Ang (1-7) derviative oligopeptides for the treatment of pain and other indications

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/or impairment, pain, and traumatic brain injury.

What is claimed is: 
     
         1 . A method for providing analgesia to a subject having a neuropathy, the method comprising administering a therapeutically effective amount of an oligopeptide derivative having 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 and glycosylated forms thereof, glutamic acid and glycosylated forms thereof, and alanine;   A 2  is selected from the group consisting of arginine, histidine, and lysine;   A 3  is selected from the group consisting of valine, alanine, isoleucine, and leucine;   A 4  is selected from the group consisting of tyrosine and glycosylated forms thereof, phenylalanine, and tryptophan;   A 5  is selected from the group consisting of isoleucine, valine, alanine, and leucine;   A 6  is selected from the group consisting of histidine, arginine, and lysine;   A 7  is serine or a glycosylated form thereof; and   A 8  is absent.   
     
     
         2 . The method of  claim 1 , wherein the neuropathy is selected from the group consisting of HIV-induced neuropathy, diabetic neuropathy, and chemotherapeutic neuropathy. 
     
     
         3 . The method of  claim 1 , wherein the neuropathy is diabetic neuropathy. 
     
     
         4 . The method of  claim 1 , wherein at least one amino acid is glycosylated with a monosaccharide or disaccharide. 
     
     
         5 . The method of  claim 4 , wherein at least one of the monosacharides or disaccharides is selected from the group consisting of glucose, galactose, xylose, fucose, rhamnose, lactose, cellobiose, and melibiose. 
     
     
         6 . The method of  claim 1 , wherein A 7  is glycosylated. 
     
     
         7 . The method of  claim 6 , wherein A 7  is glycosylated with a saccharide selected from the group consisting of glucose, galactose, xylose, fucose, rhamnose, lactose, cellobiose, and melibiose. 
     
     
         8 . The method of  claim 7 , wherein the saccharide is glucose or lactose. 
     
     
         9 . The method of  claim 1 , wherein A 7  is terminated with an amino group. 
     
     
         10 . The method of  claim 7 , wherein A 7  is terminated with an amino group. 
     
     
         11 . The method of  claim 1 , wherein the oligopeptide is Ang 1-6-Ser(OGlc)-NH 2  (SEQ ID NO: 10). 
     
     
         12 . The method of  claim 1 , wherein the oligopeptide is Ang 1-6-Ser(OLac)-NH 2 . 
     
     
         13 . The method of  claim 1 , wherein the oligopeptide comprises at least one D-amino acid. 
     
     
         14 . The method of  claim 1 , wherein each of A 1 -A 8  is a D-amino acid. 
     
     
         15 . A method for providing analgesia to a subject having a neuropathy, the method comprising administering to the subject a therapeutically effective amount of an oligopeptide comprising an amino acid sequence consisting 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 and glycosylated forms thereof, glutamic acid and glycosylated forms thereof, and alanine;   A 2  is selected from the group consisting of arginine, histidine, and lysine;   A 3  is selected from the group consisting of valine, alanine, isoleucine, and leucine;   A 4  is selected from the group consisting of tyrosine and glycosylated forms thereof, phenylalanine, and tryptophan;   A 5  is selected from the group consisting of isoleucine, valine, alanine, and leucine;   A 6  is selected from the group consisting of histidine, arginine, and lysine;   A 7  is selected from the group consisting of proline, glycine, and serine and glycosylated forms thereof; and   A 8  is serine or a glycosylated form thereof.   
     
     
         16 . The method of  claim 15 , wherein the neuropathy is selected from the group consisting of HIV-induced neuropathy, diabetic neuropathy, and chemotherapeutic neuropathy. 
     
     
         17 . The method of  claim 16 , wherein the neuropathy is diabetic neuropathy. 
     
     
         18 . The method of  claim 15 , wherein A 8  is glycosylated. 
     
     
         19 . The method of  claim 18 , wherein A 8  is glycosylated with a saccharide selected from the group consisting of glucose, galactose, xylose, fucose, rhamnose, lactose, cellobiose, and melibiose. 
     
     
         20 . The method of  claim 15 , wherein A 8  is terminated with an amino group. 
     
     
         21 . The method of  claim 19 , wherein A 8  is terminated with an amino group. 
     
     
         22 . The method of  claim 15 , wherein the oligopeptide is selected from the group consisting of Ang 1-7-Ser-NH 2  (SEQ ID NO: 7), Ang 1-7-Ser(OGlc)-NH 2  (SEQ ID NO: 8), and Ang 1-6-Ser(OLac)-NH 2  (SEQ ID NO: 9).