Structure-activity studies of glucagon-like peptide-1.

Abstract

A series of analogs of glucagon-like peptide-1 (GLP-1) was made replacing each amino acid with L-alanine to identify side-chain functional groups required for interaction with the GLP-1 receptor. In the case of L-alanine being the parent amino acid, substitution was made with the amino acid found in the corresponding position in glucagon. Binding assays were performed using the cloned rat GLP-1 receptor, and receptor activation was monitored using RIN 2A18 plasma membranes. The analogs that showed the weakest receptor binding were further compared with native GLP-1 by circular dichroism spectroscopy to investigate possible conformational changes. We conclude that the side chains in positions 7, 10, 12, 13, and 15 are directly involved in the receptor interaction while positions 28 and 29 are important for GLP-1 to adapt the conformation recognized by the receptor.