Peptide ketobenzoxazole inhibitors bound to cathepsin K.
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.
McGrath
Mary E
ME
Celera, South San Francisco, California 94080, USA. mary.mcgrath@celera.com
Sprengeler
Paul A
PA
Hill
Craig M
CM
Martichonok
Valeri
V
Cheung
Harry
H
Somoza
John R
JR
Palmer
James T
JT
Janc
James W
JW
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
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