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
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
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一种高效的泛冠状病毒融合抑制剂抑制 SARS-CoV-2（以前的 2019-nCoV）感染，该抑制剂针对其具有高介导膜融合能力的刺突蛋白
DOI：
10.1038/s41422-020-0305-x
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发表时间：
2020-03-30
期刊：
影响因子：
44.1
通讯作者：
Lu, Lu
中科院分区：
文献类型：
--
作者：
Xia, Shuai;Liu, Meiqin;Lu, Lu
最近，由SARS-CoV-2感染引起的新型冠状病毒病（COVID-19）在中国武汉爆发，对全球公共卫生构成严重威胁。为了开发特异性的抗冠状病毒治疗和预防措施，必须首先确定病毒感染的分子机制。因此，我们建立了SARS-CoV-2刺突蛋白介导的细胞-细胞融合实验，发现与SARS-CoV相比，SARS-CoV-2具有更强的质膜融合能力。我们解决了SARS-CoV-2 S蛋白S2亚基HR1和HR2结构域的六螺旋束（6-HB）核心的x射线晶体结构，揭示了HR1结构域的几个突变氨基酸残基可能与HR2结构域的相互作用增强有关。我们之前开发了一种泛冠状病毒融合抑制剂EK1，它针对HR1结构域，可以抑制不同的人类冠状病毒的感染，包括SARS-CoV和MERS-CoV。在这里，我们从EK1衍生了一系列脂肽，发现EK1C4是对抗sars - cov - 2s蛋白介导的膜融合和假病毒感染的最有效的融合抑制剂，ic50分别为1.3和15.8 nM，分别是原始EK1肽的241和149倍。EK1C4对其他人类冠状病毒假病毒的膜融合和感染也非常有效，包括SARS-CoV和MERS-CoV，以及sars - sr - cov，并有效抑制5种活的人类冠状病毒的复制，包括SARS-CoV-2。在HCoV-OC43攻击之前或之后鼻内应用EK1C4可保护小鼠免受感染，这表明EK1C4可用于预防和治疗当前流行的SARS-CoV-2和其他新出现的sarsr - cov感染。
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 crystal 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.