EMBO Molecular Medicine (Dec 2021)
Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody
- Tingting Li,
- Hongmin Cai,
- Yapei Zhao,
- Yanfang Li,
- Yanling Lai,
- Hebang Yao,
- Liu Daisy Liu,
- Zhou Sun,
- Martje Fentener van Vlissingen,
- Thijs Kuiken,
- Corine H GeurtsvanKessel,
- Ning Zhang,
- Bingjie Zhou,
- Lu Lu,
- Yuhuan Gong,
- Wenming Qin,
- Moumita Mondal,
- Bowen Duan,
- Shiqi Xu,
- Audrey S Richard,
- Hervé Raoul,
- JianFeng Chen,
- Chenqi Xu,
- Ligang Wu,
- Haisheng Zhou,
- Zhong Huang,
- Xuechao Zhang,
- Jun Li,
- Yanyan Wang,
- Yuhai Bi,
- Barry Rockx,
- Junfang Chen,
- Fei‐Long Meng,
- Dimitri Lavillette,
- Dianfan Li
Affiliations
- Tingting Li
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Hongmin Cai
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Yapei Zhao
- University of CAS Beijing China
- Yanfang Li
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Yanling Lai
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Hebang Yao
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Liu Daisy Liu
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Zhou Sun
- Hangzhou Center for Disease Control and Prevention Hangzhou China
- Martje Fentener van Vlissingen
- Erasmus Laboratory Animal Science Center Erasmus University Medical Center Rotterdam The Netherlands
- Thijs Kuiken
- European Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL) Paris France
- Corine H GeurtsvanKessel
- European Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL) Paris France
- Ning Zhang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of Microbiology Center for Influenza Research and Early‐warning (CASCIRE) CAS‐TWAS Center of Excellence for Emerging Infectious Diseases (CEEID) CAS Beijing China
- Bingjie Zhou
- University of CAS Beijing China
- Lu Lu
- University of CAS Beijing China
- Yuhuan Gong
- University of CAS Beijing China
- Wenming Qin
- National Facility for Protein Science in Shanghai Shanghai Advanced Research Institute (Zhangjiang Laboratory) CAS Shanghai China
- Moumita Mondal
- CAS Key Laboratory of Molecular Virology & Immunology Institut Pasteur of Shanghai CAS Shanghai China
- Bowen Duan
- University of CAS Beijing China
- Shiqi Xu
- University of CAS Beijing China
- Audrey S Richard
- European Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL) Paris France
- Hervé Raoul
- European Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL) Paris France
- JianFeng Chen
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Chenqi Xu
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Ligang Wu
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Haisheng Zhou
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Zhong Huang
- CAS Key Laboratory of Molecular Virology & Immunology Institut Pasteur of Shanghai CAS Shanghai China
- Xuechao Zhang
- Hangzhou Center for Disease Control and Prevention Hangzhou China
- Jun Li
- Hangzhou Center for Disease Control and Prevention Hangzhou China
- Yanyan Wang
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Yuhai Bi
- University of CAS Beijing China
- Barry Rockx
- European Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL) Paris France
- Junfang Chen
- Hangzhou Center for Disease Control and Prevention Hangzhou China
- Fei‐Long Meng
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- Dimitri Lavillette
- CAS Key Laboratory of Molecular Virology & Immunology Institut Pasteur of Shanghai CAS Shanghai China
- Dianfan Li
- State Key Laboratory of Molecular Biology State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences (CAS) Shanghai China
- DOI
- https://doi.org/10.15252/emmm.202114544
- Journal volume & issue
-
Vol. 13,
no. 12
pp. n/a – n/a
Abstract
Abstract An essential step for SARS‐CoV‐2 infection is the attachment to the host cell receptor by its Spike receptor‐binding domain (RBD). Most of the existing RBD‐targeting neutralizing antibodies block the receptor‐binding motif (RBM), a mutable region with the potential to generate neutralization escape mutants. Here, we isolated and structurally characterized a non‐RBM‐targeting monoclonal antibody (FD20) from convalescent patients. FD20 engages the RBD at an epitope distal to the RBM with a KD of 5.6 nM, neutralizes SARS‐CoV‐2 including the current Variants of Concern such as B.1.1.7, B.1.351, P.1, and B.1.617.2 (Delta), displays modest cross‐reactivity against SARS‐CoV, and reduces viral replication in hamsters. The epitope coincides with a predicted “ideal” vulnerability site with high functional and structural constraints. Mutation of the residues of the conserved epitope variably affects FD20‐binding but confers little or no resistance to neutralization. Finally, in vitro mode‐of‐action characterization and negative‐stain electron microscopy suggest a neutralization mechanism by which FD20 destructs the Spike. Our results reveal a conserved vulnerability site in the SARS‐CoV‐2 Spike for the development of potential antiviral drugs.
Keywords
- COVID‐19
- cross‐active neutralizing antibody
- destruction of spike
- receptor‐binding domain
- variants of concern
