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. tzhou@nanhulab.ac.cn.
6 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing, 100850, China. zhangxuemin@cashq.ac.cn.
7 School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. zhangxuemin@cashq.ac.cn.
8 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing, 100850, China. tli@ncba.ac.cn.
9 School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. tli@ncba.ac.cn.
# 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, N^R203K/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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