Peptide agonists of glp-1 activity

Abstract

Novel peptide agonists of GLP-1 activity useful for lowering blood glucose levels. The novel peptides comprise variants of the GLP-1 or the exendin-4 polypeptide sequence and are pharmacologically active and stable. These peptides are useful in the treatment of diseases that benefit from regulation of excess levels of blood glucose and/or regulation of gastric emptying, such as diabetes and eating disorders.

1 . (canceled) 
     
     
         2 . A method for treating type 2 diabetes mellitus in a subject in need thereof, said method comprising administering to said subject (i) a peptide conjugate comprising an exendin-4 variant coupled via its C-terminus to an amino acid sequence Z, wherein said exendin-4 variant comprises a sequence characterized by deletion of between 1 and 5 amino acid residues at positions corresponding to positions 34-38 of exendin-4(1-39) and wherein Z comprises from 4 to 20 Lys amino acid residues, or a pharmaceutically acceptable salt thereof; and (ii) an antidiabetic agent each in an amount that together is effective for the treatment of type 2 diabetes mellitus. 
     
     
         3 . The method of  claim 2 , wherein said antidiabetic agent is insulin or an oral hypoglycaemic agent. 
     
     
         4 . The method of  claim 3 , wherein said antidiabetic agent is an oral hypoglycaemic agent selected from metformin, a sulfonyl urea, or a thiazolidinedione. 
     
     
         5 . The method of  claim 2 , wherein said peptide conjugate is administered parenterally. 
     
     
         6 . The method of  claim 5 , wherein said peptide conjugate is administered subcutaneously. 
     
     
         7 . The method of  claim 5 , wherein said peptide conjugate is parenterally administered in a liquid dosage form. 
     
     
         8 . The method of  claim 2 , wherein said peptide conjugate is formulated as a lyophilized solid and reconstituted prior to administration to said subject. 
     
     
         9 . The method of  claim 2 , wherein said exendin-4 variant comprises a sequence characterized by deletion of between 1 and 3 amino acid residues at positions corresponding to positions 34-38 of exendin 4(1-39). 
     
     
         10 . The method of  claim 9 , wherein said exendin-4 variant comprises a sequence characterized by deletion of 1, 2, or 3 Pro residues at positions corresponding to positions 36-38 of exendin-4(1-3 9). 
     
     
         11 . The method of  claim 2 , wherein said amino acid sequence Z is Lys 4 , Lys 5 , Lys 6 , Lys 7 , Lys 8 , Lys 9 , or Lys 10 . 
     
     
         12 . The method of  claim 2 , wherein said peptide conjugate is administered as a free acid. 
     
     
         13 . The method of  claim 2 , wherein said peptide conjugate is administered as a pharmaceutically acceptable salt. 
     
     
         14 . The method of  claim 2 , wherein said exendin-4 variant is selected from desPro 36  exendin-4 (1-39), desPro 36 Pro 37 -exendin-4(1-39), and desPro 36 Pro 37 Pro 38 -exendin-4(1-39). 
     
     
         15 . The method of  claim 14 , wherein said peptide conjugate is selected from desPro 36 -exendin-4(1 -3 9)-Lys 6 -NH 2 , desPro 36 Pro 37 -exendin-4(1-39)-Lys 6 -NH 2 , desPro 36 Pro 37 Pro 38 -exendin-4(1-39)-Lys 6 -NH 2 , and pharmaceutically acceptable salts thereof. 
     
     
         16 . The method of  claim 15 , wherein said peptide conjugate is selected from desPro 36 -exendin-4(1-39)-Lys 6 -NH 2 , and pharmaceutically acceptable salts thereof. 
     
     
         17 . The method of  claim 16 , wherein said antidiabetic agent is selected from insulin, metformin, a sulfonyl urea, and a thiazolidinedione. 
     
     
         18 . The method of  claim 16 , wherein said antidiabetic agent is insulin.