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

• Published in: Bioorganic & medicinal chemistry 2008-12, Vol.16 (23), p.10106-10112
• Main Authors: Murage, Eunice N., Schroeder, Jonathan C., Beinborn, Martin, Ahn, Jung-Mo
• Format: Article
• Language: English
• Subjects: Alpha-helical propensity; Amino Acid Sequence; Bicyclic GLP-1 analogue; Biological and medical sciences; Cells, Cultured; Circular Dichroism; Cyclic peptides containing lactam bridges; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - chemical synthesis; Glucagon-Like Peptide 1 - chemistry; Glucagon-like peptide-1; Glucagon-Like Peptide-1 Receptor; Humans; Inhibitory Concentration 50; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Pharmacology. Drug treatments; Receptor-bound conformation; Receptors, Glucagon - agonists; Receptors, Glucagon - metabolism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.10.006

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 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 Thr 11, and that Gly 22 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.