Structural Basis of a Human Neutralizing Antibody Specific to the SARS-CoV-2 Spike Protein Receptor-Binding Domain.
Structural Basis of a Human Neutralizing Antibody Specific to the SARS-CoV-2 Spike Protein Receptor-Binding Domain.
复制标题
SARS-CoV-2 刺突蛋白受体结合域特异性人中和抗体的结构基础
DOI：
10.1128/spectrum.01352-21
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发表时间：
2021-10-31
影响因子：
3.7
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Yang M;Li J;Huang Z;Li H;Wang Y;Wang X;Kang S;Huang X;Wu C;Liu T;Jia Z;Liang J;Yuan X;He S;Chen X;Zhou Z;Chen Q;Liu S;Li J;Zheng H;Liu X;Li K;Yao X;Lang B;Liu L;Liao HX;Chen S
新出现的严重急性呼吸综合征冠状病毒-2 （SARS-CoV-2）谱系标志着2019年冠状病毒病（COVID-19）进入了一个新阶段。了解针对刺突蛋白的强效中和单克隆抗体（nab）的识别机制对于开发新疫苗和抗体药物至关重要。在这里，我们从SARS-CoV-2恢复期的B细胞受体库中分离出几种针对SARS-CoV-2刺突蛋白受体结合域（S-RBD）的单克隆抗体（mab）。在这些单克隆抗体中，nCoV617抗体对SARS-CoV-2感染表现出最有效的中和活性，并且在体内对人血管紧张素转换酶2 （ACE2）转基因小鼠模型具有预防和治疗作用。S-RBD与nCoV617配合物的晶体结构表明，nCoV617主要结合在RBD的“脊”后部，与ACE2共享有限的结合残基。在s -三聚体模型的背景下，它可能与S-RBD的“上”和“下”构象结合。体外诱变实验表明，在新出现的SARS-CoV-2新谱系B.1.1.7中发现的突变残基不影响nCoV617与S-RBD的结合。这些结果提供了一种新的抗S-RBD的人源中和抗体，并有助于疫苗的开发。COVID-19是一种由严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）引起的呼吸道疾病。新冠肺炎大流行对全球健康和经济构成严重威胁，因此有必要寻找安全有效的抗体药物和治疗方法。SARS-CoV-2刺突蛋白中的受体结合域（RBD）负责与血管紧张素转换酶2 （ACE2）受体结合。它含有多种显性中和表位，是新型冠状病毒抗体形成的重要抗原。我们的研究意义在于确定新的表位，发现抗RBD的抗体，评价抗体的中和作用。这里鉴定的抗体可能是开发针对SARS-CoV-2的临床干预措施的候选药物。
The emerging new lineages of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have marked a new phase of coronavirus disease 2019 (COVID-19). Understanding the recognition mechanisms of potent neutralizing monoclonal antibodies (NAbs) against the spike protein is pivotal for developing new vaccines and antibody drugs. Here, we isolated several monoclonal antibodies (MAbs) against the SARS-CoV-2 spike protein receptor-binding domain (S-RBD) from the B cell receptor repertoires of a SARS-CoV-2 convalescent. Among these MAbs, the antibody nCoV617 demonstrates the most potent neutralizing activity against authentic SARS-CoV-2 infection, as well as prophylactic and therapeutic efficacies against the human angiotensin-converting enzyme 2 (ACE2) transgenic mouse model in vivo. The crystal structure of S-RBD in complex with nCoV617 reveals that nCoV617 mainly binds to the back of the “ridge” of RBD and shares limited binding residues with ACE2. Under the background of the S-trimer model, it potentially binds to both “up” and “down” conformations of S-RBD. In vitro mutagenesis assays show that mutant residues found in the emerging new lineage B.1.1.7 of SARS-CoV-2 do not affect nCoV617 binding to the S-RBD. These results provide a new human-sourced neutralizing antibody against the S-RBD and assist vaccine development. IMPORTANCE COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 pandemic has posed a serious threat to global health and the economy, so it is necessary to find safe and effective antibody drugs and treatments. The receptor-binding domain (RBD) in the SARS-CoV-2 spike protein is responsible for binding to the angiotensin-converting enzyme 2 (ACE2) receptor. It contains a variety of dominant neutralizing epitopes and is an important antigen for the development of new coronavirus antibodies. The significance of our research lies in the determination of new epitopes, the discovery of antibodies against RBD, and the evaluation of the antibodies’ neutralizing effect. The identified antibodies here may be drug candidates for the development of clinical interventions for SARS-CoV-2.