SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damage and constitutes an antiviral target

Xia, Bingqing; Shen, Xurui; He, Yang; Pan, Xiaoyan; Wang, Yi; Yang, Feipu; Fang, Sui; Wu, Yan; Zuo, Xiaoli; Xie, Zhuqing; Jiang, Xiangrui; Chi, Hao; Meng, Qian; Zhou, Hu; Zhou, Yubo; Cheng, Xi; Chen, Tong; Xin, Xiaoming; Jiang, Hualiang; Xiao, Gengfu; Zhao, Qiang; Zhang, Lei-Ke; Shen, Jingshan; Li, Jia; Gao, Zhaobing

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of the virus’ excessively damaging abilities remains unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is sufficient to cause acute respiratory distress syndrome (ARDS)-like damage in vitro and in vivo. Overexpression of 2-E protein induced rapid pyroptosis-like cell death in various susceptible cells and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damage in lung and spleen. Overexpressed 2-E protein formed cation channels in host cell membranes, eventually leading to membrane rupture. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent protective effects against the 2-E-induced damage both in vitro and in vivo. Importantly, their channel inhibition, cell protection and antiviral activities were positively correlated with each other, supporting 2-E is a promising drug target against SARS-CoV-2.