Inhibition of multi-drug resistant HIV-1 reverse transcriptase by nucleoside β-triphosphates

Abstract

Despite the success of potent reverse transcriptase (RT) inhibitors against human immunodeficiency virus type 1 (HIV-1) in combination regimens, the development of drug resistant RTs constitutes a major hurdle for the long-term efficacy of current antiretroviral therapy. Nucleoside β-triphosphate analogs of adenosine and nucleoside reverse transcriptase inhibitors (NRTIs) (3′-azido-2′,3′-dideoxythymidine (AZT), 3′-fluoro-2′,3′-dideoxythymidine (FLT), and 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T)) were synthesized and their inhibitory activities were evaluated against wild-type and multidrug resistant HIV-1 RTs. Adenosine β-triphosphate (1) and AZT β-triphosphate (2) completely inhibited the DNA polymerase activity of wild type, the NRTI multi resistant, and non-nucleoside RT inhibitors (NNRTI) resistant HIV-1 RT at 10 nM, 10 μM, and 100 μM, respectively.

Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors

“…Two classes of drugs, NRTIs and NNRTIs, have been reported as inhibitors of RT [26,27,28,29,30,31]. NRTIs act as DNA chain terminators, while NNRTIs bind to a hydrophobic pocket close to the RT active site and inhibit the enzyme activity by mediating allosteric changes in the RT conformation, thus causing a distortion in the arrangement of the catalytic active site aspartyl residues [32,33,34,35,36,37].…”