Non-active Site Changes Elicit Broad-based Cross-resistance of the HIV-1 Protease to Inhibitors*

Three high level, cross-resistant variants of the HIV-1 protease have been analyzed for their ability to bind four protease inhibitors approved by the Food and Drug Administration (saquinavir, ritonavir, indinavir, and nelfinavir) as AIDS therapeutics. The loss in binding energy (ΔΔG b ) going from the wild-type enzyme to mutant enzymes ranges from 2.5 to 4.4 kcal/mol, 40–65% of which is attributed to amino acid substitutions away from the active site of the protease and not in direct contact with the inhibitor. The data suggest that non-active site changes are collectively a major contributor toward engendering resistance against the protease inhibitor and cannot be ignored when considering cross-resistance issues of drugs against the HIV-1 protease.

• Publication year

  1999

• Venue

  Journal of Biological Chemistry

• Publication date

  1999-08-20

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.274.34.23699PMID 10446127
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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