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

Abstract:

: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.

journal_name

Bioorg Med Chem

authors

Murage EN,Schroeder JC,Beinborn M,Ahn JM

doi

10.1016/j.bmc.2008.10.006

subject

Has Abstract

pub_date

2008-12-01 00:00:00

pages

10106-12

issue

23

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(08)00944-9

journal_volume

16

pub_type

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