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Antimicrobial Agents and Chemotherapy, February 1998, p. 369-376, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inhibitory Effect of 2'-Fluoro-5-Methyl-beta -L-Arabinofuranosyl-Uracil on Duck Hepatitis B Virus Replication

Stéphanie Aguesse-Germon,1 Shwu-Huey Liu,2 Michèle Chevallier,3 Christian Pichoud,1 Catherine Jamard,1 Christelle Borel,1 Chung K. Chu,4 Christian Trépo,1 Yung-Chi Cheng,2 and Fabien Zoulim1,*

INSERM U271, 69003 Lyon,1 and Department of Pathology, Laboratoires Merieux, 69007 Lyon,3 France; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 065102; and Department of Medicinal Chemistry, University of Georgia, Athens, Georgia 306024

Received 27 May 1997/Returned for modification 16 September 1997/Accepted 5 November 1997

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.

* Corresponding author. Mailing address: INSERM U271, 151 cours Albert Thomas, 69003 Lyon, France. Phone: (33) 4 72 68 19 70. Fax: (33) 4 72 68 19 71. E-mail: zoulim{at}lyon151.inserm.fr.

Antimicrobial Agents and Chemotherapy, February 1998, p. 369-376, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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