title: Inhibition of hepatitis C replicon RNA synthesis by beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine: a specific inhibitor of hepatitis C virus replication.
abstract: beta-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 (EC90)=4.6 +/- 2.0 microM. 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 EC90. 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 > or =100 mg/kg per day.
authors.affiliation: Pharmasset Inc, Princeton, NJ, USA.
authors.forename: Lieven J
authors.initials: LJ
authors.lastname: Stuyver
authors.forename: Tamara R
authors.initials: TR
authors.lastname: McBrayer
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Tharnish
authors.forename: Jeremy
authors.initials: J
authors.lastname: Clark
authors.forename: Laurent
authors.initials: L
authors.lastname: Hollecker
authors.forename: Stefania
authors.initials: S
authors.lastname: Lostia
authors.forename: Tammy
authors.initials: T
authors.lastname: Nachman
authors.forename: Jason
authors.initials: J
authors.lastname: Grier
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bennett
authors.forename: Meng-Yu
authors.initials: MY
authors.lastname: Xie
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: John D
authors.initials: JD
authors.lastname: Morrey
authors.forename: Justin L
authors.initials: JL
authors.lastname: Julander
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Furman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D012093:Replicon / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; C504520:2'-deoxy-2'-fluoro-2'-C-methylcytidine; D003841:Deoxycytidine