Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2020,（4）
• 页码范围: 343-355
• 页数: 13页
• 语种: 英文

摘要

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 defined.Therefore,we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV.We solved the X-ray cnystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the 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 the HR2 domain.We previously developed a pan-coronavirus fusion inhibitor,EK1,which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested,including SARS-CoV and MERS-CoV.Here we generated a series of lipopeptides derived from EK1 and found that 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 the original 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,and potently inhibited the replication of 5 live human coronaviruses examined,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 the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.