TY - JOUR T1 - Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19 JF - bioRxiv DO - 10.1101/2020.10.06.328336 SP - 2020.10.06.328336 AU - Wanchao Yin AU - Xiaodong Luan AU - Zhihai Li AU - Leike Zhang AU - Ziwei Zhou AU - Minqi Gao AU - Xiaoxi Wang AU - Fulai Zhou AU - Jingjing Shi AU - Erli You AU - Mingliang Liu AU - Qingxia Wang AU - Qingxing Wang AU - Yi Jiang AU - Hualiang Jiang AU - Gengfu Xiao AU - Xuekui Yu AU - Shuyang Zhang AU - H. Eric Xu Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/06/2020.10.06.328336.abstract N2 - The COVID-19 pandemic by non-stop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report the discovery of suramin, a 100-year-old drug, as a potent inhibitor of the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) through 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 COVID-19. The 2.6 Å cryo-EM structure of the viral RdRp bound to suramin reveals two binding sites of suramin, with one site directly blocking the binding of the RNA template strand and the other site clash with the RNA primer strand near the RdRp catalytic active site, therefore inhibiting the viral RNA replication. Furthermore, suramin potently inhibits SARS-CoV-2 duplication in Vero E6 cells. These results provide a structural mechanism for the first non-nucleotide inhibitor of the SARS-CoV-2 RdRp and a rationale for repurposing suramin for treating COVID-19.One Sentence Summary Discovery and mechanism of suramin as potent SARS-CoV-2 RNA polymerase inhibitor and its repurposing for treating COVID-19.Competing Interest StatementThe authors have declared no competing interest. ER -