Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin
Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin
复制标题
苏拉明抑制 SARS-CoV-2 RNA 聚合酶的结构基础
DOI：
10.1038/s41594-021-00570-0
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发表时间：
2021-03-05
影响因子：
16.8
通讯作者：
Eric Xu, H.
中科院分区：
文献类型：
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作者：
Yin, Wanchao;Luan, Xiaodong;Eric Xu, H.
由SARS-CoV-2持续感染引发的新冠肺炎大流行继续肆虐全球许多国家。在这里，我们报道了苏拉明，一个有100年历史的药物，是SARS-CoV-2RNA依赖的RNA聚合酶(RdRp)的有效抑制剂，通过阻断RNA与酶的结合而起作用。在生化分析中，苏拉明及其衍生物的效力至少是目前批准用于治疗新冠肺炎的核苷酸药物瑞德韦的20倍。与苏拉明结合的病毒RdRp的2.6RdRp冷冻电子显微镜结构显示有两个结合位点。一个位点直接阻断RNA模板链的结合，另一个位点与RdRp催化位点附近的RNA引物链发生冲突，从而抑制RdRp的活性。苏拉明抑制Vero E6细胞中的病毒复制，尽管这种效果背后的原因可能是各种各样的。我们的结果为SARS-CoV-2 RdRp的非核苷酸抑制剂提供了结构机制。
The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.