Peptide ketobenzoxazole inhibitors bound to cathepsin K
Mary E McGrath1, Paul A Sprengeler, Craig M Hill
1Celera, South San Francisco, California 94080, USA. mary.mcgrath@celera.com
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.
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