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Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2.

ABSTRACT: The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds angiotensin-converting enzyme 2 (ACE2) on host cells to initiate entry, and soluble ACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. By using deep mutagenesis, mutations in ACE2 that increase S binding are found across the interaction surface, in the asparagine 90-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 those of 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.

SUBMITTER: Chan KK

PROVIDER: S-EPMC7574912 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2.

Chan Kui K KK Dorosky Danielle D Sharma Preeti P Abbasi Shawn A SA Dye John M JM Kranz David M DM Herbert Andrew S AS Procko Erik E

Science (New York, N.Y.) 20200804 6508

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds angiotensin-converting enzyme 2 (ACE2) on host cells to initiate entry, and soluble ACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. By using deep mutagenesis, mutations in ACE2 that increase S binding are found across the interaction surface, in the asparagine 90-glycosylation motif and at buried sites. The mutational landscape provides a blueprint for understanding the sp ...[more]

PMID: 32753553

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