title: 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.
authors.affiliation: Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador São-carlense, 400CEP 13560-970, São Carlos, SP, Brazil.
authors.forename: Sandra
authors.initials: S
authors.lastname: Krauchenco
authors.forename: Nadia H
authors.initials: NH
authors.lastname: Martins
authors.forename: Mario
authors.initials: M
authors.lastname: Sanches
authors.forename: Igor
authors.initials: I
authors.lastname: Polikarpov
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D024882:Drug Resistance, Viral; D004789:Enzyme Activation / Q000187:drug effects; D006678:HIV / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000821:virology; D016333:HIV Protease / Q000737:chemistry / Q000145:classification* / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D050296:Microbial Viability / Q000187:drug effects / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D019888:Nelfinavir / Q000494:pharmacology; D011110:Polymorphism, Genetic; D019438:Ritonavir / Q000494:pharmacology; D016415:Sequence Alignment
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; D019888:Nelfinavir; D019438:Ritonavir