Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille Université, UMR 7257, 13009, Marseille, France.
Faculty of Sciences, Department of Chemistry, Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, D-20146, Hamburg, Germany.
Nat Commun. 2020 Sep 17;11(1):4682. doi: 10.1038/s41467-020-18463-z.
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.
持续的 2019 年冠状病毒病（COVID-19）大流行是由严重急性呼吸系统综合症冠状病毒 2 型（SARS-CoV-2）引起的，这凸显了对抗病毒治疗药物的迫切需求。病毒 RNA 依赖性 RNA 聚合酶（RdRp）是一个很有前途的靶点，聚合酶抑制剂已成功用于治疗多种病毒疾病。我们在此证明，法匹拉韦主要通过致死性诱变发挥抗病毒作用。SARS-CoV RdRp 复合物的活性至少比已知的任何其他病毒 RdRp 高 10 倍。它具有异常高的核苷酸掺入率和高错误率，可轻易将法匹拉韦插入病毒 RNA 中，在已经低的 SARS-CoV-2 基因组胞嘧啶含量中引发 C 到 U 和 G 到 A 的转换。冠状病毒 RdRp 复合物是 SARS-CoV 的阿喀琉斯之踵，支持核苷类似物作为治疗 COVID-19 的有前途的候选药物。
