Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies
Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies
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DOI：
10.1016/j.cell.2020.04.031
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发表时间：
2020-05-28
期刊：
影响因子：
64.5
通讯作者：
McLellan, Jason S.
中科院分区：
文献类型：
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作者：
Wrapp, Daniel;De Vlieger, Dorien;McLellan, Jason S.
冠状病毒利用一种名为Spike(S)的大包膜蛋白来接触宿主细胞受体并催化膜融合。由于这些S蛋白所起的重要作用，它们是治疗学发展的一个脆弱的靶点。在这里，我们描述了从灌流稳定的冠状病毒尖峰免疫的骆驼中分离出单域抗体(VHH)。这些VHH分别中和MERS冠状病毒和SARSCoV-1 S假型病毒。这些VHH与各自的病毒靶标结合的晶体结构显示了两个不同的表位，但这两个VHH都干扰了受体的结合。我们还显示了SARS-CoV-1 S指导的VHH与SARS-CoV-2 S之间的交叉反应，并证明这种交叉反应VHH以双价人Ig G Fc融合的形式中和SARS-CoV-2 S伪型病毒。这些数据为VHH中和致病性β冠状病毒提供了分子基础，并表明这些分子可能在冠状病毒暴发期间用作有用的治疗药物。
Coronaviruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics. Here, we describe the isolation of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARSCoV-1 S pseudotyped viruses, respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S and demonstrate that this cross-reactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks.