Cathepsin K and the Design of Inhibitors of Cathepsin K

Dennis   S.   Yamashita; Robert   A.   Dodds

Abstract

Cathepsin K, a cysteine protease of the papain family, was identified by sequencing complementary DNA libraries derived from osteoclasts. Cathepsin K can cleave bone proteins such as Type I collagen, osteopontin, and osteonectin. The localization and maturation of cathepsin K in activated osteoclasts have been characterized. Furthermore, mutation of the gene expressing cathepsin K in humans results in pycnodysostosis, an autosomal recessive condition, resulting in osteopro-sis and increased bone fragility. Knockout of cathepsin K in the mouse also results in retarded bone matrix degradation and osteopetrosis. Together, these data demonstrate that inhibition of cathepsin K should result in a dimunition of osteoclast-mediated bone resorption. Several novel classes of cathepsin K inhibitors have been designed from X-ray co-crystal structures of peptide aldehydes bound to papain. The convergence of the design of novel inhibitors and the discovery of cathepsin K has created opportunities to further understand bone and cartilage biology as well as provide new therapeutic agents for the treatment of disease states in man such as osteoporosis.

Keywords: cathepsin K, Design Inhibitors, cysteine protease, Sequencing complementary DNA, osteoclasts, Type 1 collagen, osteonectin, pycndoysostosis, osteoprosis, osteoclast mediated bone resorption, xray co crystal structures, peptide aldehydes, RANK protein, homeostasis, integrin, NF kB, cDNA, Expression, interstitial collagenase activity, deficiency, irreversible cysteine protease inhibitors, azapeptides, acyloxymethylketones, SAR Peptide aldehydes vs, histocompatability complex MHC, papain, trypsin