Abstract
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-1IIIB 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,147V, 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¡ 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.
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References
Meek, T. D. (1992) J. Enz. Inhib. 6, 65–98.
Wlodawer, A., and Erickson, J. W. (1993) Annu. Rev. Biochem. 62, 543–585.
Darke, P. L., and Huff, J. R. (1994) Adv. Pharmacol. 25, 399–454.
Pillay, D., Getman, M. B. D., and Richman, D. D. (1995) Rev. Med. Virology 5, 23–33.
De Clercq, E. (1995) J. Med. Chem. 38, 2491–2517.
XI International Conference on AIDS, Vancouver, Canada, 1996. Abstract # Mo. B. 1137 and # Mo. B. 170.
Studenberg, S. D., Dhal, R. A, and Wooley, J. L. on “Pharmacokinetics, Excretion, and Mass Balance Studies in Dogs with 141W94 (VX-478), an HIV-1 Protease Inhibitor.” Presented at the 7th International Society for the Study of Xenobiotics, San Diego, CA, 1996. Abstract # 327.
Painter, G. R., Ching, S., Reynolds, D., St.Clair, M., Sadler, B. M., Elkins, M., Blum, R., Domsife, R., Livingston, D., Partaledis, J. A., Pazhanisamy, S., Tung, R. and Tisdale, M. (1996) Drugs of the Future 21, 347–350.
St. Clair, M.H., Millard, J., Tisdale, M., Parry, N., Sadler, B.M., Blum, M. R., and Painter, G. on “Invitro antiviral activity of 141W94 (VX-478) in combination with other antiviral agents.” Presented at the Consensus Symposium on Combined Antiviral Therapy, Lisbon, Portugal, July 26, 1995.
Schooley, R. on “Preliminary data on the safty and antiviral efficacy of the novel protease inhibitor 141W94 in HIV-infected patients with 150 to 400 CD4+ cells/mm3” Presented at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La. Abstract # LB7a.
Schechter, I., and Berger, A. (1967) Biochem. Biophys. Res. Commun. 27, 157–162.
Partaledis, J. A., Yamaguchi, K., Tisdale, M., Blair, E. E., Falcione, C., Maschera, B., Myers, R. E., Pazhanisamy, S., Futer, O., Cullinan, A. B., Stuver, C. M., Byrn, R. A., and Livingston, D. J. (1995) J. Virology. 69, 5228–5235.
Pazhanisamy, S., Stuver, C. M., Cullinan, A. B., Margolin, N., Rao, B. G. and Livingston, D. J. (1996) J. Biological Chem. 271, 17979–17985.
Collins, J. R., Burt, S. K., and Erickson, J. W. (1995) Nature Struct. Biol. 2, 334–338.
Debouk, C. (1991) Adv. Exp. Med. Biol. 306,407–415.
Gulnik, S. V., Suvorov, L. I., Liu, B., Yu, B., Anderson, B., Mitsuya, H., and Erickson, J. W. (1995) Biochem. 34, 9282–9287.
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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: James, M.N.G. (eds) Aspartic Proteinases. Advances in Experimental Medicine and Biology, vol 436. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5373-1_10
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DOI: https://doi.org/10.1007/978-1-4615-5373-1_10
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