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Effectiveness of commercial inhibitors against subtype F HIV-1 protease.

Abstract
Subtype F wild type HIV protease has been kinetically characterized using six commercial inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) commonly used for HIV/AIDS treatment, as well as inhibitor TL-3 and acetyl-pepstatin. We also obtained kinetic parameters for two multi-resistant proteases (one of subtype B and one of subtype F) harboring primary and secondary mutations selected by intensive treatment with ritonavir/nelfinavir. This newly obtained biochemical data shows that all six studied commercially available protease inhibitors are significantly less effective against subtype F HIV proteases than against HIV proteases of subtype B, as judged by increased K(i) and biochemical fitness (vitality) values. Comparison with previously reported kinetic values for subtype A and C HIV proteases show that subtype F wild type proteases are significantly less susceptible to inhibition. These results demonstrate that the accumulation of natural polymorphisms in subtype F proteases yields catalytically more active enzymes with a large degree of cross-resistance, which thus results in strong virus viability.
AuthorsSandra Krauchenco, Nadia H Martins, Mario Sanches, Igor Polikarpov
JournalJournal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 24 Issue 3 Pg. 638-45 (Jun 2009) ISSN: 1475-6374 [Electronic] England
PMID18825538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • HIV Protease Inhibitors
  • HIV Protease
  • Nelfinavir
  • Ritonavir
Topics
  • Amino Acid Sequence
  • Binding Sites
  • Drug Resistance, Viral
  • Enzyme Activation (drug effects)
  • HIV (drug effects, enzymology, genetics)
  • HIV Infections (drug therapy, genetics, virology)
  • HIV Protease (chemistry, classification, genetics, metabolism)
  • HIV Protease Inhibitors (classification, pharmacology, therapeutic use)
  • Humans
  • Kinetics
  • Microbial Viability (drug effects, genetics)
  • Molecular Sequence Data
  • Mutation
  • Nelfinavir (pharmacology)
  • Polymorphism, Genetic
  • Ritonavir (pharmacology)
  • Sequence Alignment

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