Nanomolar peptides and derivatives to differentially modulate ephrin receptors

Patent metadata

Field	Value
Publication number	US-2022144893-A1
Application number	US-202017438824-A
Country	US
Kind code	A1
Filing date	Mar 13, 2020
Priority date	Mar 14, 2019
Publication date	May 12, 2022
Grant date	—

Abstract

Disclosed herein are methods and compositions engineered to modulate EphA2, including novel peptides with unexpectedly high specificity and binding affinity. The compositions described herein can be attenuated to treat subjects suffering from diseases and/or conditions.

First claim

What is claimed is:

1 . A method of treating a disease or condition in a subject comprising administering to the subject a therapeutically effective amount of a peptide comprising X1-A-Y-P-D-S-V-P-X2, wherein
X1 is Y-S or W-L; X2 is any one of M-M-S, Mam, Yam, Y-K, Y-S-K, Y-G-S-K, Y-G-S-G-K, Y-R, or Y-S; and a half-life extending molecule, the addition of which slows down excretion of the peptide from the subject.

2 . The method of claim 1 , wherein the peptide further comprises a GSGSK linker on a carboxyl terminus (“C-terminal”).

3 . The method in any one of claims 1 - 2 , wherein the peptide further comprises biotin on the C-terminal.

4 . The method of claim 1 , wherein the peptide further comprises a β-A (Alanine) on an amino terminus (“N-terminal”).

5 . The method of claim 4 , wherein the peptide further comprises biotin on a carboxyl terminus (“C-terminal”).

6 . The method of claim 4 , wherein the peptide further comprises P-K on a carboxyl terminus (“C-terminal”).

7 . The method of claim 6 , wherein the peptide further comprises biotin on the C-terminal.

8 . The method of claim 6 , wherein the C-terminal of the peptide is amidated.

9 . The method of claim 8 , wherein the peptide further comprises biotin on the C-terminal.

10 . The method of claim 6 , wherein the peptide further comprises acetylation of a Lys14 side chain.

11 . The method of claim 1 , wherein the peptide further comprises a biotinylated alanine on an amino terminus (“N-terminal”).

12 . The method of claim 11 , wherein the peptide further comprises P-K on a carboxyl terminus (“C-terminal”).

13 . The method of claim 12 , wherein the C-terminal of the peptide is amidated.

14 . A method of treating a subtype of a disease or condition in a subject comprising administering to the subject a therapeutically effective amount of a peptide comprising X1-A-Y-P-D-S-V-P-X2, wherein
X1 is Y-S or W-L; X2 is any one of M-M-S, Mam, Yam, Y-K, Y-S-K, Y-G-S-K, Y-G-S-G-K, Y-R, or Y-S; and a half-life extending molecule, the addition of which slows down excretion of the peptide from the subject.

15 . The method of claim 14 , wherein the peptide further comprises a GSGSK linker on a carboxyl terminus (“C-terminal”).

16 . The method in any one of claims 14 - 15 , wherein the peptide further comprises biotin on the C-terminal.

17 . The method of claim 14 , wherein the peptide further comprises a β-A (Alanine) on an amino terminus (“N-terminal”).

18 . The method of claim 17 , wherein the peptide further comprises biotin on a carboxyl terminus (“C-terminal”).

19 . The method of claim 17 , wherein the peptide further comprises P-K on a carboxyl terminus (“C-terminal”).

20 . The method of claim 19 , wherein the peptide further comprises biotin on the C-terminal.

21 . The method of claim 19 , wherein the C-terminal of the peptide is amidated.

22 . The method of claim 21 , wherein the peptide further comprises biotin on the C-terminal.

23 . The method of claim 19 , wherein the peptide further comprises acetylation of a Lys14 side chain.

24 . The method of claim 14 , wherein the peptide further comprises a biotinylated alanine on an amino terminus (“N-terminal”).

25 . The method of claim 24 , wherein the peptide further comprises P-K on a carboxyl terminus (“C-terminal”).

26 . The method of claim 25 , wherein the C-terminal of the peptide is amidated.

27 . A method of preventing or reversing the onset of a subset of a disease or condition in a subject suffering from a disease or condition comprising administering to the subject a therapeutically effective amount of a peptide comprising X1-A-Y-P-D-S-V-P-X2, wherein
X1 is Y-S or W-L; X2 is any one of M-M-S, Mam, Yam, Y-K, Y-S-K, Y-G-S-K, Y-G-S-G-K, Y-R, or Y-S; and a half-life extending molecule, the addition of which slows down excretion of the peptide from the subject.

28 . The method of claim 27 , wherein the peptide further comprises a GSGSK linker on a carboxyl terminus (“C-terminal).

29 . The method in any one of claims 27 - 28 , wherein the peptide further comprises biotin on the C-terminal.

30 . The method of claim 27 , wherein the peptide further comprises a β-A (Alanine) on an amino terminus (“N-terminal”).

31 . The method of claim 30 , wherein the peptide further comprises biotin on a carboxyl terminus (“C-terminal”).

32 . The method of claim 30 , wherein the peptide further comprises P-K on a carboxyl terminus (“C-terminal”).

33 . The method of claim 32 , wherein the peptide further comprises biotin on the C-terminal.

34 . The method of claim 32 , wherein the C-terminal of the peptide is amidated.

35 . The method of claim 34 , wherein the peptide further comprises biotin on the C-terminal.

36 . The method of claim 32 , wherein the peptide further comprises acetylation of a Lys14 side chain.

37 . The method of claim 27 , wherein the peptide further comprises a biotinylated alanine on an amino terminus (“N-terminal”).

38 . The method of claim 37 , wherein the peptide further comprises P-K on a carboxyl terminus (“C-terminal”).

39 . The method of claim 38 , wherein the C-terminal of the peptide is amidated.

40 . The method in any one of claims 1 - 39 , wherein the disease or condition is a parasitic infection.

41 . The method in any one of claims 1 - 39 , wherein the disease or condition is pathological forms of angiogenesis.

42 . The method in any one of claims 1 - 39 , wherein the disease or condition comprises an inflammatory disease.

43 . The method of claim 42 , wherein the inflammatory disease is atherosclerosis.

44 . The method in any one of claims 1 - 39 , wherein the disease or condition is cancer.

45 . The method in claim 44 , wherein the cancer comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof.

46 . A composition comprising a peptide comprising X1-A-Y-P-D-S-V-P-X2, wherein
X1 is Y-S or W-L; and X2 is any one of M-M-S, Mam, Yam, Y-K, Y-S-K, Y-G-S-K, Y-G-S-G-K, Y-R, or Y-S.

47 . The composition of claim 46 , wherein the peptide further comprises a GSGSK linker on a carboxyl terminus (“C-terminal”).

48 . The composition in any one of claims 46 - 47 , wherein the peptide further comprises biotin on the C-terminal.

49 . The composition of claim 46 , wherein the peptide further comprises a β-A (Alanine) on an amino terminus (“N-terminal”).

50 . The composition of claim 49 , wherein the peptide further comprises biotin on a carboxyl terminus (“C-terminal”).

51 . The composition of claim 49 , wherein the peptide further comprises P-K on a carboxyl terminus (“C-terminal”).

52 . The composition of claim 51 , wherein the peptide further comprises biotin on the C-terminal.

Assignees

• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Pasquale Elena B

Classifications

• A61K47/56

  the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule · CPC title

• A61K38/10

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/08 Primary

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