Extinction of West Nile virus by Favipiravir through lethal mutagenesis. [PublishAheadOfPrint]

Favipiravir is an antiviral agent effective against several RNA viruses. The drug has been shown to protect mice against experimental infection with a lethal dose of West Nile virus (WNV), a mosquito-borne flavivirus responsible for outbreaks of meningitis and encephalitis for which no antiviral therapy has been licensed; however, the mechanism of action of the drug is still not well understood. Here, we describe the potent in vitro antiviral activity of favipiravir against WNV, showing that it decreases the virus-specific infectivity and drives the virus to extinction. Two passages of WNV in the presence of 1mM favipiravir -a concentration which is more than 10-fold lower than its cytotoxic concentration 50 (CC₅₀)- resulted in a significant increase of mutation frequency in the mutant spectrum, and in a bias towards A-to-G and G-to-A transitions relative to the population passaged in absence of the drug. These data, together with the fact that the drug is already licensed in Japan against influenza virus and in clinical trial against Ebola virus, point to favipiravir as a promising antiviral agent to fight medically relevant flaviviral infections, such as that caused by WNV.

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