Discovery of human ACE2 variants with altered recognition by the SARS-CoV-2 spike protein

PLoS One. 2021 May 12;16(5):e0251585. doi: 10.1371/journal.pone.0251585. eCollection 2021.

Abstract

Understanding how human ACE2 genetic variants differ in their recognition by SARS-CoV-2 can facilitate the leveraging of ACE2 as an axis for treating and preventing COVID-19. In this work, we experimentally interrogate thousands of ACE2 mutants to identify over one hundred human single-nucleotide variants (SNVs) that are likely to have altered recognition by the virus, and make the complementary discovery that ACE2 residues distant from the spike interface influence the ACE2-spike interaction. These findings illuminate new links between ACE2 sequence and spike recognition, and could find substantial utility in further fundamental research that augments epidemiological analyses and clinical trial design in the contexts of both existing strains of SARS-CoV-2 and novel variants that may arise in the future.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics*
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Binding Sites / genetics
  • COVID-19 / genetics
  • COVID-19 / metabolism*
  • Genetic Variation / genetics
  • Humans
  • Models, Molecular
  • Peptidyl-Dipeptidase A / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Protein Binding / genetics
  • Receptors, Virus / genetics
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / metabolism
  • SARS-CoV-2 / pathogenicity
  • Spike Glycoprotein, Coronavirus / genetics*
  • Spike Glycoprotein, Coronavirus / metabolism
  • Virus Replication / genetics

Substances

  • Receptors, Virus
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2