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.
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 Short-term therapy could not prevent a rebound of viral replication after the drug was withdrawn.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.
Zoulim
F
F
INSERM U271, Lyon, France.
Dannaoui
E
E
Borel
C
C
Hantz
O
O
Lin
T S
TS
Liu
S H
SH
Trépo
C
C
Cheng
Y C
YC
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D015139:Blotting, Southern; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000096:biosynthesis*; D004372:Ducks; D005260:Female; D018347:Hepadnaviridae Infections / Q000188:drug therapy*; D015611:Hepatitis B Virus, Duck / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000998:Antiviral Agents; D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; C085719:2',3'-dideoxy-beta-5-fluorocytidine; D016047:Zalcitabine