VX-478 (141W94), a potent inhibitor of HIV protease, is in late stage clinical trials for the treatment of HIV infection and AIDS. Resistant viruses were raised in vitro by passage of HIV-1(IIIB) in the presence of increasing concentrations of VX-478 and the related hydroxyethylamino sulfonamide inhibitor VB-11,328. By direct PCR analysis of selected viruses, a number of mutations were identified (L10F, M46I, I47V, I50V and I84V) in the protease gene. These mutations were introduced into recombinant HIV-1 protease and the mutant enzymes assayed against a panel of inhibitors of diverse chemical structure. For VX-478, significant increases in IC90 and K(i) were observed for virus or protease, respectively, containing I50V single mutation or an M46I/I47V/I50V triple mutation. The mutant proteases were also characterized for their kinetic competence to process substrates representing cleavage sites of gag-pol viral polypeptide. The kinetic data were interpreted with the aid of molecular modeling to understand the effect of mutations on inhibitor binding and processing of the gag-pol polypeptide to generate infective virions.
CITATION STYLE
Pazhanisamy, S., Partaledis, J. A., Rao, B. G., & Livingston, D. J. (1998). In vitro selection and characterization of VX-478 resistant HIV-1 variants. In Advances in Experimental Medicine and Biology (Vol. 436, pp. 75–83). Springer New York LLC. https://doi.org/10.1007/978-1-4615-5373-1_10
Mendeley helps you to discover research relevant for your work.