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The Nucleoside Analogue D-carba T Blocks HIV-1 Reverse Transcription

  1. Author:
    Boyer, P. L.
    Vu, B. C.
    Ambrose, Z.
    Julias, J. G.
    Warnecke, S.
    Liao, C. Z.
    Meier, C.
    Marquez, V. E.
    Hughes, S. H.

  2. Author Address

    Boyer, Paul L.; Vu, B. Christie, Ambrose, Zandrea, Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Julias, John G.] SAIC Frederick, Frederick, MD 21702 USA. [Warnecke, Svenja, Meier, Chris] Univ Hamburg, Fac Sci, Dept Chem, D-20146 Hamburg, Germany. [Liao, Chenzhong, Marquez, Victor E.] NCI, Med Chem Lab, Frederick, MD 21702 USA.
    1. Year: 2009
  2. Journal: Journal of Medicinal Chemistry
    1. 52
    2. 17
    3. Pages: 5356-5364
  4. Type of Article: Article
  1. 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.

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  2. DOI: 10.1021/jm801176e
  3. PMID: 19678643

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