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. RichardHervé Raoul, Jian Feng Chen, Chenqi Xu, Ligang Wu, Haisheng Zhou, Zhong Huang, Xuechao Zhang, Jun Li, Yanyan Wang, Yuhai Bi, Barry Rockx, Dimitri Lavillette, Junfang Chen*, Fei Long Meng*, Dianfan Li*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article numbere14544
JournalEMBO Molecular Medicine
Issue number12
Publication statusPublished - 7 Dec 2021

Bibliographical note

Funding Information:
We thank Prof. Yao Cong at the authors? institute for providing the S plasmid, and Dr. Yanxing Wang and Mr. Yitian Luo for technical assistance on negative staining. We thank the staff members of the Large-scale Protein Preparation System for equipment maintenance and management, at the SSRF-BL18U1 and BL19U1 beamlines at National Facility for Protein Science (Shanghai) and of the electron microscope facility for technical support and assistance. This work has been supported by the Strategic Priority Research Program of CAS (XDB37020204, D. Li; XDB29010102, Y.B.), Key Program of CAS Frontier Science (QYZDB-SSW-SMC037, D. Li), CAS Facility-based Open Research Program (2017), the National Natural Science Foundation of China (NSFC) (31870726, D. Li; 31870153, D. La; 31970880, F.L.M), Ministry of Science and Technology of China (2020YFC0845900, D. La.; 2017YFA0506700, F.L.M), CAS President's International Fellowship Initiative (2020VBA0023, DLa), the Key R & D Program of Jiangsu Province (Social Development) Project (BE2019625, DLa), Science and Technology Commission of Shanghai Municipality (STCSM) (20ZR1466700, D. Li; 20490760200, F.L.M), Shanghai Municipal Science and Technology Major Project (20431900402, D. La.), Innovation Capacity Building Project of Jiangsu province Nanjing Unicorn Academy of innovation (BM2020019, D. La.), the ERINHA-Advance project (funding from the European Union?s Horizon 2020 Research & Innovation program, grant agreement No. 824061), and Science and Technology Commission of Hangzhou Municipality (202013A02, J.C.). This project is included in RECOVER European Union?s Horizon 2020 research and innovation program under grant agreement No 101003589. Y.B. is supported by the NSFC Outstanding Young Scholars (31822055) and Youth Innovation Promotion Association of the Chinese Academy of Sciences (Youth Innovation Promotion Association CAS) (2017122). F.L.M is supported by a CAS grant (JCTD-2020-17).

Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.


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