Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants

Nat Chem Biol. 2022 Mar;18(3):342-351. doi: 10.1038/s41589-021-00965-6. Epub 2022 Jan 19.


Vaccine hesitancy and emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) escaping vaccine-induced immune responses highlight the urgency for new COVID-19 therapeutics. Engineered angiotensin-converting enzyme 2 (ACE2) proteins with augmented binding affinities for SARS-CoV-2 spike (S) protein may prove to be especially efficacious against multiple variants. Using molecular dynamics simulations and functional assays, we show that three amino acid substitutions in an engineered soluble ACE2 protein markedly augmented the affinity for the S protein of the SARS-CoV-2 WA-1/2020 isolate and multiple VOCs: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). In humanized K18-hACE2 mice infected with the SARS-CoV-2 WA-1/2020 or P.1 variant, prophylactic and therapeutic injections of soluble ACE22.v2.4-IgG1 prevented lung vascular injury and edema formation, essential features of CoV-2-induced SARS, and above all improved survival. These studies demonstrate broad efficacy in vivo of an engineered ACE2 decoy against SARS-CoV-2 variants in mice and point to its therapeutic potential.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Angiotensin-Converting Enzyme 2 / chemistry*
  • Animals
  • Antiviral Agents
  • COVID-19 / prevention & control*
  • Drug Discovery
  • Humans
  • Lung Injury
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Engineering*
  • Respiratory Distress Syndrome
  • SARS-CoV-2*
  • Severe Acute Respiratory Syndrome


  • Antiviral Agents
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2