An engineered decoy receptor for SARS-CoV-2 broadly binds protein S sequence variants

Kui K Chan, Timothy JC Tan, Krishna K Narayanan, Erik Procko

Research output: Working paper

Abstract

The spike S of SARS-CoV-2 recognizes ACE2 on the host cell membrane to initiate entry. Soluble decoy receptors, in which the ACE2 ectodomain is engineered to block S with high affinity, potently neutralize infection and, due to close similarity with the natural receptor, hold out the promise of being broadly active against virus variants without opportunity for escape. Here, we directly test this hypothesis. We find an engineered decoy receptor, sACE22.v2.4, tightly binds S of SARS-associated viruses from humans and bats, despite the ACE2-binding surface being a region of high diversity. Saturation mutagenesis of the receptor-binding domain followed by in vitro selection, with wild type ACE2 and the engineered decoy competing for binding sites, failed to find S mutants that discriminate in favor of the wild type receptor. We conclude that resistance to engineered decoys will be rare and that decoys may be active against future outbreaks of SARS-associated betacoronaviruses.Competing Interest StatementThe University of Illinois has filed a provisional patent for engineered decoy receptors and E.P. and K.K.C. are co-founders of Orthogonal Biologics, Inc.
Original languageEnglish (US)
PublisherCold Spring Harbor Laboratory Press
Number of pages15
DOIs
StateIn preparation - Oct 19 2020

Publication series

NamebioRxiv
PublisherCold Spring Harbor Laboratory Press

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