West Nile virus (WNV) is a medically important emerging arbovirus causing serious neuroinfections in humans and against which no approved antiviral therapy is currently available. In this study, we demonstrate that 2'-C-methyl- or 4'-azido-modified nucleosides are highly effective inhibitors of WNV replication, showing nanomolar or low micromolar anti-WNV activity and negligible cytotoxicity in cell culture. One representative of C2'-methylated nucleosides, 7-deaza-2'-C-methyladenosine, significantly protected WNV-infected mice from disease progression and mortality. Twice daily treatment at 25 mg/kg starting at the time of infection resulted in 100% survival of the mice. This compound was highly effective, even if the treatment was initiated 3 days postinfection, at the time of a peak of viremia, which resulted in a 90% survival rate. However, the antiviral effect of 7-deaza-2'-C-methyladenosine was absent or negligible when the treatment was started 8 days postinfection (i.e., at the time of extensive brain infection). The 4'-azido moiety appears to be another important determinant for highly efficient inhibition of WNV replication in vitro However, the strong anti-WNV effect of 4'-azidocytidine and 4'-azido-aracytidine was cell type dependent and observed predominantly in porcine kidney stable (PS) cells. The effect was much less pronounced in Vero cells. Our results indicate that 2'-C-methylated or 4'-azidated nucleosides merit further investigation as potential therapeutic agents for treating WNV infections as well as infections caused by other medically important flaviviruses.

• Klíčová slova
• West Nile virus, antiviral agents, flavivirus, nucleoside analogs,
• MeSH
• antivirové látky terapeutické užití   MeSH
• buněčné linie MeSH
• Cercopithecus aethiops MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• prasata MeSH
• progrese nemoci MeSH
• replikace viru účinky léků   MeSH
• RNA-dependentní RNA-polymerasa antagonisté a inhibitory   MeSH
• tubercidin analogy a deriváty   terapeutické užití   MeSH
• Vero buňky MeSH
• viremie farmakoterapie   MeSH
• virus západního Nilu účinky léků   genetika   MeSH
• západonilská horečka farmakoterapie   patologie   virologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-deaza-2'-C-methyladenosine MeSH Prohlížeč
• antivirové látky MeSH
• RNA-dependentní RNA-polymerasa MeSH
• tubercidin MeSH