Inhibitory effect of 2'-fluoro-5-methyl-beta-L-arabinofuranosyl-uracil on duck hepatitis B virus replication.
The antiviral activity of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), a novel L-nucleoside analog of thymidine known to be an inhibitor of hepatitis B virus (HBV) replication in hepatoma cells (2.2.1.5 cell line), was evaluated in the duck HBV (DHBV) model. Short-term oral administration (5 days) of L-FMAU (40 mg/kg of body weight/day) to experimentally infected ducklings induced a significant decrease in the level of viremia. This antiviral effect was sustained in animals when therapy was prolonged for 8 days. The histological study showed no evidence of liver toxicity in the L-FMAU-treated group. By contrast, microvesicular steatosis was found in the livers of dideoxycytidine-treated animals. L-FMAU administration in primary duck hepatocyte cultures infected with DHBV induced a dose-dependent inhibition of both virion release in culture supernatants and intracellular viral DNA synthesis, without clearance of viral covalently closed circular DNA. By using a cell-free system for the expression of an enzymatically active DHBV reverse transcriptase, it was shown that L-FMAU triphosphate exhibits an inhibitory effect on the incorporation of dAMP in the viral DNA primer. Thus, our data demonstrate that L-FMAU inhibits DHBV replication in vitro and in vivo. Long-term administration of L-FMAU for the eradication of viral infection in animal models of HBV infection should be evaluated.
Aguesse-Germon
S
S
INSERM U271, Lyon, France.
Liu
S H
SH
Chevallier
M
M
Pichoud
C
C
Jamard
C
C
Borel
C
C
Chu
C K
CK
Trépo
C
C
Cheng
Y C
YC
Zoulim
F
F
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004279:DNA, Viral / Q000187:drug effects* / Q000378:metabolism; D004372:Ducks; D018347:Hepadnaviridae Infections / Q000188:drug therapy* / Q000821:virology; D015611:Hepatitis B Virus, Duck / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004279:DNA, Viral; D001086:Arabinofuranosyluracil; C034935:clevudine