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

Content Provider	PubMed Central
Author	Thompson, Scott K. Halbert, Stacie M. Bossard, Mary J. Tomaszek, Thaddeus A. Levy, Mark A. Zhao, Baoguang Smith, Ward W. Abdel Meguid, Sherin S. Janson, Cheryl A. D’alessio, Karla J. Mcqueney, Michael S. Amegadzie, Bernard Y. Hanning, Charles R. Desjarlais, Renee L. Briand, Jacques Sarkar, Susanta K. Huddleston, Michael J. Ijames, Carl F. Carr, Steven A. Garnes, Keith T. Shu, Art Heys, J. Richard Bradbeer, Jeremy Denise, Zembryki Liz, Lee-rykaczewski James, Ian E. Lark, Michael W. Drake, Fred H. Gowen, Maxine Gleason, John G. Veber, Daniel F.
Copyright Year	1997
Abstract	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.
Starting Page	14249
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	26
Volume Number	94
Language	English
Publisher	The National Academy of Sciences of the USA
Publisher Date	1997-12-23
Access Restriction	Open
Rights Holder	The National Academy of Sciences of the USA
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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