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GCG inhibits SARS-CoV-2 replication by disrupting the liquid phase condensation of its nucleocapsid protein

Author

Listed:
  • Ming Zhao

    (National Center of Biomedical Analysis
    Nanhu Laboratory)

  • Yu Yu

    (National Center of Biomedical Analysis
    The First Hospital of Jilin University)

  • Li-Ming Sun

    (National Center of Biomedical Analysis)

  • Jia-Qing Xing

    (National Center of Biomedical Analysis)

  • Tingting Li

    (National Center of Biomedical Analysis)

  • Yunkai Zhu

    (Fudan University)

  • Miao Wang

    (National Center of Biomedical Analysis)

  • Yin Yu

    (Fudan University)

  • Wen Xue

    (National Center of Biomedical Analysis)

  • Tian Xia

    (National Center of Biomedical Analysis)

  • Hong Cai

    (National Center of Biomedical Analysis)

  • Qiu-Ying Han

    (National Center of Biomedical Analysis)

  • Xiaoyao Yin

    (National Center of Biomedical Analysis)

  • Wei-Hua Li

    (National Center of Biomedical Analysis)

  • Ai-Ling Li

    (National Center of Biomedical Analysis)

  • Jiuwei Cui

    (The First Hospital of Jilin University)

  • Zhenghong Yuan

    (Fudan University)

  • Rong Zhang

    (Fudan University)

  • Tao Zhou

    (Nanhu Laboratory)

  • Xue-Min Zhang

    (National Center of Biomedical Analysis
    Fudan University)

  • Tao Li

    (National Center of Biomedical Analysis
    Fudan University)

Abstract

Lack of detailed knowledge of SARS-CoV-2 infection has been hampering the development of treatments for coronavirus disease 2019 (COVID-19). Here, we report that RNA triggers the liquid–liquid phase separation (LLPS) of the SARS-CoV-2 nucleocapsid protein, N. By analyzing all 29 proteins of SARS-CoV-2, we find that only N is predicted as an LLPS protein. We further confirm the LLPS of N during SARS-CoV-2 infection. Among the 100,849 genome variants of SARS-CoV-2 in the GISAID database, we identify that ~37% (36,941) of the genomes contain a specific trio-nucleotide polymorphism (GGG-to-AAC) in the coding sequence of N, which leads to the amino acid substitutions, R203K/G204R. Interestingly, NR203K/G204R exhibits a higher propensity to undergo LLPS and a greater effect on IFN inhibition. By screening the chemicals known to interfere with N-RNA binding in other viruses, we find that (-)-gallocatechin gallate (GCG), a polyphenol from green tea, disrupts the LLPS of N and inhibits SARS-CoV-2 replication. Thus, our study reveals that targeting N-RNA condensation with GCG could be a potential treatment for COVID-19.

Suggested Citation

  • Ming Zhao & Yu Yu & Li-Ming Sun & Jia-Qing Xing & Tingting Li & Yunkai Zhu & Miao Wang & Yin Yu & Wen Xue & Tian Xia & Hong Cai & Qiu-Ying Han & Xiaoyao Yin & Wei-Hua Li & Ai-Ling Li & Jiuwei Cui & Zh, 2021. "GCG inhibits SARS-CoV-2 replication by disrupting the liquid phase condensation of its nucleocapsid protein," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22297-8
    DOI: 10.1038/s41467-021-22297-8
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    Cited by:

    1. Sophie Marianne Korn & Karthikeyan Dhamotharan & Cy M. Jeffries & Andreas Schlundt, 2023. "The preference signature of the SARS-CoV-2 Nucleocapsid NTD for its 5’-genomic RNA elements," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Jiang Ren & Shuai Wang & Zhi Zong & Ting Pan & Sijia Liu & Wei Mao & Huizhe Huang & Xiaohua Yan & Bing Yang & Xin He & Fangfang Zhou & Long Zhang, 2024. "TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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