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. Favipiravir (T-705) is an inhibitor of viral RNA-dependent-RNA-polymerases (RdRp) and clinical trials for the treatment of COVID-19 are ongoing. Here, the authors show that SARS-CoV nsp12 is the fastest known viral RdRp and they provide insights into the mechanism of action of Favipiravir, demonstrating that its antiviral effect on SARS-CoV-2 is primarily mediated through lethal mutagenesis.
【저자키워드】 SARS-CoV-2, Viral proteins, 【초록키워드】 COVID-19, Treatment, coronavirus, clinical trial, pandemic, Nsp12, T-705, SARS-CoV, Antiviral effect, Corona, SARS-CoV-2 genome, RdRP, antiviral therapeutics, Viral RNA, inhibitor, mechanism of action, Viral diseases, Coronavirus-2, Mutagenesis, nucleoside analogue, nucleotide, cytosine, acute respiratory syndrome, complex, candidate, insertion, polymerase, caused, Achille, provoking, 【제목키워드】 Rapid, Viral RNA, Mutagenesis, complex, polymerase,