title: Peptide ketobenzoxazole inhibitors bound to cathepsin K.
abstract: Potent inhibitors of human cysteine proteases of the papain family have been made and assayed versus a number of relevant family members. We describe the synthesis of peptide alpha-ketoheterocyclic inhibitors that occupy binding subsites S1'-S3 of the cysteine protease substrate recognition cleft and that form a reversible covalent bond with the Cys 25 nucleophile. X-ray crystal structures of cathepsin K both unbound and complexed with inhibitors provide detailed information on protease/inhibitor interactions and suggestions for the design of tight-binding, selective molecules.
authors.affiliation: Celera, South San Francisco, California 94080, USA. mary.mcgrath@celera.com
authors.forename: Mary E
authors.initials: ME
authors.lastname: McGrath
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sprengeler
authors.forename: Craig M
authors.initials: CM
authors.lastname: Hill
authors.forename: Valeri
authors.initials: V
authors.lastname: Martichonok
authors.forename: Harry
authors.initials: H
authors.lastname: Cheung
authors.forename: John R
authors.initials: JR
authors.lastname: Somoza
authors.forename: James T
authors.initials: JT
authors.lastname: Palmer
authors.forename: James W
authors.initials: JW
authors.lastname: Janc
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D001583:Benzoxazoles / Q000737:chemistry*; D001665:Binding Sites / Q000235:genetics; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D014443:Tyrosine / Q000235:genetics; D014633:Valine / Q000235:genetics
chemical_list: D001583:Benzoxazoles; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D011994:Recombinant Proteins; D001224:Aspartic Acid; D014443:Tyrosine; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; D014633:Valine