Cathepsin K and the design of inhibitors of cathepsin K

Cathepsin K, a cysteine protease of the papain family, was identified by se quencing complementary DNA libraries derived from osteoclasts. Cathepsin K can cleave bone proteins such as Type I collagen, osteopontin, and osteonec tin. The localization and maturation of cathepsin K in activated osteoclast s have been characterized. Furthermore, mutation of the gene expressing cat hepsin K in humans results in pycnodysostosis, an autosomal recessive condi tion, resulting in osteoprosis and increased bone fragility. Knockout of ca thepsin K in the mouse also results in retarded bone matrix degradation and osteopetrosis. Together, these data demonstrate that inhibition of catheps in K should result in a dimunition of osteoclast-mediated bone resorption. Several novel classes of cathepsin K inhibitors have been designed from X-r ay co-crystal structures of peptide aldehydes bound to papain. The converge nce of the design of novel inhibitors and the discovery of cathepsin K has created opportunities to further understand bone and cartilage biology as w ell as provide new therapeutic agents for the treatment of disease states i n man such as osteoporosis.