Designing anti-AIDS drugs targeting the major mechanism of HIV-1 RT resistance to nucleoside analog drugs

HIV reverse transcriptase (RT) is the target of a number of important anti-AIDS drugs. Drugs that inhibit RT are either nucleoside reverse transcriptase inhibitors (NRTIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Combinations of various anti-AIDS drugs (highly active anti-retroviral therapies or HAART) can reduce the viral load to non-detectable levels. However, the development of drug resistance leads to the emergence of HIV strains that are resistant to multiple anti-AIDS drugs. The nucleotide analogs that are used as anti-HIV-1 drugs lack the normal 3′-OH and as a consequence act as chain-terminators when incorporated into DNA. One mechanism of nucleoside analog resistance involves ATP-based excision to unblock chain-terminated primers and allow HIV replication to continue. There is an urgent need for new drugs and for new therapies that can overcome the excision mechanism of resistance. Compounds that disrupt the binding of the excision reaction substrate(s) (the blocked primer and/or ATP and/or pyrophosphate), or mimic the dinucleoside tetraphosphate product of the ATP-based excision reaction are potential inhibitors of excision. Detailed understanding of drug resistance mechanisms can reveal novel targets for anti-viral agents.