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

Paul L Boyer1, B Christie Vu, Zandrea Ambrose

  • 1HIV Drug Resistance Program, NCI-Frederick, Frederick, Maryland 21702, USA.

Journal of Medicinal Chemistry
|August 15, 2009
PubMed

Insights

Novel nucleoside reverse transcriptase inhibitors (NRTIs) show promise against drug-resistant HIV-1. D-carba T, a carbocyclic nucleoside, effectively inhibits viral replication with no observed toxicity in cell cultures.

Area of Science:

  • Biochemistry
  • Virology
  • Medicinal Chemistry

Background:

  • HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs) is a significant clinical challenge.
  • This resistance often arises from mutations in reverse transcriptase (RT) that promote NRTI excision via pyrophosphorolysis.
  • Developing NRTIs that overcome these resistance mechanisms is crucial for effective HIV-1 treatment.

Purpose of the Study:

  • To evaluate novel nucleoside analogs, specifically D-carba T, for their efficacy against HIV-1 RT mutants exhibiting excision proficiency.
  • To investigate the mechanism of action and potential therapeutic value of D-carba T in the context of NRTI resistance.

Main Methods:

  • Synthesis and characterization of D-carba T, a carbocyclic nucleoside analog.
  • Assessment of D-carba T's conversion to its active triphosphate form (D-carba T-TP) by host cell kinases.
  • Evaluation of HIV-1 RT's incorporation of D-carba T-TP and subsequent nucleotide addition kinetics.
  • Testing the antiviral activity of D-carba T against viral vectors utilizing NRTI-resistant HIV-1 RTs.
  • In vitro toxicity assessments in cultured cells.

Main Results:

  • D-carba T is efficiently converted to D-carba T-TP by host kinases.
  • HIV-1 RT readily incorporates D-carba T-TP, but subsequent dNTP addition to the primer terminus is significantly slowed.
  • D-carba T demonstrated effective inhibition of viral vectors harboring NRTI-resistant HIV-1 RTs.
  • No significant toxicity was observed in cultured cells treated with D-carba T.

Conclusions:

  • Carbocyclic nucleoside analogs like D-carba T represent a promising strategy for combating NRTI-resistant HIV-1.
  • The unique structure of D-carba T confers resistance to pyrophosphorolytic excision, a key resistance mechanism.
  • Further development of NRTIs based on the carbocyclic pseudosugar scaffold holds potential for improved HIV-1 treatment regimens.

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