This is a preprint.
Mutations from bat ACE2 orthologs markedly enhance ACE2-Fc neutralization of SARS-CoV-2
- PMID: 32637954
- PMCID: PMC7337384
- DOI: 10.1101/2020.06.29.178459
Mutations from bat ACE2 orthologs markedly enhance ACE2-Fc neutralization of SARS-CoV-2
Update in
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Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2.PLoS Pathog. 2021 Apr 9;17(4):e1009501. doi: 10.1371/journal.ppat.1009501. eCollection 2021 Apr. PLoS Pathog. 2021. PMID: 33836016 Free PMC article.
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus ) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize the ability of S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, and RaTG13 to bind a range of ACE2 orthologs. We observed that the SARS-CoV-2 RBD bound human, pangolin, and horseshoe bat ( R. macrotis) ACE2 more efficiently than the SARS-CoV-1 or RaTG13 RBD. Only the RaTG13 RBD bound rodent ACE2 orthologs efficiently. Five mutations drawn from ACE2 orthologs of nine Rhinolophus species enhanced human ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 by an immunoadhesin form of human ACE2 (ACE2-Fc). Two of these mutations impaired neutralization of SARS-CoV-1. An ACE2-Fc variant bearing all five mutations neutralized SARS-CoV-2 five-fold more efficiently than human ACE2-Fc. These data narrow the potential SARS-CoV-2 reservoir, suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of ACE2-Fc.
Conflict of interest statement
Declaration of Interests
M.R.G., C.C.B., M.D.A., and M.F. are all cofounders of, and have an equity interest in Emmune Inc., a small biotech company that specializes in the development of antibody-like antiviral therapies.
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