. The overall aim of this proposal is to study the biochemical pharmacology of anti-HIV-1 compounds, including mechanisms of action, resistance, and toxicity. The current compound of interest are anti-HIV-1 nucleoside analogs, especially beta-L- dideoxynucleosides. The focus of the proposed studies is the elucidation of key host cellular biochemical determinants that are shared by all anti- HIV-1 nucleoside analogs and the interaction of beta-D(+) and beta-L(-)- dideoxynucleoside analogs.
The specific aims are 1a) to characterize molecularly a cytoplasmic DNA exonuclease that may constitute a significant mechanism of viral resistance to anti-HV-nucleoside analogs, 1b) to study regulation of the exonuclease by HIV-1 and anti-HIV-1 to anti-HIV-1 nucleoside analogs and the synergistic antiviral interaction of beta-L(-)-dideoxycytidine analogs with d4T, 2a) to purify and characterize the mitochondrial dNTP carrier, including the 29kDA protein, 2b) to study substrate specificity and transport kinetics of the dNTP carrier, 2c) to establish the role of the dNTP carrier in the toxicity of nucleoside analogs against mitochondrial DNA synthesis, and 2d) to study the mechanism of the protective effect of beta-L(-)-dideoxycytidine analogs on the mitochondrial toxicity of anti-HIV-1 beta-D(+)-dideoxynucleosides.
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