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

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 ACE...

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Bibliographic Details
Published in:Science 2020-09, Vol.369 (6508), p.1261-1265
Main Authors: Chan, Kui K, Dorosky, Danielle, Sharma, Preeti, Abbasi, Shawn A, Dye, John M, Kranz, David M, Herbert, Andrew S, Procko, Erik
Format: Article
Language:English
Subjects:
ACE2
Affinity
Amino Acid Substitution
Angiotensin
Angiotensin-Converting Enzyme 2
Asparagine
Betacoronavirus - metabolism
Binding
Binding Sites
Binding, Competitive
Biochem
Cell Line
Coronaviridae
Coronaviruses
COVID-19
Dimers
Enzymes
Glycosylation
Humans
Microbio
Models, Molecular
Monoclonal antibodies
Mutagenesis
Mutation
Neutralization
Peptidyl-dipeptidase A
Peptidyl-Dipeptidase A - chemistry
Peptidyl-Dipeptidase A - genetics
Peptidyl-Dipeptidase A - metabolism
Protein Binding
Protein Engineering
Protein Interaction Domains and Motifs
Protein Multimerization
Proteins
Receptors
Receptors, Coronavirus
Receptors, Virus - chemistry
Receptors, Virus - genetics
Receptors, Virus - metabolism
Respiratory diseases
SARS-CoV-2
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Similarity
Spike Glycoprotein, Coronavirus - chemistry
Spike Glycoprotein, Coronavirus - metabolism
Spike protein
Viral diseases
Viruses
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.abc0870