tetano
Editor, Senior Moderator
Science
. 2020 Aug 4;eabc0870.
doi: 10.1126/science.abc0870. Online ahead of print.
Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2
Kui K Chan[SUP] 1 [/SUP], Danielle Dorosky[SUP] 2 [/SUP], Preeti Sharma[SUP] 3 [/SUP], Shawn A Abbasi[SUP] 2 [/SUP], John M Dye[SUP] 2 [/SUP], David M Kranz[SUP] 3 [/SUP], Andrew S Herbert[SUP] 2 4 [/SUP], Erik Procko[SUP] 5 [/SUP]
Affiliations
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.
. 2020 Aug 4;eabc0870.
doi: 10.1126/science.abc0870. Online ahead of print.
Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2
Kui K Chan[SUP] 1 [/SUP], Danielle Dorosky[SUP] 2 [/SUP], Preeti Sharma[SUP] 3 [/SUP], Shawn A Abbasi[SUP] 2 [/SUP], John M Dye[SUP] 2 [/SUP], David M Kranz[SUP] 3 [/SUP], Andrew S Herbert[SUP] 2 4 [/SUP], Erik Procko[SUP] 5 [/SUP]
Affiliations
- PMID: 32753553
- DOI: 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.