title: Synthesis and activity of phosphinic tripeptide inhibitors of cathepsin C.
abstract: Phosphinic tripeptide analogues Gly-Xaapsi[P(O)(OH)CH(2)]-Gly have been developed as inhibitors of cathepsin C (DPP I), a lysosomal, papain-like cysteine protease. The target compounds were synthesised by addition of methyl acrylate to the appropriate phosphinic acids followed by the N-terminus elongation using mixed anhydride procedure. The latter step has been demonstrated to be a suitable method for N-terminal extension of the phosphinic pseudopeptide analogues without requirement of hydroxyphosphinyl protection. The title compounds appeared to be moderate inhibitors of the cathepsin C. However, although designed as transition state analogues, they surprisingly exhibited noncompetitive mode of binding to cathepsin C. Differences in kinetics of C-terminal acids and esters have been additionally observed.
authors.affiliation: Institute of Organic Chemistry, Biochemistry and Biotechnology, Wrocław University of Technology, Wybrzeze Wyspiańskiego 27, 50-370 Wrocław, Poland. artur.mucha@pwr.wroc.pl
authors.forename: Artur
authors.initials: A
authors.lastname: Mucha
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Paweł
authors.forename: Józef
authors.initials: J
authors.lastname: Hurek
authors.forename: Pawel
authors.initials: P
authors.lastname: Kafarski
mesh_terms: D020789:Cathepsin C / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D009842:Oligopeptides; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D020789:Cathepsin C