Structure and Design of Potent and Selective Cathepsin K Inhibitors

Cynomolgus Monkey (Macaca fascicularis) Cathepsin K: Cloning, Expression, Purification, and Activation

“…Three of the four substitutions were conservative and would not be predicted to significantly alter the autoactivation process. However, the Leu 97 / Ala 97 substitution was in an area which appeared to be critical for the autoactivation of human cathepsin K. Specifically, the in vitro activation of human cathepsin K proceeds through a mechanism in which the propeptide domain is initially cleaved at three preferred sites, after residues Glu 19 , Ser…”

“…It has been speculated that autoactivation occurs in the low pH environment of the resorption pit or in an endosome. Several classes of selective and potent inhibitors of recombinant human mature cathepsin K have been reported (19,20).…”

Design of potent and selective human cathepsin K inhibitors that span the active site

“…1). The overlay of these two crystal structures led to the successful design of a potent class of 1,3-diamino-2-propanones that span both sides of the active site (compound 3) (12). The present report describes the design and synthesis of the bis(aza) analogs of 3 as well as diacylhydrazines containing a thiazole amide bond isostere that are potent and selective inhibitors of cathepsin K and span both sides of its active site.…”

Expression inEscherichia coli, Refolding, and Purification of Human Procathepsin K, an Osteoclast-Specific Protease

“…The crystal structure of human mature cathepsin K has been described previously (6,7) which has led to the identification of several classes of inhibitors targeted at the mature enzyme (6,8,9). However, efforts to crystallize the proenzyme expressed in baculovirus-infected insect cells have been unsuccessful (C. Janson, unpublished data).…”