Effectiveness of commercial inhibitors against subtype F HIV-1 protease

Autor(es)

Krauchenco, Sandra ^[1] ; Martins, Nadia H. ^[1] ; Sanches, Mario ^[2] ; Polikarpov, Igor ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, IFSC, BR-13560970 Sao Carlos, SP - Brazil

^[2] Lab Nacl Luz Sincrotron, BR-13084971 Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Enzyme Inhibition and Medicinal Chemistry; v. 24, n. 3, p. 638-645, 2009.
• Citações Web of Science: 4

Resumo

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 acetylpepstatin. 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. (AU)

• Processo FAPESP: 99/03387-4 - Estudos estruturais de proteínas usando luz síncrotron
• Beneficiário: Igor Polikarpov
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 04/11890-8 - Estudos estruturais e cinéticos de proteases de subtipos brasileiros de HIV-1 e seus complexos com inibidores
• Beneficiário: Sandra Krauchenco
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 06/00182-8 - Biofísica estrutural dos receptores nucleares e proteínas relacionadas
• Beneficiário: Igor Polikarpov
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 04/12201-1 - Resolução estrutural da protease de HIV-1 do subtipo C selvagem
• Beneficiário: Nádia Helena Martins
• Modalidade de apoio: Bolsas no Brasil - Mestrado