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Antimicrobial Agents and Chemotherapy, March 2006, p. 955-961, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.955-961.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Characterization of the Anti-Hepatitis B Virus Activity and Cross-Resistance Profile of 2',3'-Dideoxy-3'-Fluoroguanosine

A.-C. Jacquard,{dagger} M.-N. Brunelle,{dagger} C. Pichoud, D. Durantel, S. Carrouée-Durantel, C. Trepo, and F. Zoulim*

INSERM U271, Lyon, France

Received 23 June 2005/ Returned for modification 18 August 2005/ Accepted 3 January 2006

The fluorinated guanosine analog 2',3'-dideoxy-3'-fluoroguanosine (FLG) was shown to inhibit wild-type (wt) hepatitis B virus (HBV) replication in a human hepatoma cell line permanently expressing HBV. Experiments performed in the duck model of HBV infection also showed its in vivo antiviral activity. In this study, we investigated the mechanism of inhibition of FLG on HBV replication and its profile of antiviral activity against different HBV or duck hepatitis B virus (DHBV) drug-resistant mutants. We found that FLG-triphosphate inhibits weakly the priming of the reverse transcription compared to adefovir-diphosphate in a cell-free system assay allowing the expression of an enzymatically active DHBV reverse transcriptase. It inhibits more potently wt DHBV minus-strand DNA synthesis compared to lamivudine-triphosphate and shows a similar activity compared to adefovir-diphosphate. FLG-triphosphate was most likely a competitive inhibitor of dGTP incorporation and a DNA chain terminator. In Huh7 cells transiently transfected with different HBV constructs, FLG inhibited similarly the replication of wt, lamivudine-resistant, adefovir-resistant, and lamivudine-plus-adefovir-resistant HBV mutants. These results were consistent with those obtained in the DHBV polymerase assay using the same drug-resistant polymerase mutants. In conclusion, our data provide new insights in the mechanism of action of FLG-triphosphate on HBV replication and demonstrate its inhibitory activity on drug-resistant mutant reverse transcriptases in vitro. Furthermore, our results provide the rationale for further clinical evaluation of FLG in the treatment of drug-resistant virus infection and in the setting of combination therapy to prevent or delay drug resistance.

* Corresponding author. Mailing address: INSERM U271, 151 Cours Albert Thomas, 69424 Lyon cedex 03, France. Phone: 33-4-72-68-19-70. Fax: 33-4-72-68-19-71. E-mail: zoulim{at}lyon.inserm.fr.

{dagger} A.-C.J. and M.-N.B. contributed equally to this work.

Antimicrobial Agents and Chemotherapy, March 2006, p. 955-961, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.955-961.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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