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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cells, Cultured
  • Circular Dichroism
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / chemical synthesis
  • Glucagon-Like Peptide 1 / chemistry*
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / metabolism
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / metabolism
  • Structure-Activity Relationship

Substances

  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Peptides, Cyclic
  • Receptors, Glucagon
  • Glucagon-Like Peptide 1