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Viral RNA-dependent RNA polymerase inhibitor 7-deaza-2'-C-methyladenosine prevents death in a mouse model of West Nile virus infection

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EYER Luděk FOJTÍKOVÁ Martina NENCKA Radim RUDOLF Ivo HUBÁLEK Zdeněk RŮŽEK Daniel

Rok publikování 2019
Druh Článek v odborném periodiku
Časopis / Zdroj ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
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Doi http://dx.doi.org/10.1128/AAC.02093-18
Klíčová slova West Nile virus; antiviral agents; flavivirus; nucleoside analogs
Popis 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=-Cmethyladenosine, 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=-Cmethyladenosine 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.

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