title: Phosphinic peptides as potent inhibitors of zinc-metalloproteases.
abstract: The development of transition-state analogs is a major objective in enzymology, not only for developing potent inhibitors of enzymes but also for dissecting enzyme catalytic mechanisms. Phosphinic peptides, which share closed structural similarities with the transition-state of peptide substrate upon hydrolysis, have thus been considered for identifying potent inhibitors of proteases. Focusing on the zinc-proteases family, this review presents the most important synthetic efforts performed to obtain the desired compounds. Crystal structures of the phosphinic peptides in interaction with their zinc-protease targets are reported to illustrate the structural features which may explain the potency of these compounds and how they contribute to uncover key enzyme catalytic residues. Based on a remarkable metabolic stability, phosphinic peptides can be used to probe the in vivo function of zinc-proteases. Progress on chemistry and better understanding on the functional roles of zinc-proteases should allow transferring these compounds from shelf to clinic.
authors.affiliation: Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece, dgeorgia@chem.uoa.gr.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Georgiadis
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
mesh_terms: D000818:Animals; D001407:Bacillus / Q000737:chemistry / Q000201:enzymology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D010721:Phosphinic Acids / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000737:chemistry / Q000201:enzymology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D010455:Peptides; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D045726:Metalloproteases; D015032:Zinc