Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike

Cell Host Microbe. 2020 Sep 9;28(3):445-454.e6. doi: 10.1016/j.chom.2020.06.010. Epub 2020 Jun 19.

Abstract

There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.

Keywords: CR3022; SARS-CoV-2; X-ray crystallography; antibody; cryo-electron microscopy; epitope; neutralization; receptor binding domain; spike; therapeutic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Amino Acid Sequence
  • Angiotensin-Converting Enzyme 2
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / therapeutic use
  • Antibodies, Viral / immunology*
  • Antibodies, Viral / therapeutic use
  • Antigen-Antibody Complex / chemistry
  • Betacoronavirus / chemistry*
  • Betacoronavirus / genetics
  • Betacoronavirus / immunology*
  • COVID-19
  • COVID-19 Vaccines
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / immunology
  • Coronavirus Infections / prevention & control
  • Coronavirus Infections / therapy*
  • Coronavirus Infections / virology
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Host Microbial Interactions / immunology
  • Humans
  • Models, Molecular
  • Neutralization Tests
  • Pandemics
  • Peptidyl-Dipeptidase A / chemistry
  • Pneumonia, Viral / immunology
  • Pneumonia, Viral / therapy*
  • Pneumonia, Viral / virology
  • Receptors, Virus / chemistry
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / chemistry*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology*
  • Viral Vaccines / immunology
  • Viral Vaccines / therapeutic use
  • Virus Internalization

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antigen-Antibody Complex
  • COVID-19 Vaccines
  • Receptors, Virus
  • Spike Glycoprotein, Coronavirus
  • Viral Vaccines
  • spike protein, SARS-CoV-2
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • COVID-19 drug treatment