title: Development of novel G-protein-coupled receptor 54 agonists with resistance to degradation by matrix metalloproteinase.
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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomita
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008968:Molecular Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D004151:Dipeptides; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D020782:Matrix Metalloproteinases