide in the
composition.
[0048] The amount of provided peptides that may be combined with
carrier materials to produce a composition in a single dosage form
will vary depending upon the patient to be treated and the
particular mode of administration.
Exemplification
[0049] Standard solid phase techniques were employed to synthesize
the disclosed peptides. Fmoc (fluorenylmethyloxycarbonyl) chemistry
occurred on PEG-base Rink Amide resin, 0.45 mmol/g loading.
Side-chain protection of Fmoc amino acid included t-Bu (t-butyl) on
Asp, Ser, Tyr and D-Tyr; Trt (trityl) on Asn and Cys; Boc
(tert-butyloxycarbonyl) on Lys; Pbf
(2,2,4,6,7-pentamethyldihydrobenzofurane) on Arg, Fmoc on K* (i.e.,
Fmoc-Lys(Fmoc)-OH was used to coupled to the resin).
General Procedure
1. Fmoc Deprotection
[0050] Fmoc deprotection was performed using 20% piperidine in DMF
(dimethylformamide) or 20% piperidine/0.1% 6-Cl HOBt
(Hydroxybenzotriazole) in DMF, 5 min+20 min for each
deprotection.
2. Coupling of Fmoc Amino Acids
[0051] Acylations were carried out using 3-fold Fmoc amino acids
activated with DIC (3eq.) (N,N'-Diisopropylcarbodiimide) in the
presence of 6-Cl-HOBt (3eq.). Each coupling reaction took on
average 1-3 h for completion. Kaiser test was used throughout for
the in-process control of the coupling completion and the Fmoc
deprotection. In the case that the Kaiser test was not
satisfactory, re-couplings were done using DIC/6-Cl HOBt or HCTU
(2-(6-Chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium
hexafluorophosphate)/OxymaPure.
3. Resin Cleavage and Peptide Recovery
[0052] Peptidyl resin was extensively washed with DCM
(dicloromethane) and methanol to remove the trace of DMF and dried
at RT overnight. Peptidyl resin was cleavaged with the mixture of
TFA/TIS/EDT/H.sub.2O (trifluoracetic
acid/triethylsilane/1,2-ethanedithiol/water) (92.5/2.5/2.5/2.5,
v/v/v/v) for 2.5-3 h under nitrogen bubbling. Peptides were
collected by precipitation in cold diethyl ether/Hexane (1/1,
v/v).
4. Purification of Linear Peptide
[0053] Crude liner peptide was purified using Phenomenex Gemini
C-18 prep column. 21.5 mm.times.250 mm. The peptide was then dried
by lyophilization..
5. Disulfide Bridge Formation
[0054] Purified linear peptide was dissolved in 0.1M ammonium
bicarbonate (3-5 mg/ml), stand open to air for 2 days. Frequent
HPLC testings were done to monitor the cyclization process. After
cyclization, use TFA to adjust to acidic. isolated the product by
lyophilization.
6. Cyclic Peptide Purification
[0055] Peptides were purified using the following conditions.
Column: Phenomenex Gemini, 5u, C18, 110A, 250.times.21.2 mm Mobile
phase A: 0.1% TFA in Acetonitrile/H.sub.2O (50/50). Mobile phase B:
0.1% TFA/H.sub.2O. Gradient: 0-100% A in 120 min Wavelength: 229
nm. Flow rate: 16-20 ml/min.
7. Isolation of Human Uromodulin
[0056] Uromodulin was precipitated from fresh urine from healthy
donors using 0.58M NaCl. The precipitate was then washed with 0.58M
NaCl and resuspended in water. The uromodulin was dialyzed
extensively against water to remove salt and other contaminants
(MWCo=50 KD). Samples were then stored at -20.degree. C. without
lyophilization. Good overall purity was seen by gel
electrophoresis.
8. General Binding Assays
[0057] Enzyme-linked immunosorbant assays (ELISA) were performed on
the disclosed peptides. Plates were coated with the following light
chain clones overnight at 4.degree. C.: 0.05 uM BER (subtype
lambda, isolated from SP2/0 cells), 0.2 uM ROC (subtype kappa,
isolated from CHO cells), and 0.3 uM BEN (subtype lambda, isolated
from CHO cells). The plates were washed and treated with bovine
serum albumin (BSA) overnight at 4.degree. C. For peptide plates,
10 nM biotin-uromodulin was mixed with peptide overnight at
4.degree. C. Plates were then washed and results were revealed
using streptaviding-HRP (horseradish peroxidase) and
3,3',5,5'-tetramethylbenzidine (TMB). Results are shown in Table
3.
TABLE-US-00007 TABLE 3 Binding Inhibition SEQ (IC.sub.50 uM) ID No.
Sequence BER BEN ROC 2 AhaCAAWDDSLNGPVCKK 500 500 500 3
AhaCnLQALRTPLYTCKK 16.0 12.0 14.9 4 AhaCLSADSSGSYLYVCKK 500 66 500
5 AhaCQVWDNSVGVCKK 500 >120 18.5 6 AhaCQSYDNTLSGSYVCKK >120
19 >120 7 AhaCQSYDNTLSGSLCKK 500 500 500 8 AhaCQSYDARNV 500 58.2
500 9 AhaCQSYDHNNQ 500 26.7 500 10 AhaCQSYDSTNEGVCKK 500 500 500 11
AhaCQQSYSIPWTCKK 34.4 3.2 20.8 12 AhaCQQSYSIPYTCKK 22.9 2.5 27.3 13
AhaCQQYDSLPLTCKK 21.3 3.3 31.9 14 AhaCQQYSYLPITCK*K* 17.3 2.8 20.9
15 AhaCQQYSTAPWTCKK 500 16.7 500 16 AhaCQQYYSAPPTCKK 500 14.3
>120 17 AhaCQQYKNYPWTCKK 500 7.3 >120 18 AhaCQHYDYLPITCK*K*
14.8 0.9 13.7 19 AhaCQHYGSSALTCKK 52 3.3 16.4 20 AhaCQQSYSIPWTCK*K*
60.1 2.6 nt 21 AhaCQQSYSIPYTCK*K* 49.8 nt 75.5 22
AhaCQQ*SYSIPWTCK*K* 96.9 nt nt 23 AhaCQQS*YSIPWTCK*K* 54.1 nt nt 24
AhaCQQSY*SIPWTCK*K* 67.8 nt nt 25 AhaCQQ*SYSIPYTCK*K* 35.9 nt 22.0
26 AhaCQQS*YSIPYTCK*K* 30.1 nt 27.5 27 AhaCQQSY*SIPYTCK*K* 27.1 2.8
26.5 28 AhaCEQSYSIPYTCKK 24.9 nt 25.2 29 AhaCQESYSIPYTCKK 26.3 nt
25.5 30 AhaCQQEYSIPYTCKK 26.5 nt 25.9 31 AhaCQQSESIPYTCKK 25.9 nt
24.1 32 AhaCQQSYEIPYTCKK Nt nt 28 33 AhaCQQSYSEPYTCKK >120 nt
>120 34 AhaCQQSYSIEYTCKK >500 nt >120 35 AhaCQQSYSIPETCKK
>120 nt >120 36 AhaCQQSYSIPYECKK >120 nt >500 37
AhaCRQSYSIPYTCKK 49.8 nt 27.9 38 AhaCQRSYSIPYTCKK 55 nt 26.4 39
AhaCQQRYSIPYTCKK 20.7 nt 22.1 40 AhaCQQSRSIPYTCKK 23.5 nt 26.2 41
AhaCQQSYRIPYTCKK 20.9 nt 21.6 42 AhaCQQSYSRPYTCKK 27.8 nt 29.5 43
AhaCQQSYSIRYTCKK >500 nt >120 44 AhaCQQSYSIPRTCKK 24.9 nt 25
45 AhaCQQSYSIPYRCKK >500 nt >500 46 AhaCQQSY*SIPYTCK*K*K*K*
23.4 nt 35.0 47 K*K*CQQSY*SIPYTCK*K* 32.3 nt 33.5 48
AhaPenQQSY*SIPYTPenK*K* 120.0 nt 120.0 49 oxCCQQSY*SIPYTCK*K* 43.3
nt 41.2 50 AhaCQQYSYLPITCK*K* 17.3 nt nt 51 AhaCQQYSYLPITCR*R* 13.6
nt nt 52 AhaCQQSYLPITCK*K* 69.0 nt nt 53 AhaCQQYSLPITCK*K* 120.0 nt
nt 54 AhaCQQYDLPITCK*K* 120.0 nt nt 56 AhaCnLQALRTPLYTCR*R* 10.6
2.0 18.1 nt = not tested
8. Ex Vivo Conditions
[0058] Binding inhibition, stability, and solubility data was
obtained for peptides of the Formula SEQ ID No. 1. These results
are shown in Table 4. MLC.sub.90 represents the lowest IC.sub.50 at
which uromodulin binding to 90% of the light chains tested was
inhibited. KBB is kidney brush border enzyme.
TABLE-US-00008 TABLE 4 SEQ Binding ID Inhibition Stability
Solubility No. MLC.sub.90 Plasma.sub.50% KBB.sub.50% Urine.sub.80%
(saline, mg/mL) 11 nt <5 min 5 min >2 hrs .gtoreq.100 27 27.1
>120 min >60 min >2 hrs .gtoreq.100
9. Pharmacokinetic Evaluations
[0059] The plasma pharmacokinetics of SEQ ID No. 27 was evaluated
following intravenous (IV) bolus injection (FIG. 1) and 2 hour IV
infusion (FIG. 2) in rats. Similarly, FIG. 3 plasma
pharmacokinetics of SEQ ID No. 27 following intraperitoneal
injection of SEQ ID No. 27 when compared with SEQ ID No. 4 in rat.
This data establishes that peptides having SEQ ID No. 1, in
particular SEQ ID No. 27, has high efficacy and very good
dose-exposure proportionally over a broad range of doses.
[0060] Surprisingly, and perhaps most notably, the clearance rate
of SEQ ID No. 27 was essentially equal to the glomerular filtration
rate, e.g., after infusion of 10 mg/kg of SEQ ID No. 27 for 2 hours
to 6 rats, the percentage of intact peptide recovered in the urine
was 100%.+-.22% (mean.+-.SD). See FIG. 4.
[0061] It will be appreciated that the scope of this invention is
to be defined by the appended claims rather than by the specific
embodiments that have been represented by way of example. The
contents of all references (including literature references, issued
patents, published patent applications, and co-pending patent
applications) cited throughout this application are hereby
expressly incorporated herein in their entireties by reference.
Unless otherwise defined, all technical and scientific terms used
herein are accorded the meaning commonly known to one with ordinary
skill in the art.
Sequence CWU 1
1
56116PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha or ArgMOD_RES(3)..(8)Any
natural or non-natural amino acidMOD_RES(10)..(10)Any natural or
non-natural amino acidMOD_RES(13)..(14)Lys or
ArgMOD_RES(15)..(16)Lys, Arg or not presentSee specification as
filed for detailed description of substitutions and preferred
embodiments 1Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa Pro Xaa Thr Cys Xaa
Xaa Xaa Xaa 1 5 10 15 216PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 2Xaa Cys
Ala Ala Trp Asp Asp Ser Leu Asn Gly Pro Val Cys Lys Lys 1 5 10 15
315PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)AhaMOD_RES(3)..(3)Norleucine 3Xaa
Cys Leu Gln Ala Leu Arg Thr Pro Leu Tyr Thr Cys Lys Lys 1 5 10 15
417PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 4Xaa Cys Leu Ser Ala Asp Ser
Ser Gly Ser Tyr Leu Tyr Val Cys Lys 1 5 10 15 Lys 514PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 5Xaa Cys Gln Val Trp Asp Asn Ser Val Gly
Val Cys Lys Lys 1 5 10 617PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 6Xaa Cys
Gln Ser Tyr Asp Asn Thr Leu Ser Gly Ser Tyr Val Cys Lys 1 5 10 15
Lys 716PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 7Xaa Cys Gln Ser Tyr Asp Asn
Thr Leu Ser Gly Ser Leu Cys Lys Lys 1 5 10 15 810PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 8Xaa Cys Gln Ser Tyr Asp Ala Arg Asn Val
1 5 10 910PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 9Xaa Cys Gln Ser Tyr Asp His
Asn Asn Gln 1 5 10 1015PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 10Xaa Cys
Gln Ser Tyr Asp Ser Thr Asn Glu Gly Val Cys Lys Lys 1 5 10 15
1114PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 11Xaa Cys Gln Gln Ser Tyr Ser
Ile Pro Trp Thr Cys Lys Lys 1 5 10 1214PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 12Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Tyr
Thr Cys Lys Lys 1 5 10 1314PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 13Xaa Cys
Gln Gln Tyr Asp Ser Leu Pro Leu Thr Cys Lys Lys 1 5 10
1414PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)AhaMOD_RES(13)..(14)D-Lys 14Xaa Cys
Gln Gln Tyr Ser Tyr Leu Pro Ile Thr Cys Lys Lys 1 5 10
1514PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 15Xaa Cys Gln Gln Tyr Ser Thr
Ala Pro Trp Thr Cys Lys Lys 1 5 10 1614PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 16Xaa Cys Gln Gln Tyr Tyr Ser Ala Pro Pro
Thr Cys Lys Lys 1 5 10 1714PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 17Xaa Cys
Gln Gln Tyr Lys Asn Tyr Pro Trp Thr Cys Lys Lys 1 5 10
1814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)AhaMOD_RES(13)..(14)D-Lys 18Xaa Cys
Gln His Tyr Asp Tyr Leu Pro Ile Thr Cys Lys Lys 1 5 10
1914PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 19Xaa Cys Gln His Tyr Gly Ser
Ser Ala Leu Thr Cys Lys Lys 1 5 10 2014PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(13)..(14)D-Lys 20Xaa Cys Gln Gln
Ser Tyr Ser Ile Pro Trp Thr Cys Lys Lys 1 5 10 2114PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(13)..(14)D-Lys 21Xaa Cys Gln Gln
Ser Tyr Ser Ile Pro Tyr Thr Cys Lys Lys 1 5 10 2214PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(4)..(4)D-GlnMOD_RES(13)..(14)D-Lys
22Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Trp Thr Cys Lys Lys 1 5 10
2314PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(5)..(5)D-SerMOD_RES(13)..(14)D-Lys
23Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Trp Thr Cys Lys Lys 1 5 10
2414PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(6)..(6)D-TyrMOD_RES(13)..(14)D-Lys
24Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Trp Thr Cys Lys Lys 1 5 10
2514PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(4)..(4)D-GlnMOD_RES(13)..(14)D-Lys
25Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Tyr Thr Cys Lys Lys 1 5 10
2614PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(5)..(5)D-SerMOD_RES(13)..(14)D-Lys
26Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Tyr Thr Cys Lys Lys 1 5 10
2714PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(6)..(6)D-TyrMOD_RES(13)..(14)D-Lys
27Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Tyr Thr Cys Lys Lys 1 5 10
2814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 28Xaa Cys Glu Gln Ser Tyr Ser
Ile Pro Tyr Thr Cys Lys Lys 1 5 10 2914PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 29Xaa Cys Gln Glu Ser Tyr Ser Ile Pro Tyr
Thr Cys Lys Lys 1 5 10 3014PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 30Xaa Cys
Gln Gln Glu Tyr Ser Ile Pro Tyr Thr Cys Lys Lys 1 5 10
3114PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 31Xaa Cys Gln Gln Ser Glu Ser
Ile Pro Tyr Thr Cys Lys Lys 1 5 10 3214PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 32Xaa Cys Gln Gln Ser Tyr Glu Ile Pro Tyr
Thr Cys Lys Lys 1 5 10 3314PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 33Xaa Cys
Gln Gln Ser Tyr Ser Glu Pro Tyr Thr Cys Lys Lys 1 5 10
3414PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 34Xaa Cys Gln Gln Ser Tyr Ser
Ile Glu Tyr Thr Cys Lys Lys 1 5 10 3514PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 35Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Glu
Thr Cys Lys Lys 1 5 10 3614PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 36Xaa Cys
Gln Gln Ser Tyr Ser Ile Pro Tyr Glu Cys Lys Lys 1 5 10
3714PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 37Xaa Cys Arg Gln Ser Tyr Ser
Ile Pro Tyr Thr Cys Lys Lys 1 5 10 3814PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 38Xaa Cys Gln Arg Ser Tyr Ser Ile Pro Tyr
Thr Cys Lys Lys 1 5 10 3914PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 39Xaa Cys
Gln Gln Arg Tyr Ser Ile Pro Tyr Thr Cys Lys Lys 1 5 10
4014PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 40Xaa Cys Gln Gln Ser Arg Ser
Ile Pro Tyr Thr Cys Lys Lys 1 5 10 4114PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 41Xaa Cys Gln Gln Ser Tyr Arg Ile Pro Tyr
Thr Cys Lys Lys 1 5 10 4214PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 42Xaa Cys
Gln Gln Ser Tyr Ser Arg Pro Tyr Thr Cys Lys Lys 1 5 10
4314PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)Aha 43Xaa Cys Gln Gln Ser Tyr Ser
Ile Arg Tyr Thr Cys Lys Lys 1 5 10 4414PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Aha 44Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Arg
Thr Cys Lys Lys 1 5 10 4514PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Aha 45Xaa Cys
Gln Gln Ser Tyr Ser Ile Pro Tyr Arg Cys Lys Lys 1 5 10
4616PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(6)..(6)D-TyrMOD_RES(13)..(16)D-Lys
46Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Tyr Thr Cys Lys Lys Lys Lys 1
5 10 15 4715PRTArtificial SequenceDescription of Artificial
Sequence Synthetic
peptideMOD_RES(1)..(2)D-LysMOD_RES(7)..(7)D-TyrMOD_RES(14)..(15)D-Lys
47Lys Lys Cys Gln Gln Ser Tyr Ser Ile Pro Tyr Thr Cys Lys Lys 1 5
10 15 4814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(2)..(2)PenMOD_RES(6)..(6)D-TyrMOD_RES(12-
)..(12)PenMOD_RES(13)..(14)D-Lys 48Xaa Xaa Gln Gln Ser Tyr Ser Ile
Pro Tyr Thr Xaa Lys Lys 1 5 10 4914PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)Sulfo-D-alanineMOD_RES(6)..(6)D-TyrMOD_RES(13)..(-
14)D-Lys 49Xaa Cys Gln Gln Ser Tyr Ser Ile Pro Tyr Thr Cys Lys Lys
1 5 10 5014PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)AhaMOD_RES(13)..(14)D-Lys 50Xaa Cys
Gln Gln Tyr Ser Tyr Leu Pro Ile Thr Cys Lys Lys 1 5 10
5114PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)AhaMOD_RES(13)..(14)D-Arg 51Xaa Cys
Gln Gln Tyr Ser Tyr Leu Pro Ile Thr Cys Arg Arg 1 5 10
5213PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)AhaMOD_RES(12)..(13)D-Lys 52Xaa Cys
Gln Gln Ser Tyr Leu Pro Ile Thr Cys Lys Lys 1 5 10
5313PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)AhaMOD_RES(12)..(13)D-Lys 53Xaa Cys
Gln Gln Tyr Ser Leu Pro Ile Thr Cys Lys Lys 1 5 10
5413PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)AhaMOD_RES(12)..(13)D-Lys 54Xaa Cys
Gln Gln Tyr Asp Leu Pro Ile Thr Cys Lys Lys 1 5 10
5514PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(1)..(1)AhaMOD_RES(13)..(14)D-Arg 55Xaa Cys
Gln Gln Ser Tyr Ser Ile Pro Tyr Thr Cys Arg Arg 1 5 10
5615PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptideMOD_RES(1)..(1)AhaMOD_RES(3)..(3)NorleucineMOD_RES(14)..(15)D-Arg
56Xaa Cys Leu Gln Ala Leu Arg Thr Pro Leu Tyr Thr Cys Arg Arg 1 5
10 15
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