EPHA4 cyclic peptide antagonists for neuroprotection and neural repair

Patent metadata

Field	Value
Publication number	US-10322161-B2
Application number	US-201515326442-A
Country	US
Kind code	B2
Filing date	Jul 15, 2015
Priority date	Jul 15, 2014
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

The present specification discloses APY cyclic peptides having EphA4 antagonistic activity, pharmaceutical compositions containing such EphA4 antagonists, and methods and uses of treating an EphA4-based disease, disorder or pathology in an individual using such APY cyclic peptides or pharmaceutical compositions.

First claim

The invention claimed is:

1. An EphA4 receptor antagonist comprising a cyclic peptide having a length of 12 amino acids and including the sequence X 1 -X 2 -X 3 -C 4 -X 5 -X 6 -X 7 -βA 8 -X 9 -W-X 11 -C 12 (SEQ ID NO: 3), wherein X 1 is independently βA, D-A, A, E, G, Q, D, L, S, F, or Y; X 2 is independently P, A, G, Ahx, Ava, γAbu, βA or Sar; X 3 is independently Y, F, W, V, L, H or I; X 5 is independently V or L; X 6 is independently Y, F, W or H; X 7 is independently any amino acid; X 9 is independently any amino acid; and X 11 is independently any amino acid; wherein C 4 and C 12 form a disulfide bridge; and wherein C 12 is optionally amidated.

2. The EphA4 receptor antagonist according to claim 1 , wherein X 1 is independently βA, D-A, A, E, G or Q; X 2 is P; X 3 is independently Y, F, W, V, L or H; X 5 is V; X 6 is independently Y, F or W; X 7 is independently any amino acid except P; X 9 is independently any amino acid except P; and/or X 11 is independently any amino acid except P.

3. The EphA4 receptor antagonist according to claim 2 , wherein X 3 is independently Y, F or W.

4. The EphA4 receptor antagonist according to claim 2 , wherein X 7 is independently R, T, N, D, S, Q, Y, K, A, G or E; X 9 is independently S, E, T, V, D, Y, Q, V, W, R, N, L, K or H; and X 11 is independently S, E, L, N, V, I, H, K, M, D, W, T or G.

5. The EphA4 receptor antagonist according to claim 4 , wherein X 7 is independently R, T, N, D, S, or Q; X 9 is independently S, E, T, V, W, R, L, D, Y; and X 11 is independently S, E, L, N, T, K, V, I or H.

6. The EphA4 receptor antagonist according to claim 5 , wherein X 7 is independently R, T, N, D, S, or Q; X 9 is independently S, E, T, V, D, Y; and X 11 is independently S, E, L, N, K, V, I or H.

7. The EphA4 receptor antagonist according to claim 6 , wherein X 7 is independently R, T, or N; X 9 is independently S, E, T or V; and is independently S, E, L or N.

8. The EphA4 receptor antagonist according to claim 1 , wherein the sequence comprises X 1 -P 2 -X 3 -C 4 -X 5 -X 6 -X 7 -βA 8 -X 9 -W 10 -X 11 -C 12 (SEQ ID NO: 6), wherein C 4 and C 12 form a disulfide bridge; and wherein C 12 is optionally amidated.

9. The EphA4 receptor antagonist according to claim 1 , wherein the sequence comprises X 1 -X 2 -X 3 -C 4 -V 5 -X 6 -X 7 -βA 8 -X 9 -W 10 -X-C 12 (SEQ ID NO: 9), wherein C 4 and C 12 form a disulfide bridge; and wherein C 12 is optionally amidated.

10. The EphA4 receptor antagonist according to claim 1 , wherein the sequence comprises X 1 -P 2 -X 3 -C 4 -V 5 -X 6 -X 7 -βA 8 -X 9 -W 10 -X 11 -C 12 (SEQ ID NO: 12), wherein C 4 and C 12 form a disulfide bridge; and wherein C 12 is optionally amidated.

11. The EphA4 receptor antagonist according to claim 1 , wherein the sequence comprises X 1 -P 2 -Y 3 -C 4 -V 5 -X 6 -X 7 -βA 8 -X 9 -W 10 -X 11 -C 12 (SEQ ID NO: 15), wherein C 4 and C 12 form a disulfide bridge; and wherein C 12 is optionally amidated.

12. The EphA4 receptor antagonist according to claim 1 , wherein the sequence comprises X 1 -P 2 -X 3 -C 4 -V 5 -Y 6 -X 7 -βA 8 -X 9 -W 10 -X 11 -C 12 (SEQ ID NO: 18), wherein X 1 is independently βA, D-A, A, E, G or Q; X 3 is independently Y, F, W, V, L or H; X 7 is independently any amino acid except P; X 9 is independently any amino acid except P; and X 11 is independently any amino acid except P; wherein C 4 and C 12 form a disulfide bridge; and wherein C 12 is optionally amidated.

13. The EphA4 receptor antagonist according to claim 1 , wherein the sequence comprises X 1 -P 2 -Y 3 -C 4 -V 5 -Y 6 -X 7 -βA 8 -X 9 -W 10 -X 11 -C 12 (SEQ ID NO: 21), wherein X 1 is independently βA, D-A, A, E, G or Q; X 7 is independently any amino acid except P; X 9 is independently any amino acid except P; and is independently any amino acid except P; wherein C 4 and C 12 form a disulfide bridge; and wherein C 12 is optionally amidated.

14. The EphA4 receptor antagonist according to claim 1 , wherein the sequence comprises X 1 -P 2 -Y 3 -C 4 -V 5 -Y 6 -R 7 -βA 8 -X 9 -W 10 -X 11 -C 12 (SEQ ID NO: 24), wherein X 1 is independently βA, D-A, A, E, G or Q; X 9 is independently any amino acid except P; and is independently any amino acid except P; wherein C 4 and C 12 form a disulfide bridge; and wherein C 12 is optionally amidated.

15. The EphA4 receptor antagonist according to claim 1 , wherein C 12 is amidated.

16. The EphA4 receptor antagonist according to claim 1 , wherein the sequence is APYCVYRβASWSC (SEQ ID NO: 35), APYCVYRβASWSC-am (SEQ ID NO: 36), APYCVYKβASWSC-am (SEQ ID NO: 45), βAPYCVYRβASWSC (SEQ ID NO: 46), βAPYCVYRβASWSC-am (SEQ ID NO: 47), βAPYCVYKβASWSC-am (SEQ ID NO: 48), βAPYCVYRβAEWEC (SEQ ID NO: 49), βAPYCVYRβAEWEC-am (SEQ ID NO: 50), D-APYCVYRβASWSC (SEQ ID NO: 51), D-APYCVYRβASWSC-am (SEQ ID NO: 52), APYCVWRβASWSC (SEQ ID NO: 53), APYCVYTβAEWLC (SEQ ID NO: 54), APYCVYNβATWNC (SEQ ID NO: 55), APYCVYRβAVWEC (SEQ ID NO: 56), APVCVWRβASWSC (SEQ ID NO: 57), APLCVWRβASWSC (SEQ ID NO: 58), APLCVYRβASWSC (SEQ ID NO: 59), APWCVFRβASWSC (SEQ ID NO: 60), APHCVFRβASWSC (SEQ ID NO: 61), APFCLYTβADWVC (SEQ ID NO: 62), APYCVYDβATWIC (SEQ ID NO: 63), APYCVYSβATWHC (SEQ ID NO: 64), APYCVYDβASWNC (SEQ ID NO: 65), APYCVYQβAYWKC (SEQ ID NO: 66), APYCVYRβASWSC (SEQ ID NO: 67), EPYCVYRβASWSC (SEQ ID NO: 68), APLCVYRβASWSC (SEQ ID NO: 69), Ahx-YCVYRβASWSC-am (SEQ ID NO: 119), Ava-YCVYRβASWSC-am (SEQ ID NO: 120), yAbu-YCVYRβASWSC-am (SEQ ID NO: 121), βA-YCVYRβASWSC-am (SEQ ID NO: 122), GYCVYRβASWSC-am (SEQ ID NO: 123) or Sar1-YCVYRβASWSC-am (SEQ ID NO: 124).

17. A pharmaceutical composition comprising one or more EphA4 receptor antagonist according to claim 1 .

18. The pharmaceutical composition according to claim 17 , wherein the one or more EphA4 receptor antagonist are each present in an amount of between about 100 ng to about 1,000 μg.

19. The pharmaceutical composition according to claim 17 , wherein the pharmaceutical composition further comprises one or more pharmaceutical acceptable carriers.

20. A method of treating an EphA4-based disease, disorder or pathology, the method comprising administering an EphA4 receptor antagonist as defined in claim 1 or a pharmaceutical composition as defined in claim 17 to an individual in need thereof, wherein administration reduces one or more symptoms associated with the EphA4-based disease, disorder or pathology.

Assignees

• Sanford Burnham Prebys Medical Discovery Inst
• Scripps Research Inst

Inventors

• Pasquale Elena B
• Dawson Philip
• Olson Erika
• Riedl Stefan J

Classifications

• A61K38/12 Primary

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• C07K7/64

  Cyclic peptides containing only normal peptide links · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K5/12

  Cyclic peptides {with only normal peptide bonds in the ring} · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title