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A soluble ACE2 microbody protein fused to a single immunoglobulin Fc domain is a potent inhibitor of SARS-CoV-2 infection in cell culture

View ORCID ProfileTakuya Tada, Chen Fan, Ramanjit Kaur, Kenneth A. Stapleford, Harry Gristick, Crina Nimigean, Nathaniel R. Landau
doi: https://doi.org/10.1101/2020.09.16.300319
Takuya Tada
1Department of Microbiology, NYU Langone Medical Center
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Chen Fan
2Department of Anesthesiology, Weill Cornell Medical College
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Ramanjit Kaur
1Department of Microbiology, NYU Langone Medical Center
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Kenneth A. Stapleford
1Department of Microbiology, NYU Langone Medical Center
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Harry Gristick
3Division of Biology and Biological Engineering, California Institute of Technology
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Crina Nimigean
2Department of Anesthesiology, Weill Cornell Medical College
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Nathaniel R. Landau
1Department of Microbiology, NYU Langone Medical Center
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  • For correspondence: nathaniel.landau@med.nyu.edu
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Summary

Soluble forms of ACE2 have recently been shown to inhibit 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 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 inhibited entry of lentiviral SARS-CoV-2 spike protein pseudotyped virus and live SARS-CoV-2 with a potency 10-fold higher than unmodified soluble ACE2 and was active after initial virus binding to the cell. The ACE2 microbody inhibited the entry of ACE2-specific β coronaviruses and viruses with the high infectivity variant D614G spike. The ACE2 microbody may be a valuable therapeutic for COVID-19 that is active against SARS-CoV-2 variants and future coronaviruses that may arise.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 17, 2020.
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A soluble ACE2 microbody protein fused to a single immunoglobulin Fc domain is a potent inhibitor of SARS-CoV-2 infection in cell culture
Takuya Tada, Chen Fan, Ramanjit Kaur, Kenneth A. Stapleford, Harry Gristick, Crina Nimigean, Nathaniel R. Landau
bioRxiv 2020.09.16.300319; doi: https://doi.org/10.1101/2020.09.16.300319
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A soluble ACE2 microbody protein fused to a single immunoglobulin Fc domain is a potent inhibitor of SARS-CoV-2 infection in cell culture
Takuya Tada, Chen Fan, Ramanjit Kaur, Kenneth A. Stapleford, Harry Gristick, Crina Nimigean, Nathaniel R. Landau
bioRxiv 2020.09.16.300319; doi: https://doi.org/10.1101/2020.09.16.300319

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