Evaluation of anti-HIV-1 mutagenic nucleoside analogues.

Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of "lethal mutagenesis" that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly.

5-Modified-2'-dU and 2'-dC as mutagenic anti HIV-1 proliferation agents: synthesis and activity.

With the goal of limiting HIV-1 proliferation by increasing the mutation rate of the viral genome, we synthesized a series of pyrimidine nucleoside analogues modified in position 5 of the aglycone moiety but unmodified on the sugar part. The synthetic strategies allow us to prepare the targeted compounds directly from commercially available nucleosides. All compounds were tested for their ability to reduce HIV-1 proliferation in cell culture.

Synthesis and primary evaluation of novel HIV-1 inhibitors.

The overcoming of antiviral drug resistance is an important challenge in the treatment of HIV-1 infection. According to the theory of viral error catastrophe, slightly increasing the mutation rate could exceed the error threshold for viability of a viral population and kill it. Investigation of this mechanism could lead to the discovery of new antiviral agents capable of bypassing viral resistance.

HIV-1 reverse transcriptase inhibitors.

Reverse transcriptase (RT) is one of the three enzymes encoded by the human immunodeficiency virus type 1 (HIV-1), the etiological agent of AIDS. Together with protease inhibitors, drugs inhibiting the RNA- and DNA-dependant DNA polymerase activity of RT are the major components of highly active antiretroviral therapy (HAART), which has dramatically reduced mortality and morbidity of people living with HIV-1/AIDS in developed countries. In this study, we focus on RT inhibitors approved by the US Food and Drugs Administration (FDA) or in phases II and III clinical trials.