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. We demonstrate here that Favipiravir predominantly exerts an antiviral effect through 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.
Highlights
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
There has been remarkably little biochemical characterisation of nsp[12] and a lack of fundamental data to guide the design of antiviral therapeutics and study their mechanism of action (MoA)
This enzyme readily incorporates T-705-ribose-5′-phosphate into viral RNA in vitro, and cell culture based infectious virus studies show an increase in mutations in the presence of Favipiravir
Summary
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. To determine the efficacy and MoA of T-705 against SARS-CoV we first characterised nsp[12] primerdependent activity using traditional annealed primer-template (PT) and self-priming hairpin (HP) RNAs that may confer additional stability on the elongation complex (Supplementary Fig. 1c).
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