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

Kui K. Chan, Danielle Dorosky, Preeti Sharma, Shawn A. Abbasi, John M. Dye, David M. Kranz, Andrew S. Herbert, Erik Procko

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1261-1265
Number of pages5
JournalScience
Volume369
Issue number6508
DOIs
StatePublished - Sep 4 2020

Keywords

  • Coronavirus
  • COVID-19
  • severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • Novel coronavirus
  • 2019-nCoV
  • Pandemic

ASJC Scopus subject areas

  • General

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