GLP-1-analogues Resistant to Degradation by Dipeptidyl-Peptidase IV in Vitro

Regul Pept. 2000 Jan 29;86(1-3):103-11. doi: 10.1016/s0167-0115(99)00095-6.

Abstract

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and improves glycemic control in type 2 diabetes. In serum the peptide is degraded by dipeptidyl peptidase IV (DPP IV). The resulting short biological half-time limits the therapeutic use of GLP-1. DPP IV requires an intact alpha-amino-group of the N-terminal histidine of GLP-1 in order to perform its enzymatic activity. Therefore, the following GLP- analogues with alterations in the N-terminal position 1 were synthesized: N-methylated- (N-me-GLP-1), alpha-methylated (alpha-me-GLP-1), desamidated- (desamino-GLP-1) and imidazole-lactic-acid 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 receptor 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 by 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 intracellular cAMP production in RINm5F cells in concentrations comparable to GLP-1. N-terminal modifications might therefore be useful in the development of long-acting GLP-1 analogues for type 2 diabetes therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Chromatography, High Pressure Liquid
  • Cyclic AMP / metabolism
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / metabolism*
  • Glucagon / analogs & derivatives*
  • Glucagon / chemical synthesis
  • Glucagon / metabolism*
  • Glucagon-Like Peptide 1
  • Insulinoma
  • Molecular Structure
  • Peptide Fragments / metabolism*
  • Protein Precursors / metabolism*
  • Rats
  • Receptors, G-Protein-Coupled
  • Receptors, Gastrointestinal Hormone / metabolism
  • Tumor Cells, Cultured

Substances

  • Peptide Fragments
  • Protein Precursors
  • Receptors, G-Protein-Coupled
  • Receptors, Gastrointestinal Hormone
  • secretin receptor
  • Glucagon-Like Peptide 1
  • Glucagon
  • Cyclic AMP
  • Dipeptidyl Peptidase 4