GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and improves g lycemic control in type 2 diabetes. In serum the peptide is degraded by dip eptidyl peptidase IV (DPP IV). The resulting short biological half-time lim its the therapeutic use of GLP-1. DPP IV requires an intact cr-amino-group of the N-terminal histidine of GLP-1 in order to perform its enzymatic acti vity. Therefore, the following GLP-1 analogues with alterations in the N-te rminal position 1 were synthesized: N-methylated-(N-me-GLP-1), alpha-methyl ated (alpha-me-GLP-1), desamidated-(desamino-GLP-1) and imidazole-lactic-ac id substituted GLP-1 (imi-GLP-1). All GLP-1 analogues except alpha-me-GLP-1 were hardly degraded by DPP IV in vitro. The GLP-1 analogues showed recept or affinity and in vitro biological activity comparable to native GLP-1 in RINm5F cells. GLP-1 receptor affinity was highest for imi-GLP-1, followed b y alpha-me-GLP-1 and N-me-GLP-1. Only desamino-GLP-1 showed a 15-fold loss of receptor affinity compared to native GLP-1. All analogues stimulated int racellular cAMP production in RINm5F cells in concentrations comparable to GLP-1. N-terminal modifications might therefore be useful in the developmen t of long-acting CLP-1 analogues for type 2 diabetes therapy. (C) 2000 Else vier Science B.V. All rights reserved.