Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir

Corresponding authors: Yechun Xu, Shuyang Zhang, Yan Zhang and H. Eric Xu

Affiliations: The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; School of Medicine, Tsinghua University, Haidian District, Beijing 100084, China; Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China; University of Chinese Academy of Sciences, Beijing 100049, China; WuxiBiortus Biosciences Co. Ltd., Jiangyin 214437, China; Center of Cryo-Electron Microscopy, Zhejiang University School of Medicine, Hangzhou 310058, China; Center of Diagnostic Electron Microscopy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China; Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou 310058, China.

Publication date: this article was published online on June 26, 2020

DOI: 10.1126/science.abc1560

Highlights

Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. In this article, the authors report the cryo–electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation.

Nomination Reasons

The researchers reveal how the template-primer RNA is recognized by RdRp and how chain elongation is inhibited by remdesivir. Structure comparison and sequence alignment suggest that the mode of substrate RNA recognition and remdesivir inhibition of RdRp is highly conserved in diverse RNA viruses, providing a foundation for designing broad-spectrum antiviral drugs based on nucleotide analogs. Moreover, their structural work provides 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 SARS-CoV-2 infection.

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