An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2

Cell Rep. 2020 Dec 22;33(12):108528. doi: 10.1016/j.celrep.2020.108528. Epub 2020 Dec 1.


Soluble forms of angiotensin-converting enzyme 2 (ACE2) have recently been shown to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We report on an improved soluble ACE2, termed a "microbody," in which the ACE2 ectodomain is fused to Fc domain 3 of the immunoglobulin (Ig) heavy chain. The protein is smaller than previously described ACE2-Ig Fc fusion proteins and contains an H345A mutation in the ACE2 catalytic active site that inactivates the enzyme without reducing its affinity for the SARS-CoV-2 spike. The disulfide-bonded ACE2 microbody protein inhibits entry of SARS-CoV-2 spike protein pseudotyped virus and replication of live SARS-CoV-2 in vitro and in a mouse model. Its potency is 10-fold higher than soluble ACE2, and it can act after virus bound to the cell. The microbody inhibits the entry of β coronaviruses and virus with the variant D614G spike. The ACE2 microbody may be a valuable therapeutic for coronavirus disease 2019 (COVID-19) that is active against viral variants and future coronaviruses.

Keywords: ACE2 transgenic; D614G; Fc fusion; SARS-CoV-2; coronavirus; entry inhibitor; lentiviral pseudotype; microbody; soluble ACE2; spike protein.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Animals
  • Antiviral Agents / pharmacology*
  • COVID-19 / prevention & control
  • COVID-19 / virology
  • Disease Models, Animal
  • Disulfides / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Immunoglobulin Fc Fragments / metabolism*
  • Male
  • Mice, Transgenic
  • Microbodies / metabolism*
  • Protein Domains
  • Protein Multimerization
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / pathogenicity
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / metabolism
  • Virion / metabolism
  • Virus Internalization / drug effects


  • Antiviral Agents
  • Disulfides
  • Immunoglobulin Fc Fragments
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2