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Coevolutionary analysis of resistance-evading peptidomimetic inhibitors of HIV-1 protease

Academic Article
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Overview

authors

  • Rosin, C. D.
  • Belew, R. K.
  • Morris, G. M.
  • Olson, Arthur
  • Goodsell, David

publication date

  • February 1999

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • We have developed a coevolutionary method for the computational design of HIV-1 protease inhibitors selected for their ability to retain efficacy in the face of protease mutation. For HIV-1 protease, typical drug design techniques are shown to be ineffective for the design of resistance-evading inhibitors: An inhibitor that is a direct analogue of one of the natural substrates will be susceptible to resistance mutation, as will inhibitors designed to fill the active site of the wild-type or a mutant enzyme. Two design principles are demonstrated: (i) For enzymes with broad substrate specificity, such as HIV-1 protease, resistance-evading inhibitors are best designed against the immutable properties of the active site-the properties that must be conserved in any mutant protease to retain the ability to bind and cleave all of the native substrates. (ii) Robust resistance-evading inhibitors can be designed by optimizing activity simultaneously against a large set of mutant enzymes, incorporating as much of the mutational space as possible.

subject areas

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Drug Design
  • Evolution, Molecular
  • HIV Protease
  • HIV Protease Inhibitors
  • HIV-1
  • Kinetics
  • Point Mutation
  • Thermodynamics
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Identity

PubMed Central ID

  • PMC15469

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.96.4.1369

PubMed ID

  • 9990030
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Additional Document Info

start page

  • 1369

end page

  • 1374

volume

  • 96

issue

  • 4

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