ANG-(1-7) derivative oligopeptides and methods for using and producing the same

Patent metadata

Field	Value
Publication number	US-9670251-B2
Application number	US-201615134073-A
Country	US
Kind code	B2
Filing date	Apr 20, 2016
Priority date	Jul 21, 2014
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The present invention provides oligopeptides, in particular, Ang-(1-7) derivatives, and methods for using and producing the same. In one particular embodiment, oligopeptides of the invention have higher blood-brain barrier penetration and/or in vivo half-life compared to the native Ang-(1-7), thereby allowing oligopeptides of the invention to be used in a wide variety of clinical applications including in treatment of cognitive dysfunction and/of impairment.

First claim

What is claimed is:

1. A heptapeptide comprising the formula: A1-A2-A3-A4-A5-A6-A7-A8 (SEQ ID NO:1) wherein
A1 is selected from the group consisting of aspartic acid, glutamic acid, alanine, and glycosylated forms thereof;
A2 is selected from the group consisting of arginine, histidine, lysine, and glycosylated forms thereof;
A3 is selected from the group consisting of valine, alanine, isoleucine, leucine, and glycosylated forms thereof;
A4 is selected from the group consisting of tyrosine, phenylalanine, tryptophan, and glycosylated forms thereof;
A5 is selected from the group consisting of isoleucine, valine, alanine, leucine, and glycosylated forms thereof;
A6 is selected from the group consisting of histidine, arginine, lysine, and glycosylated forms thereof;
A7 is serine or a glycosylated form thereof; and
A8 is absent, and wherein at least one of A1-A7 is glycosylated.

2. The heptapeptide of claim 1 , wherein at least one of A1-A7 comprises a monosaccharide or disaccharide.

3. The heptapeptide of claim 2 , wherein at least one of the monosaccharides or disaccharides is selected from the group consisting of glucose, galactose, xylose, fucose, rhamnose, lactose, cellobiose, and melibiose.

4. The heptapeptide of claim 1 , wherein A7 is a serine that is terminated with an amino group.

5. The heptapeptide of claim 4 , wherein A7 is a glycosylated serine that is terminated with an amino group.

6. The heptapeptide of claim 5 , wherein the oligopeptide has the formula of SEQ ID NO: 10.

7. The heptapeptide of claim 1 , wherein the oligopeptide comprises at least one D-amino acid.

8. The heptapeptide of claim 1 , wherein each of A1-A7 is a D-amino acid.

9. The heptapeptide of claim 1 , wherein A1 is alanine.

10. The heptapeptide of claim 9 , wherein at least one of A1-A7 comprises a monosaccharide or disaccharide.

11. The heptapeptide of claim 10 , wherein at least one of the monosaccharides or disaccharides is selected from the group consisting of glucose, galactose, xylose, fucose, rhamnose, lactose, cellobiose, and melibiose.

12. The heptapeptide of claim 9 , wherein A7 is a glycosylated serine.

13. The heptapeptide of claim 12 , wherein the A7 serine is glycosylated with glucose or lactose.

14. The heptapeptide of claim 9 , wherein A7 is terminated with an amino group.

15. The heptapeptide of claim 14 , wherein A7 is a glycosylated serine that is terminated with an amino group.

16. The heptapeptide of claim 9 , wherein the oligopeptide comprises at least one D-amino acid.

17. The heptapeptide of claim 9 , wherein each of A1-A7 is a D-amino acid.

18. A method for treating cognitive dysfunction in a subject diagnosed as having congestive heart failure, comprising administering to the patient a therapeutically effective amount of a heptapeptide having the formula: A1-A2-A3-A4-A5-A6-A7-A8 (SEQ ID NO:1) wherein
A1 is selected from the group consisting of aspartic acid, glutamic acid, alanine, and glycosylated forms thereof;
A2 is selected from the group consisting of arginine, histidine, lysine, and glycosylated forms thereof;
A3 is selected from the group consisting of valine, alanine, isoleucine, leucine, and glycosylated forms thereof;
A4 is selected from the group consisting of tyrosine, phenylalanine, tryptophan, and glycosylated forms thereof;
A5 is selected from the group consisting of isoleucine, valine, alanine, leucine, and glvcosvlated forms thereof;
A6 is selected from the group consisting of histidine, arginine, lysine, and glycosylated forms thereof;
A7 is serine or a glycosylated form thereof; and
A8 is absent.

19. The method of claim 18 , wherein at least one of A1-A7 is substituted with a monosaccharide or disaccharide.

20. The method of claim 18 , wherein the heptapeptide has the formula of SEQ ID NO: 10.

21. The method of claim 18 , wherein the heptapeptide comprises at least one D-amino acid.

Assignees

• Univ Arizona

Inventors

• Hay Meredith
• Konhilas John
• Polt Robin L
• Jones Evan

Classifications

• 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

• C07K9/001

  the peptide sequence having less than 12 amino acids and not being part of a ring structure · 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

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• A61K38/085

  Angiotensins · CPC title