title: GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro.
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.
authors.affiliation: Department of Medicine I, St. Josef-Hospital, Ruhr-University of Bochum, Medical School, Gudrunstr, Germany. baptist.gallwitz@ruhr-uni-bochum.de
authors.forename: B
authors.initials: B
authors.lastname: Gallwitz
authors.forename: T
authors.initials: T
authors.lastname: Ropeter
authors.forename: C
authors.initials: C
authors.lastname: Morys-Wortmann
authors.forename: R
authors.initials: R
authors.lastname: Mentlein
authors.forename: E G
authors.initials: EG
authors.lastname: Siegel
authors.forename: W E
authors.initials: WE
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D005934:Glucagon / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D007340:Insulinoma; D015394:Molecular Structure; D010446:Peptide Fragments / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D010446:Peptide Fragments; D011498:Protein Precursors; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; C029937:secretin receptor; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4