2',3'-dideoxy-beta-L-5-fluorocytidine inhibits duck hepatitis B virus reverse transcription and suppresses viral DNA synthesis in hepatocytes, both in vitro and in vivo.
AUTOR(ES)
Zoulim, F
RESUMO
beta-L-Nucleoside analogs represent a new class of potent antiviral agents with low cytotoxicity which provide new hope in the therapy of chronic hepatitis B virus (HBV) infections. We evaluated the anti-HBV activity of 2',3'-dideoxy-beta-L-5-fluorocytidine (beta-L-F-ddC), a beta-L-nucleoside analog derived from 2',3'-dideoxycytidine (ddC), in the duck HBV (DHBV) model. This compound was previously shown to inhibit HBV DNA synthesis in a stably transfected hepatoma cell line (F2215). Using a cell-free system for the expression of an enzymatically active DHBV polymerase, we could demonstrate that the triphosphate form of beta-L-F-ddC does inhibit hepadnavirus reverse transcription. In primary duck hepatocyte culture, beta-L-F-ddC showed a potent inhibitory effect on DHBV DNA synthesis which was concentration dependent. Although beta-L-F-ddC was shown to be less active than ddC against the DHBV reverse transcriptase in vitro, beta-L-F-ddC was a stronger inhibitor in hepatocytes. The oral administration of beta-L-F-ddC in experimentally infected ducklings showed that beta-L-F-ddC is a potent inhibitor of viral replication in vivo. Short-term therapy could not prevent a rebound of viral replication after the drug was withdrawn. Preventive therapy with beta-L-F-ddC could delay the onset of viremia by only 1 day compared with the time to the onset of viremia in the control group. The in vivo inhibitory effect of beta-L-F-ddC was much stronger than that of ddC and was not associated with signs of toxicity. Our data show that beta-L-F-ddC inhibits hepadnavirus reverse transcription and is a strong inhibitor of viral replication both in vitro and in vivo.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=163132Documentos Relacionados
- Inhibition of duck hepatitis B virus replication by 2',3'-dideoxy-3'-fluoroguanosine in vitro and in vivo.
- Anti-Hepatitis B Virus Activity and Metabolism of 2′,3′-Dideoxy-2′,3′-Didehydro-β-l(−)-5-Fluorocytidine
- Characterization of the Antiviral Effect of 2′,3′-Dideoxy-2′, 3′-Didehydro-β-l-5-Fluorocytidine in the Duck Hepatitis B Virus Infection Model
- Mechanism of inhibition of duck hepatitis B virus polymerase by (-)-beta-L-2',3'-dideoxy-3'-thiacytidine.
- Pharmacokinetics of β-l-2′,3′-Dideoxy-5-Fluorocytidine in Rhesus Monkeys