TY - JOUR
T1 - Search for α-helical propensity in the receptor-bound conformation of glucagon-like peptide-1
AU - Murage, Eunice N.
AU - Schroeder, Jonathan C.
AU - Beinborn, Martin
AU - Ahn, Jung Mo
N1 - Funding Information:
This work was supported in part by Welch Foundation (AT-1595, J.-M.A.), Texas Advanced Research Program (009741-0031-2006, J.-M.A.), and American Diabetes Association (7-07-JF-02, J.-M.A.; 7-05-RA-08, M.B.). The authors also thank Kevin A. Schug at the University of Texas at Arlington for his generous help on ESI-MS analysis.
PY - 2008/12/1
Y1 - 2008/12/1
N2 - 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.
AB - 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.
KW - Alpha-helical propensity
KW - Bicyclic GLP-1 analogue
KW - Cyclic peptides containing lactam bridges
KW - Glucagon-like peptide-1
KW - Receptor-bound conformation
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U2 - 10.1016/j.bmc.2008.10.006
DO - 10.1016/j.bmc.2008.10.006
M3 - Article
C2 - 18952440
AN - SCOPUS:55749095379
SN - 0968-0896
VL - 16
SP - 10106
EP - 10112
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 23
ER -