State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China.
Nat Microbiol. 2022 Jul;7(7):1063-1074. doi: 10.1038/s41564-022-01155-3. Epub 2022 Jun 30.
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 α- and β-coronaviruses, including the SARS-CoV-2 variants. 76E1 also binds its epitope in peptides from γ- and δ-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.
冠状病毒的频繁爆发凸显了对能够对抗多种冠状病毒类型的抗病毒药物和疫苗的需求。我们从一名 COVID-19 康复患者中分离出一种名为 76E1 的人源抗体，并报告称它对多种 α-和 β-冠状病毒具有广谱中和活性，包括 SARS-CoV-2 变体。76E1 还与 γ-和 δ-冠状病毒的肽段结合其表位。76E1 在预防和治疗性的小鼠动物模型中均能预防 SARS-CoV-2 和 HCoV-OC43 的感染。结构和功能研究表明，76E1 靶向 Spike 蛋白内的一个独特表位，该表位包含高度保守的 S2' 位点和融合肽。76E1 结合的表位在 SARS-CoV-2 Spike 三聚体的预融合状态下部分埋藏在结构中，但当 Spike 蛋白与 ACE2 结合时会暴露出来。这一观察结果表明，76E1 在 Spike 三聚体从预融合状态向融合后状态的转变过程中结合到该表位的中间状态，从而阻止了膜融合和病毒进入。我们希望通过鉴定出 76E1 可以识别的这个关键表位，将为基于表位的下一代泛冠状病毒疫苗和抗病毒药物的设计提供指导。
