ORALLY ACTIVE PEPTIDES THAT PREVENT CELL DAMAGE AND DEATH

• US 20080194488A1
• Filed: 04/14/2008
• Published: 08/14/2008
• Est. Priority Date: 08/18/1999
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America), Ramot at Tel Aviv University Limited (Tel Aviv University)
• Original Assignee: National Institutes of Health (NIH) (Government of the United States of America), Ramot at Tel Aviv University Limited (Tel Aviv University)
• Inventors: Brenneman, Douglas E., Spong, Catherine Y., Gozes, Illana, Giladi, Eliezer, Pinhasov, Albert
• Granted Patent: US 8,017,578 B2
• Time in Patent Office: Days
• US Class Current: 514/1.1
• CPC Class Codes: A61K 38/04 Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof enzyme inhibitors A61K38/005; gastrins A61K38/2207, somatostatins A61K38/31, melanotropins A61K38/34 ; protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3

Abstract

This invention provides an ADNF polypeptide comprising an active core site, the active core site comprising at least one D-amino acid. The invention also provides a pharmaceutical composition comprising an ADNF polypeptide comprising an active core site, the active core site comprising at least one D-amino acid. In particular, the pharmaceutical composition of the invention is orally active. The invention further provides methods for reducing neuronal cell death, methods for reducing oxidative stress, and methods for reducing a condition associated with fetal alcohol syndrome using the ADNF polypeptides and the pharmaceutical compositions of the invention.

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an Activity Dependent Neurotrophic Factor (ADNF) polypeptide, wherein the ADNF polypeptide is a member selected from the group consisting of:

(a) an ADNF I polypeptide comprising an active core site having the following amino acid sequence;

2. The pharmaceutical composition of claim 1, wherein the ADNF polypeptide is an ADNF I polypeptide and wherein the active core site of the ADNF I polypeptide comprises at least one D-amino acid.

3. The pharmaceutical composition of claim 2, wherein both N-terminal and C-terminal amino acids of the active core site of the ADNF I polypeptide are D-amino acids.

4. The pharmaceutical composition of claim 2, wherein the active core site of the ADNF I polypeptide comprises all D-amino acids.

5. The pharmaceutical composition of claim 2, wherein the ADNF I polypeptide is Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:

1).

6. The pharmaceutical composition of claim 5, wherein the ADNF I polypeptide comprises all D-amino acids.

7. The pharmaceutical composition of claim 1, wherein the ADNF polypeptide is an ADNF III polypeptide and wherein the active core site of the ADNF III polypeptide comprises at least one D-amino acid.

8. The pharmaceutical composition of claim 7, wherein both N-terminal and C-terminal amino acids of the active core site of the ADNF III polypeptide are D-amino acids.

9. The pharmaceutical composition of claim 7, wherein the active core site of the ADNF III polypeptide comprises all D-amino acids.

10. The pharmaceutical composition of claim 7, wherein the ADNF III polypeptide is Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:

2).

11. The pharmaceutical composition of claim 10, wherein the ADNF III polypeptide comprises all D-amino acids.

12. The pharmaceutical composition of claim 1, wherein the ADNF polypeptide is a mixture of an ADNF I polypeptide of part (a) and an ADNF III polypeptide of part (b) and wherein at least one of the ADNF I polypeptide and the ADNF III polypeptide comprises an active core site comprising at least one D-amino acid.

13. The pharmaceutical composition of claim 12, wherein both N-terminal and C-terminal amino acids of the active core site of the ADNF I polypeptide are D-amino acids, and wherein both N-terminal and C-terminal amino acids of the active core site of the ADNF III polypeptide are D-amino acids.

14. The pharmaceutical composition of claim 12, wherein the active core site of the ADNF I polypeptide comprises all D-amino acids, and wherein the active core site of the ADNF III polypeptide comprises all D-amino acids.

15. The pharmaceutical composition of claim 12, wherein the ADNF I polypeptide is Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:

1) and wherein the ADNF III polypeptide is Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO;

2).

16. The pharmaceutical composition of claim 15, wherein the ADNF I polypeptide comprises all D-amino acids and wherein the ADNF III polypeptide comprises all D-amino acids.

17. The pharmaceutical composition of claim 12, wherein the ADNF polypeptide I comprises all D-amino acids and wherein the ADNF III polypeptide comprises all L-amino acids.

18. The pharmaceutical composition of claim 12, wherein the ADNF I polypeptide comprises all L-amino acids, and wherein the ADNF III polypeptide comprises all D-amino acids.

19. The pharmaceutical composition of claim 1, wherein the composition is formulated for intranasal, intraperitoneal, subcutaneous, gavage, sublingual, intravenous, or oral administration.

20. The pharmaceutical composition of claim 1, wherein the composition is formulated for oral administration.

21. The pharmaceutical composition of claim 4, wherein the composition is formulated for oral administration.

22. The pharmaceutical composition of claim 9, wherein the composition is formulated for oral administration.

23. The pharmaceutical composition of claim 14, wherein the composition is formulated for oral administration.