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.

由严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2) 引起的 2019 年冠状病毒病 (COVID-19) 大流行，凸显了抗病毒治疗的迫切需要。病毒RNA依赖性RNA聚合酶（RdRp）是一个有前途的靶标，聚合酶抑制剂已成功用于治疗多种病毒性疾病。我们在此证明法匹拉韦主要通过致死诱变发挥抗病毒作用。SARS-CoV RdRp 复合物的活性比任何其他已知病毒 RdRp 至少高 10 倍。它具有异常高的核苷酸掺入率和高错误率，使法维匹拉韦能够轻松插入病毒 RNA，从而在胞嘧啶含量已经很低的 SARS-CoV-2 基因组中引发 C 到 U 和 G 到 A 的转变。冠状病毒 RdRp 复合物是 SARS-CoV 的致命弱点，支持核苷类似物作为治疗 COVID-19 的有希望的候选药物。