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

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

Author information

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

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.

PMID:
19678643
PMCID:
PMC2756836
DOI:
10.1021/jm801176e
[Indexed for MEDLINE]
Free PMC Article

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