Ang-(1-7) derviative oligopeptides and methods for using and producing the same

Patent metadata

Field	Value
Publication number	US-2016016996-A1
Application number	US-201514801557-A
Country	US
Kind code	A1
Filing date	Jul 16, 2015
Priority date	Jul 21, 2014
Publication date	Jan 21, 2016
Grant date	—

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 . An oligopeptide derivative of the formula:
A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 (SEQ ID NO:1)
wherein
A 1 is selected from the group consisting of aspartic acid, glutamic acid, alanine, and a derivative thereof;
A 2 is selected from the group consisting of arginine, histidine, lysine, and a derivative thereof;
A 3 is selected from the group consisting of valine, alanine, isoleucine, leucine, and a derivative thereof;
A 4 is selected from the group consisting of tyrosine, phenylalanine, tryptophan, and a derivative thereof;
A 5 is selected from the group consisting of isoleucine, valine, alanine, leucine, and a derivative thereof;
A 6 is selected from the group consisting of histidine, arginine, lysine, and a derivative thereof;
A 7 is selected from the group consisting of proline, glycine, serine, and a derivative thereof; and
A 8 can be present or absent, wherein when A 8 is present, A 8 is selected from the
group consisting of serine, threonine, hydroxyproline, and a derivative thereof, provided that when A 8 is absent:
(a) at least one of A 1 -A 7 is substituted with a mono- or di-carbohydrate,
(b) A 7 is terminated with an amino group, or
(c) a combination thereof.

2 . The oligopeptide derivative of claim 1 , wherein at least one of A 1 -A 7 is substituted with a mono- or di-carbohydrate.

3 . The oligopeptide derivative of claim 1 , wherein at least one of the mono- or di-carbohydrates comprises glucose, galactose, xylose, fucose, rhamnose, lactose, cellobiose, melibiose.

4 . The oligopeptide derivative of claim 1 , wherein A 8 is serine or a derivative thereof.

5 . The oligopeptide derivative of claim 1 , wherein (i) A 8 is terminated with an amino group; or (ii) A 8 is absent and A 7 is terminated with an amino group.

6 . The oligopeptide derivative of claim 5 , wherein (i) A 8 is serine that is glycosylated with glucose or lactose; or (ii) A 8 is absent and A 7 is serine that is glycosylated with glucose or lactose.

7 . The oligopeptide derivative of claim 6 , wherein A 8 is absent and A 7 is glycosylated with glucose.

8 . The oligopeptide derivative of claim 1 , wherein A 1 is aspartic acid; A 2 is arginine; A 3 is valine; A 4 is tyrosine; A 5 is isoleucine; A 6 is histidine; and (i) A 8 is absent and A 7 either is terminated with an amino group or is a glycosylated serine, or (ii) A 8 is serine terminated with an amino group.

9 . The oligopeptide derivative of claim 8 , wherein A 8 is a glycosylated serine.

10 . The oligopeptide derivative of claim 8 , wherein A 8 is absent and A 7 is a glycosylated serine that is terminated with an amino group.

11 . The oligopeptide derivative of claim 1 , wherein said oligopeptide derivative is selected from the group consisting of SEQ ID NO:1; SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13.

12 . A glycosylated Ang-(1-7) derivative having seven or eight amino acids.

13 . The glycosylated Ang-(1-7) derivative of claim 12 , wherein said glycosylated Ang-(1-7) derivative is glycosylated with xylose, fucose, rhamnose, glucose, lactose, cellobiose, melibiose, or a combination thereof.

14 . The glycosylated Ang-(1-7) derivative of claim 12 , wherein a carboxylic acid end of said glycosylated Ang-(1-7) derivative is substituted with an amino group.

15 . A method for treating cognitive impairment in a patient, said method comprising administering to a patient in need of such a treatment a therapeutically effective amount of an oligopeptide of claim 1 .

16 . A method for treating cognitive impairment in a patient, said method comprising administering to a patient in need of such a treatment a therapeutically effective amount of a glycosylated Ang-(1-7) derivative of claim 12 .

Assignees

• Univ Arizona State

Inventors

• Hay Meredith
• Konhilas John
• Polt Robin L

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

• 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

• C07K9/001

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

• A61K38/085

  Angiotensins · CPC title

• A61K38/04

  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 title