tailieunhanh - Báo cáo khoa học: Effect of sequence polymorphism and drug resistance on two HIV-1 Gag processing sites

The HIV-1 proteinase (PR) has proved to be a good target for antiretroviral therapy of AIDS, and various PR inhibi-tors are now in clinical use. However, there is a rapid selec-tionof viral variantsbearingmutations in theproteinase that are resistant to clinical inhibitors. Drug resistance also involves mutations of the nucleocapsid/p1 and p1/p6 clea-vage sites ofGag, bothin vitroandin vivo. | Eur. J. Biochem. 269 4114-4120 2002 FEBS 2002 doi Effect of sequence polymorphism and drug resistance on two HIV-1 Gag processing sites Anita Feher1. Irene T. Weber2 Peter Baaossi1. Peter Boross1. Bhuvaneshwari Mahalinaam2 . John M. Louis3 Terry D. Copeland4 Ivan Y. Torshin5 Robert W. Harrison5 and Jozsef Tozser1 1 Department of Biochemistry and Molecular Biology Faculty of Medicine University of Debrecen Hungary department of Biology Georgia State University Atlanta GA USA 3 Laboratory of Chemical Physics National Institute of Diabetes Digestive and Kidney Diseases National Institutes of Health Bethesda MD USA 4NCI-Frederick Frederick MD USA department of Computer Science Georgia State University Atlanta GA USA The HIV-1 proteinase PR has proved to be a good target for antiretroviral therapy of AIDS and various PR inhibitors are now in clinical use. However there is a rapid selection of viral variants bearing mutations in the proteinase that are resistant to clinical inhibitors. Drug resistance also involves mutations of the nucleocapsid p1 and p1 p6 cleavage sites of Gag both in vitro and in vivo. Cleavages at these sites have been shown to be rate limiting steps for polyprotein processing and viral maturation. Furthermore these sites show significant sequence polymorphism which also may have an impact on virion infectivity. We have studied the hydrolysis of oligopeptides representing these cleavage sites with representative mutations found as natural variations or that arise as resistant mutations. Wild-type and five drug resistant PRs with mutations within or outside the substrate binding site were tested. While the natural varia tions showed either increased or decreased susceptibility of peptides toward the proteinases the resistant mutations always had a beneficial effect on catalytic efficiency. Comparison of the specificity changes obtained for the various substrates suggested that the maximization of the van der Waals .

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