Defining the features and structure of neutralizing antibody targeting the silent face of the SARS‐CoV‐2 spike N‐terminal domain

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.

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Publication Details

Journal
MedComm
Published
2024-11-28
DOI
https://doi.org/10.1002/mco2.70008
Citations
5
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
1.95

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article

Defining the features and structure of neutralizing antibody targeting the silent face of the SARS‐CoV‐2 spike N‐terminal domain

Jianfen Zhuo, Yuanyuan Zhang, Canjie Chen, Jincun Zhao et al.
5 citations
MedComm
SARS-CoV-2 and COVID-19 Research
1.95
article

Defining the features and structure of neutralizing antibody targeting the silent face of the SARS‐CoV‐2 spike N‐terminal domain

Jianfen Zhuo, Yuanyuan Zhang, Canjie Chen, Jincun Zhao, Zhaoyong Zhang, Yingkang Jin, Lu Zhang, Haiyue Rao, Shu Li, Yonghao Xu, Jun Dai, Peilan Wei, Jinling Cheng, Yingying Guo, Jingxian Zhao, Airu Zhu, Jiaxin Feng, Qihong Yan, Yuanyuan Zhang, Lei Chen, Xuesong Liu, Qiang Zhou, Yimin Li, Shengnan Zhang, Linling Cheng, Yanqun Wang, Jingjun Zhang, Jiantao Chen, Xiaoqing Liu, Bin Qu, Juxue Xiao, Yuting Zhang, Xinyi Xiong, Ruoxi Cai, Jingyi Su
article en
5 citations

Abstract

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.

MedCommVol. 5(12)
Southern University of Science and Technology (CN), ShanghaiTech University (CN), Westlake University (CN), Second Affiliated Hospital of Guangzhou Medical University (CN), First Affiliated Hospital of Guangzhou Medical University (CN), Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN), State Key Laboratory of Respiratory Disease (CN), Guangdong Inspection and Quarantine Technology Center (China) (CN), Shenzhen Third People’s Hospital (CN), Guangzhou Medical University (CN)
National Natural Science Foundation of China, National Key Research and Development Program of China
Good health and well-being
Openalex Percentile: Top 13%
SARS-CoV-2 and COVID-19 Research
1.95
DOIOpen Access PDFOpenAlex
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