1. Academic Validation
  2. 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

  • Nat Struct Mol Biol. 2021 Mar;28(3):319-325. doi: 10.1038/s41594-021-00570-0.
Wanchao Yin  # 1 Xiaodong Luan  # 2 3 4 Zhihai Li  # 1 5 Ziwei Zhou  # 1 5 6 Qingxing Wang  # 6 7 Minqi Gao 8 Xiaoxi Wang 1 Fulai Zhou 1 Jingjing Shi 1 Erli You 1 Mingliang Liu 1 Qingxia Wang 1 5 Yi Jiang 1 6 Hualiang Jiang 1 6 Gengfu Xiao 7 Leike Zhang 9 10 Xuekui Yu 11 12 13 Shuyang Zhang 14 15 16 H Eric Xu 17 18
Affiliations

Affiliations

  • 1 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2 School of Medicine, Tsinghua University, Haidian District, Beijing, China.
  • 3 Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 4 Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
  • 5 Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 6 University of Chinese Academy of Sciences, Beijing, China.
  • 7 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.
  • 8 WuxiBiortus Biosciences Co. Ltd, Jiangyin, China.
  • 9 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 10 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China. [email protected].
  • 11 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 12 Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 13 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 14 School of Medicine, Tsinghua University, Haidian District, Beijing, China. [email protected].
  • 15 Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. [email protected].
  • 16 Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. [email protected].
  • 17 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 18 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • # Contributed equally.
Abstract

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.

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