Neutralization mechanism of a human antibody with pan-coronavirus reactivity including SARS-CoV-2
Neutralization mechanism of a human antibody with pan-coronavirus reactivity including SARS-CoV-2
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DOI：
10.1038/s41564-022-01155-3
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发表时间：
2022-07-01
影响因子：
28.3
通讯作者：
Sun, Bing
中科院分区：
文献类型：
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作者：
Sun, Xiaoyu;Yi, Chunyan;Sun, Bing
冠状病毒的频繁爆发突出表明，需要能够对抗多种冠状病毒类型的抗病毒药物和疫苗。我们从一名新冠肺炎康复期患者身上分离出一种名为76E1的人类抗体，据报道，它对多种甲型和乙型冠状病毒具有广泛的中和活性，包括SARS-CoV-2变种。76E1还将其表位与来自伽马冠状病毒和三角洲冠状病毒的多肽结合。76E1在预防性和治疗性小鼠动物模型中对SARS-CoV-2和HCoV-OC43感染具有交叉保护作用。结构和功能研究表明，76E1针对的是尖峰蛋白中的一个独特的表位，该表位包含高度保守的S2‘位点和融合肽。76E1结合的表位在预融合状态下部分埋在SARS-CoV-2尖峰三聚体的结构中，但当尖峰蛋白与ACE2结合时暴露出来。这一观察表明，76E1在从融合前到融合后状态的转变过程中，以尖峰三聚体的中间状态与表位结合，从而阻止膜融合和病毒进入。我们希望这一可被76E1识别的关键表位的鉴定将指导下一代泛冠状病毒疫苗和抗病毒药物的基于表位的设计。针对包括SARS-CoV-2在内的各种冠状病毒具有中和活性的广谱人类抗体，靶向于高度保守的S2‘位点和在与宿主细胞相互作用过程中暴露的刺突蛋白的融合肽。泛冠状病毒抗体在预防和治疗后保护小鼠免受SARS-CoV-2和HCoV-OC43的感染。
Frequent outbreaks of coronaviruses underscore the need for antivirals and vaccines that can counter a broad range of coronavirus types. We isolated a human antibody named 76E1 from a COVID-19 convalescent patient, and report that it has broad-range neutralizing activity against multiple alpha- and beta-coronaviruses, including the SARS-CoV-2 variants. 76E1 also binds its epitope in peptides from gamma- and delta-coronaviruses. 76E1 cross-protects against SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and therapeutic murine animal models. Structural and functional studies revealed that 76E1 targets a unique epitope within the spike protein that comprises the highly conserved S2' site and the fusion peptide. The epitope that 76E1 binds is partially buried in the structure of the SARS-CoV-2 spike trimer in the prefusion state, but is exposed when the spike protein binds to ACE2. This observation suggests that 76E1 binds to the epitope at an intermediate state of the spike trimer during the transition from the prefusion to the postfusion state, thereby blocking membrane fusion and viral entry. We hope that the identification of this crucial epitope, which can be recognized by 76E1, will guide epitope-based design of next-generation pan-coronavirus vaccines and antivirals.A broad-range human antibody with neutralizing activity against various coronaviruses, including SARS-CoV-2, targets a unique epitope within the highly conserved S2' site and the fusion peptide of the spike protein that is exposed during interaction with the host cell. The pan-coronavirus antibody protects mice against infection with SARS-CoV-2 and HCoV-OC43 following prophylactic and therapeutic treatment.