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

Eunice N. Murage, Jonathan C. Schroeder, Martin Beinborn, Jung Mo Ahn

Research output: Contribution to journalArticle

27 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)10106-10112
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number23
DOIs
StatePublished - Dec 1 2008

Keywords

  • Alpha-helical propensity
  • Bicyclic GLP-1 analogue
  • Cyclic peptides containing lactam bridges
  • Glucagon-like peptide-1
  • Receptor-bound conformation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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