Effectiveness of commercial inhibitors against subtype F HIV-1 protease |
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Authors: | Sandra Krauchenco Nadia H Martins Mario Sanches |
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Institution: | 1. Instituto de Física de S?o Carlos, Universidade de S?o Paulo, Av. Trabalhador S?o-carlense, 400CEP 13560-970, S?o Carlos, SP, Brazil;2. Laboratório Nacional de Luz Síncrotron, Caixa Postal 6192CEP 13084-971, Campinas, SP, Brazil |
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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 Ki 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. |
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Keywords: | non-B HIV protease HIV protease mutant HIV subtype F inhibitor resistance biochemical fitness natural polymorphism |
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