US2007010450A1PendingUtilityA1
Methods and compositions for the treatment of gastrointestinal disorders
Assignee: MICROBIA INC A MASSACHUSETTS CPriority: Jun 13, 2003Filed: Jun 14, 2004Published: Jan 11, 2007
Est. expiryJun 13, 2023(expired)· nominal 20-yr term from priority
A61P 9/04A61P 35/04A61P 43/00A61P 35/00A61P 29/00A61P 3/04A61P 35/02A61P 13/08A61P 1/10A61P 1/04A61P 1/00A61P 1/14A61P 1/02A61K 38/00C07K 7/08
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Claims
Abstract
Compositions and related methods for treating IBS and other gastrointestinal disorders and conditions (e.g., gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), duodenogastric reflux, Crohn's disease, ulcerative colitis, inflammatory bowel disease, functional heartburn, dyspepsia (including functional dyspepsia or nonulcer dyspepsia), gastroparesis, chronic intestinal pseudo-obstruction (or colonic pseudoobstruction), and disorders and conditions associated with constipation, e.g., constipation associated with use of opiate pain killers, post-surgical constipation, and constipation associated with neuropathic disorders as well as other conditions and disorders are described. The compositions feature peptides that activate the guanylate cyclase C (GC-C) receptor.
Claims
exact text as granted — not AI-modified1 . A purified polypeptide comprising the amino acid sequence: Xaa 1 Xaa 2 Xaa 3 Cys 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Cys 12 Xaa 13 Xaa 14 Xaa 15 Xaa 16 (SEQ ID NO:1) wherein:
Xaa 1 is Ser, Asn, Tyr, Ala, Gln, Pro, Lys, Gly, or Thr, or is missing; Xaa 2 is His, Asp, Glu, Ala, Ser, Asn, Gly, or is missing; Xaa 3 is Thr, Asp, Ser, Glu, Pro, Val or Leu; Xaa 5 is Asp, Ile or Glu; Xaa 6 is Ile, Trp or Leu; Xaa 7 is Cys, Ser, or Tyr; Xaa 8 is Ala, Val, Thr, Ile, Met or is missing; Xaa 9 is a) any amino acid, b) Phe, Tyr, Asn, Trp, c) an amino acid other than Phe, Trp, or Tyr, d) non-aromatic amino acid or e) is missing; Xaa 10 is Ala, Val, Met, Thr or Ile; Xaa 11 is Ala or Val; Xaa 13 is Ala or Thr; Xaa 14 is Gly, Ala or Ser; Xaa 15 is Cys, Tyr or is missing; and Xaa 16 is: a) Trp, Tyr or Phe to create a chymotrypsin cleavage site; b) Lys or Arg to create a trypsin cleavage site; c) is missing or d) His or Leu or Ser.
2 . The purified polypeptide of claim 1 wherein Xaa 1 is preceded by Lys or Tyr.
3 . A composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier.
4 . A composition comprising a polypeptide comprising the amino acid sequence: Xaa 1 Xaa 2 Xaa 3 Cys 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Cys 12 Xaa 13 Xaa 14 Xaa 15 Xaa 16 (SEQ ID NO:1) wherein:
Xaa 1 is Ser, Asn, Tyr, Ala, Gln, Pro, Lys, Gly, or Thr, or is missing; Xaa 2 is His, Asp, Glu, Ala, Ser, Asn, Gly, Pro or is missing; Xaa 3 is Thr, Asp, Ser, Glu, Pro, Val or Leu; Xaa 5 is Asp, Ile or Glu; Xaa 6 is Ile, Trp or Leu; Xaa 7 is Cys, Ser, or Tyr; Xaa 8 is Ala, Val, Thr, Ile, Met or is missing; Xaa 9 is Phe, Tyr, Asn, Trp, an amino acid other than Phe, Trp, or Tyr, is a non-aromatic amino acid or is missing; Xaa 10 is Ala, Val, Met, Thr or Ile; Xaa 11 is Ala or Val; Xaa 13 is Ala or Thr; Xaa 14 is Gly, Ala or Ser; Xaa 15 is Cys, Tyr or is missing; Xaa 16 is: a) Trp, Tyr or Phe to create a chymotrypsin cleavage site; b) Lys or Arg to create a trypsin cleavage site; c) is missing or d) His or Leu or Ser and a pharmaceutically acceptable carrier.
5 . A purified polypeptide comprising the amino acid sequence: Xaa 1 Xaa 2 Xaa 3 Cys 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Cys 12 Xaa 13 Xaa 14 Xaa 15 Xaa 16 (SEQ ID NO:1) wherein:
Xaa 1 is Asn, any amino acid or is missing; Xaa 2 is Asp, Glu, any amino acid or is missing; Xaa 3 is Asp or Glu; Xaa 5 is any amino acid or Glu; Xaa 6 is any amino acid or Leu; Xaa 7 is Cys; Xaa 8 is any amino acid or Val; Xaa 9 is Asn, Gln, Tyr; Xaa 10 is is any amino acid or Val; Xaa 11 is any amino acid or Ala; Xaa 13 is is any amino acid or Thr; Xaa 14 is is any amino acid or Gly; Xaa 15 is Cys; Xaa 16 is any amino acid, Leu or missing
6 . A purified polypeptide comprising the amino acid sequence: Asn 1 Xaa 2 Xaa 3 Xaa 4 Glu 5 Leu 6 Xaa 7 Val 8 Asn 9 Xaa 10 Xaa 11 Xaa 12 Thr 13 Xaa 14 Xaa 15 Leu 16 (SEQ ID NO:2)
Xaa 2 is Asp or Glu; Xaa 3 is Asp or Glu; Xaa 4 is Cys or Mpt (mercaptoproline) or Pen (penicillamine) or Dpr (diaminopropionic acid) or Asp or Glu; Xaa 7 is Cys or Mpt (mercaptoproline) or Pen (penicillamine) or Dpr (diaminopropionic acid) or Asp or Glu; Xaa 10 is Val or Pro; Xaa 11 is Ala or Alb (alpha-aminoisobutyric acid); Xaa 12 is Cys or Mpt (mercaptoproline) or Pen (penicillamine) or Dpr (diaminopropionic acid) or Asp or Glu; Xaa 14 is Gly or Ala; Xaa 15 is Cys or Mpt (mercaptoproline) or Pen (penicillamine) or Dpr (diaminopropionic acid) or Asp or Glu; and
7 . The polypeptide of claim 1 wherein Xaa 15 is other than Cys or is missing and Xaa 7 is Ser or an amino acid other than Cys.
8 . The polypeptide of claim 1 wherein at least 5 of Xaa 1 , Xaa 2 , Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaa 9 , Xaa 10 , Xaa 11 , Xaa 13 , Xaa 14 , and Xaa 16 are any amino acid other than Cys.
9 . The polypeptide of claim 1 wherein: Xaa 9 is any amino acid other than Gln.
10 . The polypeptide of claim 1 wherein Xaa 2 and Xaa 3 are Glu.
11 . A polypeptide comprising the amino acid sequence of claim 1 wherein the polypeptide is not cleaved after Xaa 9 by chymotrypsin.
12 . The polypeptide of claim 1 wherein the polypeptide does not comprise the amino acid sequence PGTCEICAYAACTGC (SEQ ID NO:4).
13 . A purified polypeptide comprising the amino acid sequence KPGTCEICAYAACTGC (SEQ ID NO:3).
14 . A purified polypeptide selected from the group consisting of:
a) a polypeptide comprising the amino acid sequence PGTCEICAXAACTGC (SEQ ID NO:84) wherein X is any amino acid other than Phe; b) a polypeptide comprising the amino acid sequence PGTCEICAXAACTGC (SEQ ID NO:84) wherein X is any amino acid other than Phe and Trp; c) a polypeptide comprising the amino acid sequence PGTCEICAXAACTGC (SEQ ID NO:84) wherein X is any amino acid other than Phe, Trp, Ile, Leu and Val; d) a polypeptide comprising the amino acid sequence PGTCEICAXAACTGC (SEQ ID NO:84) wherein X is any amino acid other than Phe, Trp, Ile, Leu, Val and His; e) a polypeptide comprising the amino acid sequence PGTCEICAXAACTGC (SEQ ID NO:84) wherein X is any non-aromatic amino acid or f) a polypeptide comprising the amino acid sequence PGTCEICAXAACTGC (SEQ ID NO:84) wherein X is missing.
15 . A purified polypeptide comprising an amino acid sequence selected from the group consisting of:
PGTCEICASAACTGC (SEQ ID NO:5)
PGTCEICATAACTGC (SEQ ID NO:6)
PGTCEICANAACTGC (SEQ ID NO:7)
PGTCEICAQAACTGC (SEQ ID NO:8)
PGTCEICARAACTGC (SEQ ID NO:9)
PGTCEICAEAACTGC (SEQ ID NO:10)
PGTCEICADAACTGC (SEQ ID NO:11)
PGTCEICAGAACTGC (SEQ ID NO:12)
PGTCEICAAAACTGC (SEQ ID NO:13)
PGTCEICAMAACTGC (SEQ ID NO:14)
PGTCEICAIAACTGC (SEQ ID NO:15)
PGTCEICALAACTGC (SEQ ID NO:16)
PGTCEICAVAACTGC (SEQ ID NO:17)
and
PGTCEICAHAACTGC (SEQ ID NO:18)
16 . A purified polypeptide comprising an amino acid sequence shown in FIG. 1 .
17 . A purified polypeptide comprising an amino acid sequence shown in FIG. 2 wherein Xaa is any amino acid.
18 . The purified polypeptide of claim 17 wherein Xaa is any amino acid other than Cys.
19 . A purified polypeptide comprising an amino acid sequence selected from the group consisting of:
PGTCEGICAYAACTGC
(SEQ ID NO:20)
PGTCEIGCAYAACTGC
(SEQ ID NO:21)
PGTCEICGAYAACTGC
(SEQ ID NO:22)
PGTCEICAGYAACTGC
(SEQ ID NO:23)
PGTCEICAYGAACTGC
(SEQ ID NO:24)
PGTCEICAYAGACTGC
(SEQ ID NO:25)
PGTCEICAYAAGCTGC
(SEQ ID NO:26)
PGTCEICAYAACGTGC
(SEQ ID NO:27)
PGTCEICAYAACTGGC
(SEQ ID NO:28)
PGTCAEICAYAACTGC
(SEQ ID NO:29)
PGTCEAICAYAACTGC
(SEQ ID NO:30)
PGTCEIACAYAACTGC
(SEQ ID NO:31)
PGTCEICAAYAACTGC
(SEQ ID NO:32)
PGTCEICAYAAACTGC
(SEQ ID NO:33)
PGTCEICAYAACATGC
(SEQ ID NO:34)
PGTCEICAYAACTAGC
(SEQ ID NO:35)
PGTCEICAYAACTGAC
(SEQ ID NO:36)
PGTCAEICAAYAACTGC
(SEQ ID NO:37)
PGTCEAICAAYAACTGC
(SEQ ID NO:38)
and
PGTCEIACAAYAACTGC
(SEQ ID NO:39)
20 . The polypeptide of claim 1 further comprising an amino acid sequence selected from: Asp Phe, the amino acid sequence of endomorphin-1, the amino acid sequence of endomorphin-2, the amino acid sequence of nocistatin, the amino acid sequence of dalargin, the amino acid sequence of lupron, and the amino acid sequence of substance P.
21 . A method for treating a gastrointestinal disorder comprising administering a composition comprising the purified polypeptide of claim 1 .
22 . The method of claim 21 wherein the gastrointestinal disorder is: a gastrointestinal motility disorder, irritable bowel syndrome, a functional gastrointestinal disorder, gastroesophageal reflux disease, duodenogastric reflux, functional heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, or colonic pseudo-obstruction.
23 . A method for treating obesity comprising administering a composition comprising the purified polypeptide of claim 1 .
24 . A method for treating congestive heart failure comprising administering a composition comprising the purified polypeptide of claim 1 .
25 . A method for treating benign prostatic hyperplasia comprising administering a composition comprising the purified polypeptide of claim 1 .
26 . A method for treating constipation comprising administering a composition comprising the purified polypeptide of claim 1 .
27 . The method of claim 21 wherein the polypeptide does not comprise the amino acid sequence PGTCEICAYAACTGC (SEQ ID NO:4) or the amino acid sequence NDDCELCVNVACTGCL (SEQ ID NO:44).
28 . A method for increasing gastrointestinal motility in a patient, the method comprising administering to the patient the polypeptide of claim 1 .
29 . A method for decreasing gastrointestinal pain or visceral pain in a patient, the method comprising administering to the patient the polypeptide of claim 1 .
30 . A method for increasing the activity of an intestinal guanylate cyclase (GC-C) receptor in a patient, the method comprising administering to the patient the polypeptide of claim 1 .
31 . A method for treating a patient suffering a gastrointestinal disorder, the method comprising administering to the patient a composition comprising a complete or partial agonist of the GC-C receptor.
32 . A method for treating a patient suffering from constipation, the method comprising administering a composition comprising a complete or partial agonist of the GC-C receptor.
33 . A method for increasing gastrointestinal motility in a patient, the method comprising administering to the patient a composition comprising a complete or partial agonist of the GC-C receptor.
34 . A method for decreasing gastrointestinal pain or visceral pain in a patient, the method comprising administering to the patient a composition comprising a complete or partial agonist of the GC-C receptor.
35 . A method for treating congestive heart failure, the method comprising administering a complete or partial agonist of the GC-C receptor.
36 . A method for treating benign prostatic hyperplasia, the method comprising administering a complete or partial agonist of the GC-C receptor.
37 . A method for treating obesity, the method comprising administering a complete or partial agonist of the GC-C receptor.
38 . A purified polypeptide comprising the amino acid sequence: Xaa 1 Xaa 2 Xaa 3 Cys 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Cys 12 Xaa 13 Xaa 14 Xaa 15 Xaa 16 (SEQ ID NO:1) wherein:
Xaa 1 is any amino acid or is missing; Xaa 2 is any amino acid or is missing; Xaa 3 is any amino acid or is missing; Xaa 5 is Glu; Xaa 6 is Tyr, Trp, Phe or Leu; Xaa 7 is Cys; Xaa 8 is any of the 20 naturally-occurring amino acids other than Cys or is missing; Xaa 9 is any of the 20 naturally-occurring amino acids; Xaa 10 is Pro or Gly; Xaa 11 is any of the 20 naturally-occurring amino acids; Xaa 13 is Thr, Val or Gly; Xaa 14 is Gly or Ala; Xaa 15 is Cys; and Xaa 16 is any of the 20 naturally-occurring amino acids or is missing.
39 . The purified polypeptide of claim 38 wherein Xaa 9 is Asn.
40 . The purified polypeptide of claim 38 wherein Xaa 11 is Ala or Thr.
41 . The purified polypeptide of claim 38 wherein Xaa 8 is missing.
42 . The purified polypeptide of claim 38 wherein Xaa 16 is Tyr.
43 . The purified polypeptide of claim 38 wherein Xaa 4 is immediately preceded by an amino acid sequence seleted from: Ser His Thr; Pro Ser Thr; Thr; Pro Asp Pro; Ile Ala Glu Asp Ser His Thr (SEQ ID NO:8604); Ile Ala Gln Asp Pro Ser Thr (SEQ ID NO:8605; Ala Asn Thr; Asn Thr; Asp Pro Asn Thr (SEQ ID NO:8606); Lys Asn Thr; Pro Asn Thr; Ile Ala Gln Asp Pro Asn Thr (SEQ ID NO:8607); Lys Pro Asn Thr (SEQ ID NO:8608); Asp Pro Gly Thr (SEQ ID NO:8609); Glu Asp Pro Gly Thr (SEQ ID NO:8610); Pro Gly Thr; Pro Ala Thr; Val Ala Ala Arg Ala Asp Leu (SEQ ID NO:8611); Gly Asp Asp; Asn Asp Glu; Gln Glu Asp; Asn Asp Asp; Arg Thr Ile Ala Asn Asp Asp (SEQ ID NO:8612); Thr Ile Ala Asn Asp Asp (SEQ ID NO:8613); Asp Asp; Arg Thr Met Asp Asn Asp Glu (SEQ ID NO:8614); Arg Thr Ile Ala Gly Asp Asp (SEQ ID NO:8615); Arg Thr IleAlaAsnAsp (SEQ ID NO:8616); Asp; GluAsp; Arg Ser Ile Ser Gln Glu Asp (SEQ ID NO:8617); Thr Asp Glu; Arg Thr Ile Ala Thr Asp Glu (SEQ ID NO:8618); Glu; Ile Ile Thr Pro Pro Asp Pro (SEQ ID NO:8619); Gln Glu Leu; Lys Asp Asp; Gln Glu Glu; Arg Tyr Ile Asn Gln Glu Glu (SEQ ID NO:8620); Ala Ser Ser Tyr Ala Ser (SEQ ID NO:8621); and Thr Ser Ser Tyr Ala Ser (SEQ ID NO:8622).
44 . A pharmaceutical composition comprising the polypeptide of claim 38 and a pharmaceutically acceptable carrier.
45 . A purified polypeptide comprising the amino acid sequence: Xaa 1 Xaa 2 Xaa 3 Cys 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Cys 12 Xaa 13 Xaa 14 Xaa 15 Xaa 16 (SEQ ID NO:1) wherein:
Xaa 1 is: a) Ser, Asn, Tyr, Ala, Gln, Pro, Lys, Gly, or Thr, or is missing; b) preceded by Lys or Tyr; c) any amino acid; d) missing; e) any amino acid other than Cys; or f) Lys or Arg; Xaa 2 is: a) His, Asp, Glu, Ala, Ser, Asn, Gly, or is missing; b) His, Asp, Glu, Ala, Ser, Asn, Gly, Pro or is missing; c) Asp, Glu, any amino acid or is missing; d) Asp or Glu; e) any amino acid other than Cys; e) Glu; f) missing; g) Trp, Tyr or Phe; or h) Lys or Arg; Xaa 3 is: a) Thr, Asp, Ser, Glu, Pro, Val or Leu; Asp or Glu; b) any amino acid other than Cys; c) Glu; d) Thr; e) Thr, Asp, Ser, Glu, Pro, Val or Leu or is missing; f) Trp, Tyr or Phe; or g) Lys or Arg; Xaa 4 is: a) Cys, Mpt (mercaptoproline), Pen (penicillamine), Dpr (diaminopropionic acid), Asp, or Glu; Xaa 5 is: a) any amino acid; b) Glu, Asp, Gln, Gly or Pro; c) Glu; d) Glu or Asp; e) Asp, Ile or Glu; f) any amino acid; or g) any amino acid other than Cys; Xaa 6 is: a) Leu, Ile, Val, Ala, Lys, Arg, Trp, Tyr or Phe; b) Leu, Ile, Val, Lys, Arg, Trp, Tyr or Phe; Leu, Ile, Lys, Arg, Trp, Tyr or Phe; c) Leu, Ile, Val, Trp, Tyr or Phe; d) Trp, Tyr, Phe or Leu; e) Leu, Ile or Val; f) Ile, Trp or Leu; g) Trp, Tyr or Phe; h) Ile or Leu; i) Tyr; j) any amino acid; k) any amino acid except Leu; l) any natural or non-natural aromatic amino acid; or m) any amino acid other than Cys; Xaa 7 is: a) Cys, Ser, or Tyr; Cys; b) Cys, Mpt (mercaptoproline), Pen (penicillamine), Dpr (diaminopropionic acid), Asp or Glu; c) Ser; or d) an amino acid other than Cys; Xaa 8 is: a) Ala, Val, or Ile; b) Ala, Val, Thr, Ile, Met or is missing; c) any amino acid; d) Val; e) any amino acid other than Cys; or f) missing; Xaa 9 is: a) any amino acid; b) any amino acid other than Phe and Tyr; c) any amino acid other than Phe, Tyr, and Trp; d) any amino acid other than Phe, Tyr, Trp, Ile, Leu and Val; e) any amino acid other than Phe, Tyr, Trp, Ile, Leu, Val, and His; f) any amino acid other than Gln; g) any amino acid other than Lys, Arg, Phe, Tyr, and Trp; h) any amino acid other than Lys, Arg, Phe, Tyr, Trp, Ile, Leu and Val; i) any amino acid other than Lys, Arg, Phe, Tyr, Trp, Ile, Leu, Val, and His; j) any non-aromatic amino acid; k) missing; l) Phe, Tyr, Asn, or Trp; m) Asn, Tyr, Asp or Ala; n) Asn, Gln, or Tyr; o) Phe or Tyr; p) Asn; or q) any amino acid other than Cys; Xaa 10 is: a) Ala, Pro or Gly; b) Pro or Gly; c) Pro; d) Ala, Val, Met, Thr or Ile; e) any amino acid; f) Val; g) Val or Pro; h) Ala or Val; i) any amino acid other than Cys; j) Pro; or k) Gly; Xaa 11 is: a) any amino acid; b) Ala, Leu, Ser, Gly, Val, Glu, Gln, Ile, Leu, Lys, Arg, or Asp; c) Ala or Gly; d) Ala; e) Ala or Val; f) any amino acid; g) Ala or Alb (alpha-aminoisobutyric acid); h) any amino acid other than Cys; i) Ala or Thr; or j) Thr. Xaa 12 is: a) Cys, Mpt (mercaptoproline), Pen (penicillamine), Dpr (diaminopropionic acid), Asp, or Glu; or b) any amino acid other than Cys; Xaa 13 is: a) Thr, Ala, Asn, Lys, Arg, or Trp; b) Thr, Ala, Lys, Arg, or Trp; c) any amino acid; d) any non-aromatic amino acid; e) Thr, Ala, or Trp; f) Trp, Tyr or Phe; g) Thr or Ala; h) any amino acid; i) Thr; j) any amino acid other than Cys; k) Thr, Val, or Gly; l) Thr or Val, m) Thr or Gly, n) Val or Thr; o) Val; p) Thr; or q) Gly; Xaa 14 is: a) Gly, Pro or Ala; b) Gly; c) any amino acid; d) Gly, Ala or Ser; e) Gly or Ala; f) any amino acid other than Cys; or g) Ala; Xaa 15 is: a) Cys, Tyr or is missing; b) Cys; c) Cys, Mpt (mercaptoproline), Pen (penicillamine), Dpr (diaminopropionic acid), Asp, Glu; or d) any amino acid other than Cys or is missing; and Xaa 16 is: a) Trp, Tyr, Phe, Asn, Ile, Val, His or Leu; b) Trp, Tyr, Phe, Asn or Leu; c) Trp, Tyr, Phe or Leu; d) Trp, Tyr, or Phe; e) Leu, Ile or Val; f) His, Leu or Ser; g) Tyr or Leu; Lys or Arg; h) His; i) any amino acid, j) Leu, or missing; k) Trp, Tyr, Phe, Lys, Arg or is missing; l) missing; m) any amino acid other than Cys; or n) Tyr.
46 . A composition comprising the polypeptide of claim 45 and a pharmaceutically acceptable carrier.
47 . A purified polypeptide comprising the amino acid sequence: Xaa 1 Xaa 2 Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Xaa 12 Xaa 13 Xaa 14 Xaa 15 Xaa 16 (SEQ ID NO:1) wherein:
Xaa 1 is any amino acid or is missing; Xaa 2 is any amino acid or is missing; Xaa 3 is any amino acid or is missing; Xaa 4 is Cys, Mpt (mercaptoproline), Pen (penicillamine), Dpr (diaminopropionic acid), Asp or Glu; Xaa 5 is Glu; Xaa 6 is Tyr, Trp, Phe or Leu; Xaa 7 is Cys, Mpt (mercaptoproline), Pen (penicillamine), Dpr (diaminopropionic acid), Asp or Glu; Xaa 8 is any amino acid other than Cys or is missing; Xaa 9 is any amino acid; Xaa 10 is Pro or Gly; Xaa 11 is any amino acid; Xaa 12 is Cys, Mpt (mercaptoproline), Pen (penicillamine), Dpr (diaminopropionic acid), Asp or Glu; Xaa 13 is Thr, Val or Gly; Xaa 14 is Gly or Ala; Xaa 15 is Cys, Mpt (mercaptoproline), Pen (penicillamine), Dpr (diaminopropionic acid), Asp or Glu; and Xaa 16 is any amino acid or is missing.Join the waitlist — get patent alerts
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