Design of Potent and Selective Human Cathepsin K Inhibitors that Span the Active Site

Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-12, Vol.94 (26), p.14249-14254
Main Authors: Thompson, S K, Halbert, S M, Bossard, M J, Tomaszek, T A, Levy, M A, Zhao, B, Smith, W W, Abdel-Meguid, S S, Janson, C A, D'Alessio, K J, McQueney, M S, Amegadzie, B Y, Hanning, C R, DesJarlais, R L, Briand, J, Sarkar, S K, Huddleston, M J, Ijames, C F, Carr, S A, Garnes, K T, Shu, A, Heys, J R, Bradbeer, J, Zembryki, D, Lee-Rykaczewski, L, James, I E, Lark, M W, Drake, F H, Gowen, M, Gleason, J G, Veber, D F
Format: Article
Language:English
Subjects:
Active sites
Adducts
Binding Sites
Biochemistry
Biological Sciences
Bone resorption
Bones
Cathepsin K
Cathepsins - antagonists & inhibitors
Cathepsins - chemistry
Chemistry
Crystal structure
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzymes
Genes
Humans
Kinetics
Mass spectrometers
Medical treatment
Osteoclasts
Physical Sciences
Protein Conformation
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Summary:Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.26.14249