Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody
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 neutralizatio...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-11-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202114544 |
| _version_ | 1827045144488050688 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Tingting Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:39:05Z |
| format | Article |
| id | doaj.art-7f206b05d79247f4a77f570a14981163 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:19:51Z |
| publishDate | 2021-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-7f206b05d79247f4a77f570a149811632024-10-28T08:50:31ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-11-01131212110.15252/emmm.202114544Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibodyTingting Li0Hongmin Cai1Yapei Zhao2Yanfang Li3Yanling Lai4Hebang Yao5Liu Daisy Liu6Zhou Sun7Martje Fentener van Vlissingen8Thijs Kuiken9Corine H GeurtsvanKessel10Ning Zhang11Bingjie Zhou12Lu Lu13Yuhuan Gong14Wenming Qin15Moumita Mondal16Bowen Duan17Shiqi Xu18Audrey S Richard19Hervé Raoul20JianFeng Chen21Chenqi Xu22Ligang Wu23Haisheng Zhou24Zhong Huang25Xuechao Zhang26Jun Li27Yanyan Wang28Yuhai Bi29Barry Rockx30Junfang Chen31Fei‐Long Meng32Dimitri Lavillette33Dianfan Li34State 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)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)University of CASState 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)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)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)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)Hangzhou Center for Disease Control and PreventionErasmus Laboratory Animal Science Center, Erasmus University Medical CenterEuropean Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL)European Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL)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), CASUniversity of CASUniversity of CASUniversity of CASNational Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute (Zhangjiang Laboratory), CASCAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai CASUniversity of CASUniversity of CASEuropean Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL)European Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL)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)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)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)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)CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai CASHangzhou Center for Disease Control and PreventionHangzhou Center for Disease Control and PreventionState 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)University of CASEuropean Research Infrastructure on Highly Pathogenic Agents (ERINHA‐AISBL)Hangzhou Center for Disease Control and PreventionState 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)CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai CASState 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)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.https://doi.org/10.15252/emmm.202114544COVID‐19cross‐active neutralizing antibodydestruction of spikereceptor‐binding domainvariants of concern |
| spellingShingle | 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 Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody EMBO Molecular Medicine COVID‐19 cross‐active neutralizing antibody destruction of spike receptor‐binding domain variants of concern |
| title | Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody |
| title_full | Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody |
| title_fullStr | Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody |
| title_full_unstemmed | Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody |
| title_short | Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody |
| title_sort | uncovering a conserved vulnerability site in sars cov 2 by a human antibody |
| topic | COVID‐19 cross‐active neutralizing antibody destruction of spike receptor‐binding domain variants of concern |
| url | https://doi.org/10.15252/emmm.202114544 |
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