Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis
Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis
复制标题
DOI：
10.1038/s41467-020-18463-z
复制
发表时间：
2020-09-17
影响因子：
16.6
通讯作者：
Canard, Bruno
中科院分区：
文献类型：
--
作者：
Shannon, Ashleigh;Selisko, Barbara;Canard, Bruno
由严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）引起的2019年冠状病毒病（COVID-19）大流行强调了对抗病毒治疗的迫切需求。病毒RNA依赖性RNA聚合酶（RdRp）是一个很有前途的靶点，聚合酶抑制剂成功地用于治疗几种病毒性疾病。我们在这里证明，法匹拉韦主要通过致死突变发挥抗病毒作用。SARS-CoV RdRp复合物的活性至少是其他已知病毒RdRp的10倍。它具有异常高的核苷酸掺入率和高错误率，允许法匹拉韦轻松插入病毒RNA中，在胞嘧啶含量已经很低的SARS-CoV-2基因组中引起C到U和G到A的转换。冠状病毒RdRp复合物代表了SARS-CoV的致命弱点，支持核苷类似物作为治疗COVID-19的有希望的候选物。
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.