复旦大学陆路/姜世勃等发现新的冠状病毒抑制剂，有望快...

hantavirus

自2020年1月以来，2019年冠状病毒病（COVID-19）已迅速传播到中国大部分地区和其他国家，截至2020年4月1日，全球确诊病例累计近70万，死亡3万余例。这些数字每天都会更新，而且预计还会进一步增加。目前已经阐明该病系感染冠状病毒SARS-CoV-2所致。冠状病毒（CoVs）是迄今为止被鉴定出的最大的RNA病毒，冠状病毒科分为4个属，分别为α，β，δ和γ冠状病毒。可以感染人类的七种冠状病毒（HCoV），SARS-CoV和SARS-CoV-2及MERS-CoV同属于β-冠状病毒谱。




随着疫情的全球扩散，开发特定的抗冠状病毒治疗和预防用生物制品，已成为研究热点并迫在眉睫。为了开发特定的SARS-CoV-2融合抑制剂，研究SARS-CoV-2的融合能力至关重要。SARS-CoV和SARS-CoV-2由刺突（S）蛋白介导膜融合过程，且均利用人类血管紧张素转化酶2（hACE2）作为受体。

本研究表明SARS-CoV-2的膜融合能力比SARS-CoV更高，这表明SARS-CoV-2的融合机制是冠状病毒融合抑制剂开发的重要目标。该研究已经解决了SARS-CoV-2的6-HB核心的X射线晶体结构，并确定了HR1结构域中几个突变的氨基酸残基，这些残基负责与HR2结构域的增强相互作用。


通过研究S蛋白介导的膜融合的结构基础，可为冠状病毒融合抑制剂的合理设计奠定基础。在之前的研究中，研究人员设计了针对HCoV S蛋白HR1结构域的泛冠状病毒融合抑制剂EK1，事实证明它可以有效抑制5种HCoV的感染，包括SARS-CoV和MERS-CoV，以及3种SARS-相关CoV（SARSr-CoV）。动物试验结果表明该肽具有预防SARS-CoV-2感染的预防和治疗潜力。


EK1肽具有预防SARS-CoV-2感染的预防和治疗潜力



通过将胆固醇分子与EK1肽缀合，该研究发现脂肽之一EK1C4对SARS-CoV-2 S介导的膜融合和PsV感染表现出强效的抑制活性，体内外试验表明EK1C4可用于预防和治疗当前正在流行的SARS-CoV-2和其他新兴SARSr-CoV的感染。




EK1C4在体外和体内均有效抑制SARS-CoV-2感染



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原文地址：https://www.nature.com/articles/s41422-020-0305-x

Title: 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

DOI: 10.1038/s41422-020-0305-x

Abstract：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.

hantavirus

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