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Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries

Academic Article
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Overview

related to degree

  • Whitby, Landon, Ph.D. in Chemical Biology, Scripps Research 2005 - 2011

authors

  • Chang, M. W.
  • Giffin, M. J.
  • Muller, R.
  • Savage, J.
  • Lin, Y. C.
  • Hong, S.
  • Jin, W.
  • Whitby, Landon
  • Elder, John
  • Boger, Dale
  • Torbett, Bruce

publication date

  • August 2010

journal

  • Biochemical Journal  Journal

abstract

  • 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.

subject areas

  • Combinatorial Chemistry Techniques
  • HIV Protease
  • HIV Protease Inhibitors
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Spectrometry, Mass, Electrospray Ionization
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Research

keywords

  • HIV-1
  • anti-retroviral therapy
  • high-diversity chemical library
  • high-throughput screening
  • kinetics
  • non-competitive inhibitor
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Identity

PubMed Central ID

  • PMC3084599

International Standard Serial Number (ISSN)

  • 0264-6021

Digital Object Identifier (DOI)

  • 10.1042/bj20091645

PubMed ID

  • 20507280
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Additional Document Info

start page

  • 527

end page

  • 532

volume

  • 429

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