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Identification of the SARS-unique domain of SARS-CoV-2 as an antiviral target

Author

Listed:
  • Bo Qin

    (Institute of Pathogen Biology Chinese Academy of Medical Sciences & Peking Union Medical College
    Ministry of Education)

  • Ziheng Li

    (Institute of Pathogen Biology Chinese Academy of Medical Sciences & Peking Union Medical College
    Ministry of Education)

  • Kaiming Tang

    (The University of Hong Kong
    The University of Hong Kong)

  • Tongyun Wang

    (The University of Hong Kong)

  • Yubin Xie

    (The University of Hong Kong)

  • Sylvain Aumonier

    (Swiss Light Source at the Paul Scherrer Institute)

  • Meitian Wang

    (Swiss Light Source at the Paul Scherrer Institute)

  • Shuofeng Yuan

    (The University of Hong Kong
    The University of Hong Kong)

  • Sheng Cui

    (Institute of Pathogen Biology Chinese Academy of Medical Sciences & Peking Union Medical College
    Ministry of Education)

Abstract

SARS-CoV-2 nsp3 is essential for viral replication and host responses. The SARS-unique domain (SUD) of nsp3 exerts its function through binding to viral and host proteins and RNAs. Herein, we show that SARS-CoV-2 SUD is highly flexible in solution. The intramolecular disulfide bond of SARS-CoV SUD is absent in SARS-CoV-2 SUD. Incorporating this bond in SARS-CoV-2 SUD allowed crystal structure determination to 1.35 Å resolution. However, introducing this bond in SARS-CoV-2 genome was lethal for the virus. Using biolayer interferometry, we screened compounds directly binding to SARS-CoV-2 SUD and identified theaflavin 3,3’-digallate (TF3) as a potent binder, Kd 2.8 µM. TF3 disrupted the SUD-guanine quadruplex interactions and exhibited anti-SARS-CoV-2 activity in Vero E6-TMPRSS2 cells with an EC50 of 5.9 µM and CC50 of 98.5 µM. In this work, we provide evidence that SARS-CoV-2 SUD harbors druggable sites for antiviral development.

Suggested Citation

  • Bo Qin & Ziheng Li & Kaiming Tang & Tongyun Wang & Yubin Xie & Sylvain Aumonier & Meitian Wang & Shuofeng Yuan & Sheng Cui, 2023. "Identification of the SARS-unique domain of SARS-CoV-2 as an antiviral target," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39709-6
    DOI: 10.1038/s41467-023-39709-6
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