Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase

Shannon, A.; Selisko, B.; Le, T.-T.-N.; Huchting, J.; Touret, F.; Piorkowski, G.; Fattorini, V.; Ferron, F.; Decroly, E.; Meier, C.; Coutard, B.; Peersen, O.; Canard, B.

doi:10.1101/2020.05.15.098731

bioRxiv · 10.1101/2020.05.15.098731

Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase

Shannon, A.·Selisko, B.·Le, T.-T.-N.·Huchting, J.·Touret, F.·Piorkowski, G.·Fattorini, V.·Ferron, F.·Decroly, E.·Meier, C.·Coutard, B.·Peersen, O.·Canard, B.

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Abstract

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. Here we show that Favipiravir exerts an antiviral effect as a nucleotide analogue through a combination of chain termination, slowed RNA synthesis and lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19.

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Shannon, A., Selisko, B., Le, T.-T.-N., Huchting, J., Touret, F., Piorkowski, G., Fattorini, V., Ferron, F., Decroly, E., Meier, C., Coutard, B., Peersen, O., Canard, B.. 2020-05-15. Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase. https://doi.org/10.1101/2020.05.15.098731

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