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Bioorg Med Chem. 2008 Dec 1;16(23):10106-12. doi: 10.1016/j.bmc.2008.10.006. Epub 2008 Oct 5.

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

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Department of Chemistry, University of Texas at Dallas, Richardson, TX 75080, USA.


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 11-21 and 23-34. It is notable that the N-terminal alpha-helix is extended to Thr(11), and that Gly(22) 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.

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