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Remdesivir overcomes the S861 roadblock in SARS-CoV-2 polymerase elongation complex.
Wu, Jiqin; Wang, Haofeng; Liu, Qiaojie; Li, Rui; Gao, Yan; Fang, Xiang; Zhong, Yao; Wang, Meihua; Wang, Quan; Rao, Zihe; Gong, Peng.
  • Wu J; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China.
  • Wang H; School of Life Sciences, Tianjin University, Tianjin 300072, China.
  • Liu Q; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China.
  • Li R; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Gao Y; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
  • Fang X; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Zhong Y; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Wang M; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Wang Q; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: wangq@shanghaitech.edu.cn.
  • Rao Z; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biom
  • Gong P; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China; Drug Discovery Center for Infectious Diseases, Nankai University, Tianjin 300350, China. Electronic addre
Cell Rep ; 37(4): 109882, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1525720
ABSTRACT
Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID-19 treatment. However, the precise working mechanism of RDV when targeting the viral RNA-dependent RNA polymerase (RdRP) has not been fully elucidated. Here, we solve a 3.0-Å structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRP elongation complex (EC) and assess RDV intervention in polymerase elongation phase. Although RDV could induce an "i+3" delayed termination in meta-stable complexes, only pausing and subsequent elongation are observed in the EC. A comparative investigation using an enterovirus RdRP further confirms similar delayed intervention and demonstrates that steric hindrance of the RDV-characteristic 1'-cyano at the -4 position is responsible for the "i+3" intervention, although two representative Flaviviridae RdRPs do not exhibit similar behavior. A comparison of representative viral RdRP catalytic complex structures indicates that the product RNA backbone encounters highly conserved structural elements, highlighting the broad-spectrum intervention potential of 1'-modified nucleotide analogs in anti-RNA virus drug development.
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Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Main subject: Antiviral Agents / Viral Proteins / RNA-Dependent RNA Polymerase / Adenosine Monophosphate / Alanine / SARS-CoV-2 Subject: Antiviral Agents / Viral Proteins / RNA-Dependent RNA Polymerase / Adenosine Monophosphate / Alanine / SARS-CoV-2 Language: English Journal: Cell Rep Year: 2021

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Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Main subject: Antiviral Agents / Viral Proteins / RNA-Dependent RNA Polymerase / Adenosine Monophosphate / Alanine / SARS-CoV-2 Subject: Antiviral Agents / Viral Proteins / RNA-Dependent RNA Polymerase / Adenosine Monophosphate / Alanine / SARS-CoV-2 Language: English Journal: Cell Rep Year: 2021
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