Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2
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Open Access
- 4 September 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 369 (6508), 1261-1265
- https://doi.org/10.1126/science.abc0870
Abstract
The spike protein S of SARS coronavirus 2 (SARS-CoV-2) binds ACE2 on host cells to initiate entry, and soluble ACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. Using deep mutagenesis, mutations in ACE2 that increase S binding are found across the interaction surface, in the N90-glycosylation motif and at buried sites. The mutational landscape provides a blueprint for understanding the specificity of the interaction between ACE2 and S and for engineering high affinity decoy receptors. Combining mutations gives ACE2 variants with affinities that rival monoclonal antibodies. A stable dimeric variant shows potent SARS-CoV-2 and -1 neutralization in vitro. The engineered receptor is catalytically active and its close similarity with the native receptor may limit the potential for viral escape.Keywords
Funding Information
- National Institute of Allergy and Infectious Diseases (R01AI129719)
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