| Summary: | Human cathepsin K is a cysteine protease that is a member of the papain
superfamily. It is selectively expressed in osteoclasts where it is involved in collagen type
I degradation during bone resorption. As such, cathepsin K represents a potential drug
target for the treatment of metabolic bone diseases such as osteoporosis.
In the search for novel inhibitors of cathepsin K, several Streptomyces strains
have been screened. The strain designated IS2-4 was observed to secrete inhibitors of
cathepsin K into its growth media. A bioassay-guided purification of the inhibitory
activity resulted in the isolation of five compounds, 6-10. Although appearing to be
derivatives of the known microbial cysteine protease inhibitor leupeptin, compounds 6-10
are structurally novel. Compounds 6 and 9 inhibited cathepsin K in a concentration
dependent manner with Ki values of 44 and 64 μM, respectively.
In addition, a 2.1 Å resolution crystal structure of cathepsin K in complex with 6
was determined. The structure revealed that compound 6 has been cleaved by cathepsin K
into acetyl-leucyl-leucine and a pyridotriazine fragment, with the former interacting with
the S1’ and S2’ subsites and the latter binding in the S2 subsite. These results suggest a
unique mechanism for the inhibition of cathepsin K. Moreover, since cathepsin K
normally prefers leucine residues at S2, the preferential binding of the pyridotriazine
fragment of 6 over the acetyl-leucyl-leucine fragment at S2 is unusual as well. === Medicine, Faculty of === Biochemistry and Molecular Biology, Department of === Graduate
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