Zhang Zhaoyong, Zhang Yuanyuan, Zhang Yuting, Cheng Linling, Zhang Lu, Yan Qihong, Liu Xuesong, Chen Jiantao, Dai Jun, Guo Yingying, Wei Peilan, Xiong Xinyi, Xiao Juxue, Zhu Airu, Zhuo Jianfen, Cai Ruoxi, Zhang Jingjun, Rao Haiyue, Qu Bin, Zhang Shengnan, Feng Jiaxin, Cheng Jinling, Su Jingyi, Chen Canjie, Li Shu, Zhang Yuanyuan, Chen Lei, Jin Yingkang, Xu Yonghao, Liu Xiaoqing, Li Yimin, Zhao Jingxian, Wang Yanqun, Zhou Qiang, Zhao Jincun
State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou China.
Center for Infectious Disease Research Research Center for Industries of the Future Zhejiang Key Laboratory of Structural Biology School of Life Sciences Westlake University Institute of Biology Westlake Institute for Advanced Study Westlake Laboratory of Life Sciences and Biomedicine Hangzhou Zhejiang Province China.
MedComm (2020). 2024 Nov 28;5(12):e70008. doi: 10.1002/mco2.70008. eCollection 2024 Dec.
Research on virus/receptor interactions has uncovered various mechanisms of antibody-mediated neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, understanding of neutralization by antibodies targeting the silent face, which recognize epitopes on glycan shields, remains limited, and their potential protective efficacy in vivo is not well understood. This study describes a silent face neutralizing antibody, 3711, which targets a non-supersite on the N-terminal domain (NTD) of the spike protein. Cryo-EM structure determination of the 3711 Fab in the spike complex reveals a novel neutralizing epitope shielded by glycans on the spike's silent face. Antibody 3711 inhibits the interaction between the receptor-binding domain (RBD) and human angiotensin-converting enzyme 2 (hACE2) through steric hindrance and exhibits superior in vivo protective effects compared to other reported NTD-targeted monoclonal antibodies (mAbs). Competition assays and antibody repertoire analysis indicate the rarity of antibodies targeting the 3711-related epitope in SARS-CoV-2 convalescents, suggesting the infrequency of NTD silent face-targeted neutralizing antibodies during SARS-CoV-2 infection. As the first NTD silent face-targeted neutralizing antibody against SARS-CoV-2, the identification of mAb 3711, with its novel neutralizing mechanism, enhances our understanding of neutralizing epitopes on glycan shields and elucidates epitope-guided viral mutations that evade specific antibodies.
对病毒/受体相互作用的研究揭示了针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的抗体介导中和的多种机制。然而，对于靶向沉默面（识别聚糖屏蔽上的表位）的抗体的中和作用的理解仍然有限，并且它们在体内的潜在保护功效尚未得到充分了解。本研究描述了一种沉默面中和抗体3711，其靶向刺突蛋白N端结构域（NTD）上的一个非超位点。刺突复合物中3711 Fab的冷冻电镜结构测定揭示了一个新的被刺突沉默面上的聚糖屏蔽的中和表位。抗体3711通过空间位阻抑制受体结合结构域（RBD）与人血管紧张素转换酶2（hACE2）之间的相互作用，并且与其他报道的靶向NTD的单克隆抗体（mAb）相比，在体内表现出优异的保护作用。竞争试验和抗体库分析表明，在SARS-CoV-2康复者中靶向3711相关表位的抗体很少见，这表明在SARS-CoV-2感染期间靶向NTD沉默面的中和抗体很少出现。作为首个针对SARS-CoV-2的靶向NTD沉默面的中和抗体，单克隆抗体3711的鉴定及其新的中和机制，增强了我们对聚糖屏蔽上中和表位的理解，并阐明了逃避特定抗体的表位导向的病毒突变。
