The nucleoside analogue D-carba T blocks HIV-1 reverse transcription

J Med Chem. 2009 Sep 10;52(17):5356-64. doi: 10.1021/jm801176e.

Abstract

A major pathway for HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs) involves reverse transcriptase (RT) mutations that enhance ATP-dependent pyrophosphorolysis, which excises NRTIs from the end of viral DNA. We analyzed novel NRTIs for their ability to inhibit DNA synthesis of excision-proficient HIV-1 RT mutants. D-carba T is a carbocyclic nucleoside that has a 3' hydroxyl on the pseudosugar. The 3' hydroxyl group allows RT to incorporate additional dNTPs, which should protect D-carba TMP from excision. D-carba T can be converted to the triphosphate form by host cell kinases with moderate efficiency. D-carba T-TP is efficiently incorporated by HIV-1 RT; however, the next dNTP is added slowly to a D-carba TMP at the primer terminus. D-carba T effectively inhibits viral vectors that replicate using NRTI-resistant HIV-1 RTs, and there is no obvious toxicity in cultured cells. NRTIs based on the carbocyclic pseudosugar may offer an effective approach for the treatment of HIV-1 infections.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Base Sequence
  • Cell Line, Tumor
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • HIV-1 / physiology
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Pyrimidine Nucleosides / adverse effects
  • Pyrimidine Nucleosides / chemistry
  • Pyrimidine Nucleosides / pharmacology*
  • Reverse Transcriptase Inhibitors / adverse effects
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Thymidine / adverse effects
  • Thymidine / analogs & derivatives*
  • Thymidine / chemistry
  • Thymidine / pharmacology
  • Virus Replication / drug effects

Substances

  • Anti-HIV Agents
  • Pyrimidine Nucleosides
  • Reverse Transcriptase Inhibitors
  • carbathymidine
  • HIV Reverse Transcriptase
  • Thymidine