Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir

Wanchao Yin; Chunyou Mao; Xiaodong Luan; Dan-Dan Shen; Qingya Shen; Haixia Su; Xiaoxi Wang; Fulai Zhou; Wenfeng Zhao; Minqi Gao; Shenghai Chang; Yuan-Chao Xie; Guanghui Tian; He-Wei Jiang; Sheng-Ce Tao; Jingshan Shen; Yi Jiang; Hualiang Jiang; Yechun Xu; Shuyang Zhang; Yan Zhang; H. Eric Xu

Besides Remdesivir, several drugs of nucleotide analogs, including Favipiravir, Ribavirin, Galidisvir, and EIDD-2801, have been shown to be efficient inhibitors in blocking SARS-CoV-2 . CC-BY-NC 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.08.032763 doi: bioRxiv preprint replication in cell-based systems (34, 35) . Like Remdesivir, these nucleotide analogs are proposed to inhibit viral RdRp indirectly through non-obligate RNA chain termination, a mechanism that requires the conversion of the parent compound to the triphosphate active form (32) . The structure of the template-RTP RdRp complex provides an excellent model to rationalize how these drugs inhibit the SARS-CoV-2 RdRp activity ( Figure 5C ). In particular, EIDD-2801 has been shown to be 3-10 times more potent than Remdesivir in blocking SARS-CoV-2 replication (35) . The N4 hydroxyl group off the cytidine ring forms an extra hydrogen bond with the side chain of K545. In addition, the cytidine base also forms an extra hydrogen bond with the guanine base from the template strand. These two extra hydrogen bonds may thus provide the explanation for the apparent higher potency for EIDD-2801 to inhibit SARS-CoV-2 replication.