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

The record-breaking infection by SARS-CoV-2 on a daily basis has inflicted emotional pain and economic burden across the globe. Enzymes that are vital for the viral life cycle are excellent antiviral drug targets as they are uniquely different from the host proteins. Among viral enzymes, RdRp is the major target of many existing nucleotide drugs. In this paper, we report the structure of the SARS-CoV-2 RdRp complex in the apo form and in the complex with a template-primer RNA and the active form of Remdesivir. The structures reveal how the template-primer RNA is recognized by the enzyme and the inhibition of the chain elongation by Remdesivir. Structure comparison and sequence alignment suggest that the mode of substrate RNA recognition and Remdesivir inhibition of RdRp are highly conserved in RdRp from diverse RNA viruses, providing a basis for designing broad spectrum antiviral drugs based on nucleotide analogs. Moreover, our structures also provide a solid template for modeling and modifying the existing nucleotide drugs, including the highly potent EIDD-2801. Together, these observations provide a rational basis to design even more potent inhibitors to combat the vicious infection of SARS-CoV-2.