Xiao-Qing Qiu, Shaui-Yao Lu, Ke-Fu Cao, Jian-Yong Tang, Dong Zhang, Feng-Yu Luo, Hong-Fa Li, Yong-Qi Li, Cheng-Yun Yang, Ya-Nan Zou, Li-Li Ren, Xiao-Zhong Peng
The unprecedented Coronavirus Disease (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective antiviral drug to control this severe infectious disease. Here, we found that the E or M membrane proteins of coronavirus could be targeted by a 28-residue antibody mimetic by fusing two antibody Fab Complementarity-Determining Regions (VHCDR1 and VLCDR3) through a cognate Framework Region (VHFR2) of the antibodies which recognize the coronavirus E or M proteins. We constructed a fusion protein, Pheromonicin-COVID-19 (PMC-COVID-19), by linking colicin Ia, a bactericidal molecule produced by E. coli which kills target cells by forming a voltage-dependent channel in target lipid bilayers, to that antibody mimetic. The E or M protein/antibody mimetic interaction initiated the formation of irreversible PMC-COVID-19 channel in the COVID-19 envelope and viral-infected host cell membrane resulting in leakage of cellular contents. PMC-COVID-19 demonstrates broad-spectrum protective efficacy against tested SARS-CoV-2 variants-induced severe acute respiratory syndrome (p<0.01-0.0001). PMC-COVID-19 significantly altered outcomes of in vivo fatal COVID-19 challenge infection without evident toxicity, making it an appropriate candidate for further clinical evaluation.