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

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3519-22. doi: 10.1016/j.bmcl.2011.05.005. Epub 2011 May 8.

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 nonnucleoside RT inhibitors (NNRTI) resistant HIV-1 RT at 10nM, 10 and 100 μM, respectively.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Dinucleoside Phosphates / pharmacology*
  • Drug Resistance, Viral / drug effects*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • Humans
  • Molecular Structure
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*

Substances

  • Anti-HIV Agents
  • Dinucleoside Phosphates
  • Enzyme Inhibitors
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase