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

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.

• Authors: 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, Zhenghong Yuan, Rong Zhang, Tao Zhou, Xue-Min Zhang, Tao Li
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 2114 (04 09 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33837182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nucleocapsid Proteins
• RNA, Viral
• gallocatechin gallate
• Catechin

Topics

• Amino Acid Substitution (drug effects)
• COVID-19 (prevention & control, virology)
• Catechin (analogs & derivatives, pharmacology)
• Genome, Viral (genetics)
• Humans
• Liquid-Liquid Extraction
• Nucleocapsid Proteins (genetics, metabolism)
• RNA, Viral (genetics, metabolism)
• SARS-CoV-2 (drug effects, genetics)
• Virus Replication (drug effects, genetics)