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.
Kenji Tomita  1 ,  Shinya Oishi ,  Hiroaki Ohno ,  Stephen C Peiper ,  Nobutaka Fujii
Affiliations
  • 1. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
PMID: 19007202 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.