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Abstract
Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus disease 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2-infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). However, the structural basis for their potent neutralizing activity remains unclear. Here, we report cryo-EM structures of the ten most potent nAbs in their native full-length IgG-form or in both IgG-form and Fab-form bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBDs in the “up” conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of a large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides a structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and its correlation with more potent neutralization and the shedding of S1 subunit.
Highlights
The global pandemic of coronavirus disease 2019 (COVID-19)caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to human health.[1,2] SARS-CoV-2 is an enveloped, positive-stranded RNA virus, belonging to the beta-coronavirus genus that includes SARS-CoV3 and the Middle Eastern respiratory syndrome coronavirus (MERS-CoV)[4] that caused epidemic in 2003 and 2012, respectively
Potent Neutralizing monoclonal antibodies (nAbs) isolated from the COVID-19 convalescent patients To understand the molecular features of the interactions of neutralizing nAbs with the S protein, we characterized ten nAbs derived from COVID-19 convalescents with strong binding and neutralizing activities, and the capacity of competing with angiotensin-converting enzyme 2 (ACE2) for receptor binding domain (RBD) binding
The binding affinity of these nAbs to RBD of SARS-CoV-2 measured by surface plasmon resonance (SPR) varied from 0.75 nM to 90.09 nM (Table 1; Supplementary information, Fig. S1), whereas the half maximal inhibitory concentration (IC50) of these nAbs ranged from 0.01 nM to 6.15 nM in the pseudovirusbased assay or from 0.03 nM to 5.95 nM in live SARS-CoV-2 virusbased assay (Table 1; Supplementary information, Fig. S1)
Summary
The global pandemic of coronavirus disease 2019 (COVID-19)caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to human health.[1,2] SARS-CoV-2 is an enveloped, positive-stranded RNA virus, belonging to the beta-coronavirus genus that includes SARS-CoV3 and the Middle Eastern respiratory syndrome coronavirus (MERS-CoV)[4] that caused epidemic in 2003 and 2012, respectively. 2 shares about 80% sequence identity with SARS-CoV, and both use angiotensin-converting enzyme 2 (ACE2) as their cellular receptor[5,6,7,8,9] that is recognized and bound by the trimeric spike (S) protein.[10,11] S protein distributes on the surface of the virion particles[12,13,14] and is proteolytically cleaved into N-terminal. S2 mediates the fusion of the viral and cellular membrane by undergoing a dramatic conformational change from the prefusion to the postfusion state[16] accompanying with the shedding of S1. RBD, which directly binds to ACE2 receptor, is a major target for development of the therapeutic nAbs against COVID-19. The “up” conformation of RBD can bind to the ACE2 receptor. It remains largely unknown how nAbs in their native bivalent form bind to and ever induce the conformational changes of the trimeric S protein
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