Cell
Volume 184, Issue 12, 10 June 2021, Pages 3192-3204.e16
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Article
Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia

https://doi.org/10.1016/j.cell.2021.04.033Get rights and content
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Highlights

  • The affinity of neutralizing antibodies does not always predict antiviral potency

  • Receptor-blocking antibodies can inhibit or enhance syncytium formation

  • Cryo-EM reveals one antibody inhibits syncytia by trapping the pre-fusion Spike

  • Another antibody acts as an allosteric effector that promotes syncytium formation

Summary

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus. Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19. As revealed by cryoelectron microscopy, multiple structures of Spike-antibody complexes have distinct binding modes that not only block ACE2 binding but also alter the Spike protein conformational cycle triggered by ACE2 binding. We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity.

Keywords

SARS-CoV-2
COVID-19
SARS-CoV
coronavirus
Spike protein
recombinant monoclonal antibody
receptor binding domain (RBD)
phage display
syncytia

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13

These authors contributed equally

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These authors contributed equally

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