tetano
Editor, Senior Moderator
EMBO Mol Med
. 2021 Oct 20;e14544.
doi: 10.15252/emmm.202114544. Online ahead of print.
Uncovering a conserved vulnerability site in SARS-CoV-2 by a human antibody
Tingting Li[SUP] 1 2 [/SUP], Hongmin Cai[SUP] 1 2 [/SUP], Yapei Zhao[SUP] 2 3 [/SUP], Yanfang Li[SUP] 1 2 [/SUP], Yanling Lai[SUP] 1 2 [/SUP], Hebang Yao[SUP] 1 2 [/SUP], Liu Daisy Liu[SUP] 1 2 [/SUP], Zhou Sun[SUP] 4 [/SUP], Martje Fentener van Vlissingen[SUP] 5 6 [/SUP], Thijs Kuiken[SUP] 6 7 [/SUP], Corine H GeurtsvanKessel[SUP] 6 7 [/SUP], Ning Zhang[SUP] 8 [/SUP], Bingjie Zhou[SUP] 2 3 [/SUP], Lu Lu[SUP] 2 3 [/SUP], Yuhuan Gong[SUP] 2 8 [/SUP], Wenming Qin[SUP] 9 [/SUP], Moumita Mondal[SUP] 3 10 [/SUP], Bowen Duan[SUP] 2 3 [/SUP], Shiqi Xu[SUP] 2 3 [/SUP], Audrey S Richard[SUP] 6 [/SUP], Hervé Raoul[SUP] 6 [/SUP], JianFeng Chen[SUP] 1 [/SUP], Chenqi Xu[SUP] 1 [/SUP], Ligang Wu[SUP] 1 [/SUP], Haisheng Zhou[SUP] 1 2 [/SUP], Zhong Huang[SUP] 3 10 [/SUP], Xuechao Zhang[SUP] 4 [/SUP], Jun Li[SUP] 4 [/SUP], Yanyan Wang[SUP] 1 2 [/SUP], Yuhai Bi[SUP] 2 8 [/SUP], Barry Rockx[SUP] 6 7 [/SUP], Junfang Chen[SUP] 4 [/SUP], Fei-Long Meng[SUP] 1 2 [/SUP], Dimitri Lavillette[SUP] 3 10 11 [/SUP], Dianfan Li[SUP] 1 [/SUP]
Affiliations
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 K[SUB]D[/SUB] 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 suggests 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.
. 2021 Oct 20;e14544.
doi: 10.15252/emmm.202114544. Online ahead of print.
Uncovering a conserved vulnerability site in SARS-CoV-2 by a human antibody
Tingting Li[SUP] 1 2 [/SUP], Hongmin Cai[SUP] 1 2 [/SUP], Yapei Zhao[SUP] 2 3 [/SUP], Yanfang Li[SUP] 1 2 [/SUP], Yanling Lai[SUP] 1 2 [/SUP], Hebang Yao[SUP] 1 2 [/SUP], Liu Daisy Liu[SUP] 1 2 [/SUP], Zhou Sun[SUP] 4 [/SUP], Martje Fentener van Vlissingen[SUP] 5 6 [/SUP], Thijs Kuiken[SUP] 6 7 [/SUP], Corine H GeurtsvanKessel[SUP] 6 7 [/SUP], Ning Zhang[SUP] 8 [/SUP], Bingjie Zhou[SUP] 2 3 [/SUP], Lu Lu[SUP] 2 3 [/SUP], Yuhuan Gong[SUP] 2 8 [/SUP], Wenming Qin[SUP] 9 [/SUP], Moumita Mondal[SUP] 3 10 [/SUP], Bowen Duan[SUP] 2 3 [/SUP], Shiqi Xu[SUP] 2 3 [/SUP], Audrey S Richard[SUP] 6 [/SUP], Hervé Raoul[SUP] 6 [/SUP], JianFeng Chen[SUP] 1 [/SUP], Chenqi Xu[SUP] 1 [/SUP], Ligang Wu[SUP] 1 [/SUP], Haisheng Zhou[SUP] 1 2 [/SUP], Zhong Huang[SUP] 3 10 [/SUP], Xuechao Zhang[SUP] 4 [/SUP], Jun Li[SUP] 4 [/SUP], Yanyan Wang[SUP] 1 2 [/SUP], Yuhai Bi[SUP] 2 8 [/SUP], Barry Rockx[SUP] 6 7 [/SUP], Junfang Chen[SUP] 4 [/SUP], Fei-Long Meng[SUP] 1 2 [/SUP], Dimitri Lavillette[SUP] 3 10 11 [/SUP], Dianfan Li[SUP] 1 [/SUP]
Affiliations
- PMID: 34672091
- DOI: 10.15252/emmm.202114544
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 K[SUB]D[/SUB] 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 suggests 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.