Effectiveness of commercial inhibitors against subtype F HIV-1 protease

Author(s)

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

Affiliation

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

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

• Document type: Journal article
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry; v. 24, n. 3, p. 638-645, 2009.
• Web of Science Citations: 4

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 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)

• FAPESP's process: 99/03387-4 - Structural studies of the proteins using synchrotron light
• Grantee: Igor Polikarpov
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 06/00182-8 - Structural biophysics of nuclear receptors and related proteins
• Grantee: Igor Polikarpov
• Support Opportunities: Research Projects - Thematic Grants