PT  - JOURNAL ARTICLE
AU  - Shuai Xia
AU  - Meiqin Liu
AU  - Chao Wang
AU  - Wei Xu
AU  - Qiaoshuai Lan
AU  - Siliang Feng
AU  - Feifei Qi
AU  - Linlin Bao
AU  - Lanying Du
AU  - Shuwen Liu
AU  - Chuan Qin
AU  - Fei Sun
AU  - Zhengli Shi
AU  - Yun Zhu
AU  - Shibo Jiang
AU  - Lu Lu
TI  - Inhibition of SARS-CoV-2 infection (previously 2019-nCoV) by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
AID  - 10.1101/2020.03.09.983247
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.09.983247
4099  - http://biorxiv.org/content/early/2020/03/12/2020.03.09.983247.short
4100  - http://biorxiv.org/content/early/2020/03/12/2020.03.09.983247.full
AB  - The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be confirmed. Therefore, we herein used a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed plasma membrane fusion capacity superior to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. We then generated a series of lipopeptides and found that the EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than that of EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, potently inhibiting replication of 4 live human coronaviruses, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by currently circulating SARS-CoV-2 and emerging SARSr-CoVs.