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

  • Nat Commun. 2021 Apr 9;12(1):2114. doi: 10.1038/s41467-021-22297-8.
Ming Zhao   #  1  2 ,  Yu Yu   #  1  3 ,  Li-Ming Sun   #  1 ,  Jia-Qing Xing  1 ,  Tingting Li  1 ,  Yunkai Zhu  4 ,  Miao Wang  1 ,  Yin Yu  4 ,  Wen Xue  1 ,  Tian Xia  1 ,  Hong Cai  1 ,  Qiu-Ying Han  1 ,  Xiaoyao Yin  1 ,  Wei-Hua Li  1 ,  Ai-Ling Li  1 ,  Jiuwei Cui  3 ,  Zhenghong Yuan  4 ,  Rong Zhang  4 ,  Tao Zhou  5 ,  Xue-Min Zhang  6  7 ,  Tao Li  8  9
Affiliations
  • 1. State Key Laboratory of Proteomics, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing, 100850, China.
  • 2. Nanhu Laboratory, Jiaxing, Zhejiang Province, 314002, China.
  • 3. Cancer Research Institute of Jilin University, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China.
  • 4. School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • 5. Nanhu Laboratory, Jiaxing, Zhejiang Province, 314002, China. [email protected].
  • 6. State Key Laboratory of Proteomics, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing, 100850, China. [email protected].
  • 7. School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. [email protected].
  • 8. State Key Laboratory of Proteomics, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing, 100850, China. [email protected].
  • 9. School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 33837182 DOI: 10.1038/s41467-021-22297-8
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.

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