Cathepsin K and the design of inhibitors of cathepsin K.
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 osteoprosis 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.
Yamashita
D S
DS
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd., King of Prussia, PA 19406, USA. Dennis_S_Yamashita@sbphrd.com
Dodds
R A
RA
D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse