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.
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.
Stuyver
Lieven J
LJ
Pharmasset Inc, Princeton, NJ, USA.
McBrayer
Tamara R
TR
Tharnish
Phillip M
PM
Clark
Jeremy
J
Hollecker
Laurent
L
Lostia
Stefania
S
Nachman
Tammy
T
Grier
Jason
J
Bennett
Matthew A
MA
Xie
Meng-Yu
MY
Schinazi
Raymond F
RF
Morrey
John D
JD
Julander
Justin L
JL
Furman
Phillip A
PA
Otto
Michael J
MJ
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*
D000998:Antiviral Agents; D012367:RNA, Viral; C504520:2'-deoxy-2'-fluoro-2'-C-methylcytidine; D003841:Deoxycytidine