The nucleoside analogue D-carba T blocks HIV-1 reverse transcription.
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.
Boyer
Paul L
PL
HIV Drug Resistance Program, NCI-Frederick, Frederick, Maryland 21702, USA.
Vu
B Christie
BC
Ambrose
Zandrea
Z
Julias
John G
JG
Warnecke
Svenja
S
Liao
Chenzhong
C
Meier
Chris
C
Marquez
Victor E
VE
Hughes
Stephen H
SH
D019380:Anti-HIV Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011741:Pyrimidine Nucleosides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D013936:Thymidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D011741:Pyrimidine Nucleosides; D018894:Reverse Transcriptase Inhibitors; C063781:carbathymidine; D054303:HIV Reverse Transcriptase; D013936:Thymidine
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