Search for α-helical propensity in the receptor-bound conformation of glucagon-like peptide-1 Original Research Article

To elucidate the receptor-bound conformation of glucagon-like peptide-1 (GLP-1), a series of conformationally constrained GLP-1 analogues were synthesized by introducing lactam bridges between Lysi and Glui+4 to form α-helices at various positions. The activity and affinity of these analogues to GLP-1 receptors suggested that the receptor-bound conformation comprises two α-helical segments between residues 11-21 and 23-34. It is notable that the N-terminal α-helix is extended to Thr11, and that Gly22 plays a pivotal role in arranging the two α-helices. Based on these findings, a highly potent bicyclic GLP-1 analogue was synthesized which is the most conformationally constrained GLP-1 analogue reported to date.