A decoy receptor for SARS-CoV-2

For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter human cells, the spike protein on the surface of the virus must bind to the host receptor protein, angiotensin-converting enzyme 2 (ACE2). A soluble version of the receptor is being explored as a therapeutic. Chan et al. used deep mutagenesis to identify ACE2 mutants that bind more tightly to the spike protein and combined mutations to further increase binding affinity (see the Perspective by DeKosky). A promising variant was engineered to be a stable dimer that has a binding affinity for the spike protein; it is comparable with neutralizing antibodies and neutralized both SARS-CoV-2 and SARS-CoV-1 in a cell-based assay. In addition, the similarity to the natural receptor may limit the possibility for viral escape.

Science, this issue p. 1261; see also p. 1167

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 90glycosylation 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.

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