Glycopeptides and uses thereof

Abstract

The present invention provides glycopeptides comprising a peptide that is covalently linked to a saccharide. The peptide portion of the glycopeptides of the invention has from about 20 to about 40 amino acid residues and at least 75% sequence identity to SEQ ID NO:1, 2, or 3. The saccharide moiety portion of the glycopeptides of the present invention comprises from 1 to about 8 carbohydrates. The present invention also relates to using the glycopeptides of the invention in treating various neurodegenerative diseases.

1 . A glycopeptide comprising a peptide that is covalently linked to a saccharide, wherein said peptide has from about 20 to about 40 amino acid residues and at least 75% sequence identity to SEQ ID NO:1; SEQ ID NO:2 or SEQ ID NO:3, and wherein said saccharide comprises from 1 to about 8 carbohydrates. 
     
     
         2 . The glycopeptide of  claim 1 , wherein said peptide is selected from the group consisting of PACAP 1-27 , PACAP 1-38 , VIP, [AC-His 1 ]PACAP-27, [Ala 2 ]PACAP-27, [Gly 20 ]PACAP-27, and Ac-[Phe(pI) 6 , Nle 17 ]-PACAP 1-27 . 
     
     
         3 . The glycopeptide of  claim 2 , wherein said [Ala 2 ]PACAP-27 is [D-Ala 2 ]PACAP-27. 
     
     
         4 . The glycopeptide of  claim 1 , wherein at least one of the amino acid residues of SEQ ID NOs:1, 2 or 3 is substituted with a substitution amino acid residue having a side-chain functional group that is glycosylated. 
     
     
         5 . The glycopeptide of  claim 4 , wherein said substitution amino acid residue comprises serine, threonine, hydroxyproline or a similar ethanolamine linker. 
     
     
         6 . The glycopeptide of  claim 1 , wherein the C-terminus end of said peptide is glycosylated. 
     
     
         7 . The glycopeptide of  claim 1 , wherein said glycopeptide is a pituitary adenylate cyclase-activating polypeptide type I receptor (PAC 1 ) agonist. 
     
     
         8 . The glycopeptide of  claim 1 , wherein said glycopeptide is a VPAC 1  agonist. 
     
     
         9 . The glycopeptide of  claim 1 , wherein said glycopeptide is a selective PAC1 and VPAC1 agonist. 
     
     
         10 . The glycopeptide of  claim 1 , wherein PAC1 binding affinity (Ki) of said glycopeptide is less than about 10 nM. 
     
     
         11 . The glycopeptide of  claim 1 , wherein VPAC1 binding affinity (Ki) of said glycopeptide is less than about 10 nM. 
     
     
         12 . The glycopeptide of  claim 1 , wherein PAC1 agonist activity (Ki) of said glycopeptide is less than about 10 nM. 
     
     
         13 . The glycopeptide of  claim 1 , wherein VPAC1 agonist activity (κi) of said glycopeptide is less than about 10 nM. 
     
     
         14 . The glycopeptide of  claim 1 , wherein said saccharide comprises from 1 to 3 carbohydrates. 
     
     
         15 . The glycopeptide of  claim 1 , wherein said saccharide is a monosaccharide, a disaccharide. 
     
     
         16 . The glycopeptide of  claim 1 , wherein said peptide comprises a plurality of glycosylated amino acid residues. 
     
     
         17 . The glycopeptide of  claim 1 , wherein said saccharide is selected from the group consisting of glucose, maltose, lactose, melibiose, maltotriose, sucrose, trehalose, altose, saccharose, maltose, cellobiose, gentibiose, isomaltose, primeveose, galactose, xylose, mannose, manosaminic acid, fucose, GalNAc, GlcNAc, idose, iduronic acid, glucuronic acid, sialic acid, and polysaccharides related to the Thompsen-Friedrich antigens (Tn). 
     
     
         18 . The glycopeptide of  claim 1 , wherein said peptide comprises a peptide of SEQ ID NO:3. 
     
     
         19 . A method for treating a neurodegenerative disease in a subject, said method comprising administering to the subject in need of such a treatment a therapeutically effective amount of a glycopeptide of  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein said glycopeptide has a higher blood-brain barrier penetration compared to said peptide in the absence of said saccharide. 
     
     
         21 - 22 . (canceled)