Inhibition of Hepatitis C Replicon RNA Synthesis by β-D-2′-deoxy-2′-fluoro-2′-<i>C</i>-Methylcytidine: A Specific Inhibitor of Hepatitis C Virus Replication

DOI Web Site 被引用文献5件

書誌事項

公開日
2006-04
権利情報
  • https://journals.sagepub.com/page/policies/text-and-data-mining-license
  • http://journals.sagepub.com/page/policies/text-and-data-mining-license
DOI
  • 10.1177/095632020601700203
公開者
SAGE Publications

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説明

<jats:p> β-D-2′-Deoxy-2′-fluoro-2′- C-methylcytidine (PSI-6130) is a cytidine analogue with potent and selective anti-hepatitis C virus (HCV) activity in the subgenomic HCV replicon assay, 90% effective concentration (EC<jats:sub>90</jats:sub>)=4.6 +2.0 µM. The spectrum of activity and cytotoxicity profile of PSI-6130 was evaluated against a diverse panel of viruses and cell types, and against two additional HCV-1b replicons. The S282T mutation, which confers resistance to 2′- C-methyl adenosine and other 2′-methylated nucleosides, showed only a 6.5-fold increase in EC<jats:sub>90</jats:sub>. When assayed for activity against bovine diarrhoea virus (BVDV), which is typically used as a surrogate assay to identify compounds active against HCV, PSI-6130 showed no anti-BVDV activity. Weak antiviral activity was noted against other flaviviruses, including West Nile virus, Dengue type 2, and yellow fever virus. These results indicate that PSI-6130 is a specific inhibitor of HCV. PSI-6130 showed little or no cytotoxicity against various cell types, including human peripheral blood mononuclear and human bone marrow progenitor cells. No mitochondrial toxicity was observed with PSI-6130. The reduced activity against the RdRp S282T mutant suggests that PSI-6130 is an inhibitor of replicon RNA synthesis. Finally, the no-effect dose for mice treated intraperitoneally with PSI-6130 for six consecutive days was ≥100 mg/kg per day. </jats:p>

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