Publication Details (including relevant citation information):
Eunice Murage, Jonathan C. Schroeder, Martin Beinborn, Jung-Mo Ahn
Bioorganic & Medicinal Chemistry, 2008, 16, 23, 10106-10112.
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 Lys-i and Glu-i+4 to form alpha-helices at various positions. The activity and affinity of these analogues to GLP-1 receptors suggested that the receptor-bound conformation comprises two alpha-helical segments between residues 1-21 and 23-34. It is notable that the N-terminal alpha-helix is extended to Thr11, and that Gly22 plays a pivotal role in arranging the two alpha-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