Uncovering a conserved vulnerability site in SARS-CoV-2 by a human antibody

EMBO Mol Med. 2021 Oct 20:e14544. doi: 10.15252/emmm.202114544. Online ahead of print.ABSTRACTAn 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 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.PMID:34672091 | DOI:10.15252/emmm.202114544

Source: Molecular Medicine - October 21, 2021 Category: Molecular Biology Authors: 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 Audre Source Type: research