ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies

Science. 2022 Aug 12;377(6607):735-742. doi: 10.1126/science.abq2679. Epub 2022 Jul 12.


The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus spike proteins from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and betacoronaviruses, including animal coronaviruses WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses showed that the fusion peptide-specific mAbs bound with different modalities to a cryptic epitope hidden in prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs.

MeSH terms

  • Angiotensin-Converting Enzyme 2* / chemistry
  • Animals
  • Antibodies, Monoclonal* / immunology
  • Antibodies, Monoclonal* / isolation & purification
  • Antibodies, Viral* / immunology
  • Antibodies, Viral* / isolation & purification
  • Broadly Neutralizing Antibodies* / immunology
  • COVID-19* / immunology
  • Humans
  • Peptides / immunology
  • Protein Binding
  • SARS-CoV-2* / immunology
  • Spike Glycoprotein, Coronavirus* / chemistry
  • Spike Glycoprotein, Coronavirus* / immunology


  • Antibodies, Monoclonal
  • Antibodies, Viral
  • Broadly Neutralizing Antibodies
  • Peptides
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2