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

2021; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41467-021-22297-8

2041-1723

Ming Zhao, Yu Yu, Li-Ming Sun, Jia‐Qing Xing, Tingting Li, Yunkai Zhu, Miao Wang, Yu Yin, Wen Xue, Tian Xia, Hong Cai, Qiuying Han, Xiaoyao Yin, Weihua Li, Ailing Li, Jiuwei Cui, Zhenghong Yuan, Rong Zhang, Tao Zhou, Xuemin Zhang, Tao Li,

RNA and protein synthesis mechanisms

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.