Potent neutralizing nanobodies resist convergent circulating variants of SARS-CoV-2 by targeting diverse and conserved epitopes

Nat Commun. 2021 Aug 3;12(1):4676. doi: 10.1038/s41467-021-24963-3.

Abstract

Interventions against variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Stable and potent nanobodies (Nbs) that target the receptor binding domain (RBD) of SARS-CoV-2 spike are promising therapeutics. However, it is unknown if Nbs broadly neutralize circulating variants. We found that RBD Nbs are highly resistant to variants of concern (VOCs). High-resolution cryoelectron microscopy determination of eight Nb-bound structures reveals multiple potent neutralizing epitopes clustered into three classes: Class I targets ACE2-binding sites and disrupts host receptor binding. Class II binds highly conserved epitopes and retains activity against VOCs and RBDSARS-CoV. Cass III recognizes unique epitopes that are likely inaccessible to antibodies. Systematic comparisons of neutralizing antibodies and Nbs provided insights into how Nbs target the spike to achieve high-affinity and broadly neutralizing activity. Structure-function analysis of Nbs indicates a variety of antiviral mechanisms. Our study may guide the rational design of pan-coronavirus vaccines and therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / chemistry
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism
  • Binding Sites
  • Broadly Neutralizing Antibodies / chemistry
  • Broadly Neutralizing Antibodies / classification
  • Broadly Neutralizing Antibodies / immunology*
  • Broadly Neutralizing Antibodies / metabolism
  • COVID-19 / prevention & control
  • COVID-19 Drug Treatment
  • Epitopes / chemistry
  • Epitopes / immunology*
  • Epitopes / metabolism
  • Humans
  • Models, Molecular
  • Mutation
  • Protein Binding
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / immunology*
  • Single-Domain Antibodies / chemistry
  • Single-Domain Antibodies / classification
  • Single-Domain Antibodies / immunology*
  • Single-Domain Antibodies / metabolism
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology
  • Spike Glycoprotein, Coronavirus / metabolism
  • Structure-Activity Relationship

Substances

  • Antibodies, Monoclonal
  • Broadly Neutralizing Antibodies
  • Epitopes
  • Single-Domain Antibodies
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2