In vitro characterization of the anti-hepatitis B virus activity and cross-resistance profile of 2',3'-dideoxy-3'-fluoroguanosine.: Anti-HBV activity of FLG
| Autor: | Jacquard, Anne-Carole, Brunelle, Marie-Noëlle, Pichoud, Christian, Durantel, David, Carrouée-Durantel, Sandra, Trépo, Christian, Zoulim, Fabien |
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| Přispěvatelé: | Zoulim, Fabien, Virus des hépatites et pathologies associées, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by Medivir and by grants from the European Community (HepBVar QLRT-2001-00977 and ViRgil LSHM-CT-2004-503359). |
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
MESH: Antiviral Agents
drug resistance MESH: Adenine MESH: Humans MESH: Cell Line Tumor MESH: Drug Resistance Viral virus diseases [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology digestive system diseases [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology MESH: Dose-Response Relationship Drug MESH: Hepatocytes MESH: Hepatitis B virus MESH: Hepatitis B Virus Duck antivirals MESH: Dideoxynucleosides MESH: Liver Neopla MESH: Ducks MESH: Animals MESH: Carcinoma Hepatocellular hepatitis B virus MESH: Lamivudine |
| Zdroj: | Antimicrob Agents Chemother Antimicrob Agents Chemother, 2006, 50 (3), pp.955-61. ⟨10.1128/AAC.50.3.955-961.2006⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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