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Cell Rep
. 2020 Dec 1;108528.
doi: 10.1016/j.celrep.2020.108528. Online ahead of print.
An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2
Takuya Tada 1 , Chen Fan 2 , Jennifer S Chen 3 , Ramanjit Kaur 1 , Kenneth A Stapleford 1 , Harry Gristick 4 , Belinda M Dcosta 1 , Craig B Wilen 3 , Crina M Nimigean 2 , Nathaniel R Landau 5
Affiliations
- PMID: 33326798
- DOI: 10.1016/j.celrep.2020.108528
Abstract
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.