Development of novel G-protein-coupled receptor 54 agonists with resistance to degradation by matrix metalloproteinase

J Med Chem. 2008 Dec 11;51(23):7645-9. doi: 10.1021/jm800930w.

Abstract

Kisspeptin-GPR54 signaling is involved in the suppression of cancer metastasis and regulation of hormonal secretion. Recently, matrix metalloproteinase mediated deactivation of kisspeptins through hydrolysis of the Gly-Leu peptide bond has been reported. In the present report, GPR54 agonistic peptides having several nonhydrolyzable Gly-Leu dipeptide isosteres were designed and synthesized. (E)-Alkene- and hydroxyethylene-type isostere-containing analogues maintained the original activity with higher stability in murine serum and resistance to MMP-9-mediated cleavage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology*
  • Drug Design
  • Ligands
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / metabolism*
  • Molecular Conformation
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Time Factors

Substances

  • Dipeptides
  • Ligands
  • Matrix Metalloproteinase Inhibitors
  • Receptors, G-Protein-Coupled
  • Matrix Metalloproteinases