Clinically approved inhibitors of the HIV-1 protease function via a competitive mechanism. A particular vulnerability of competitive inhibitors is their sensitivity to increases in substrate concentration, as may occur during virion assembly, budding and processing into a mature infectious viral particle. Advances in chemical synthesis have led to the development of new high-diversity chemical libraries using rapid in-solution syntheses. These libraries have been shown previously to be effective at disrupting protein–protein and protein–nucleic acid interfaces. We have screened 44000 compounds from such a library to identify inhibitors of the HIV-1 protease. One compound was identified that inhibits wild-type protease, as well as a drug-resistant protease with six mutations. Moreover, analysis of this compound suggests an allosteric non-competitive mechanism of inhibition and may represent a starting point for an additional strategy for anti-retroviral therapy.
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August 2010
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Research Article|
July 14 2010
Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries
Max W. Chang;
Max W. Chang
1
*Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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Michael J. Giffin;
Michael J. Giffin
1
*Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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Rolf Muller;
Rolf Muller
†Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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Jeremiah Savage;
Jeremiah Savage
*Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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Ying C. Lin;
Ying C. Lin
†Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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Sukwon Hong;
Sukwon Hong
‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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Wei Jin;
Wei Jin
‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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Landon R. Whitby;
Landon R. Whitby
‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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John H. Elder;
John H. Elder
†Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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Dale L. Boger;
Dale L. Boger
‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
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Bruce E. Torbett
Bruce E. Torbett
2
*Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, U.S.A.
2To whom correspondence should be addressed (email betorbet@scripps.edu).
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Publisher: Portland Press Ltd
Received:
October 21 2009
Revision Received:
May 08 2010
Accepted:
May 27 2010
Accepted Manuscript online:
May 27 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 429 (3): 527–532.
Article history
Received:
October 21 2009
Revision Received:
May 08 2010
Accepted:
May 27 2010
Accepted Manuscript online:
May 27 2010
Citation
Max W. Chang, Michael J. Giffin, Rolf Muller, Jeremiah Savage, Ying C. Lin, Sukwon Hong, Wei Jin, Landon R. Whitby, John H. Elder, Dale L. Boger, Bruce E. Torbett; Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries. Biochem J 1 August 2010; 429 (3): 527–532. doi: https://doi.org/10.1042/BJ20091645
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