By exploring variants of a soluble version of the receptor that SARS-CoV-2 uses to binds human cells - which are being considered as therapeutic candidates that neutralize COVID-19 infection by acting as a decoy - researchers identified one that binds the virus's spike protein tightly enough to compete with spike binding by monoclonal antibodies. Its similarity to the natural receptor on human cells may limit the possibility for the virus to "escape" it, as it would when under pressure from antibodies. The SARS-CoV-2 virus enters human cells when the spike protein binds to the host ACE2 receptor. While neutralizing antibodies to the spike protein have been isolated, the spike can develop "escape mutations" that help it evade them. Compared to antibodies, the virus may be less likely to escape neutralization by a decoy ACE2 without simultaneously decreasing affinity for this receptor. Thus, a soluble version of ACE2 is now being explored as a therapeutic. Hypothesizing that mutations in ACE2 may increase its binding affinity to SARS-CoV-2, Kui Chan and colleagues sought out such mutations using deep mutagenesis. They diversified a full-length sequence of ACE2 to create a library containing all possible single amino acid substitutions that spanned the interface between the spike protein and its binding cavity. Following expression of these variants in human cells, Chan and colleagues report one promising soluble variant, dubbed sACE2.v2.4, with a binding affinity comparable to that of neutralizing antibodies. It neutralized both SARS-CoV-2 and SARS-CoV-1 in a cell-based assay, they say, making it a powerful potential virus decoy. "It is possible that the decoy receptor will neutralize diverse ACE2-utilizing coronaviruses that have yet to cross over to humans," they note.