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, because of 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 that an engineered decoy receptor, sACE22v2.4, 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.
Highlights
Zoonotic coronaviruses have crossed over from animal reservoirs multiple times in the past two decades, and it is almost certain that wild animals will continue to be a source of devastating outbreaks
Affinity was measured by biolayer interferometry (BLI), with sACE22 [amino acids (a.a.) S19 to G732] fused at the C terminus with the Fc moiety of human immunoglobulin G1 (IgG1) immobilized to the sensor surface and monomeric 8his-tagged receptor-binding domain (RBD)
We show that an engineered decoy receptor for SARS-CoV-2 broadly binds with low-nanomolar KD to the spikes of SARS-associated betacoronaviruses that use angiotensin-converting enzyme 2 (ACE2) for entry, despite high sequence diversity within the ACE2-binding site
Summary
Zoonotic coronaviruses have crossed over from animal reservoirs multiple times in the past two decades, and it is almost certain that wild animals will continue to be a source of devastating outbreaks. As SARS-CoV-2 becomes endemic in the human population, it has the potential to mutate and undergo genetic drift and recombination To what extent this will occur as increasing numbers of people are infected and mount counter immune responses is unknown, but already a variant in the viral spike protein S (D614G) has rapidly emerged from multiple independent events and effects S protein stability and dynamics [10, 11]. Recombination of Middle East respiratory syndrome CoVs has been documented in camels [17]; there are reported cases of recombination between cocirculating SARS-CoV-2 variants [18], and SARS-CoV-2 itself may have emerged through recombination of coronavirus genomes [19] This will all have profound implications for the current pandemic’s trajectory, the potential for future coronavirus pandemics, and whether drug or vaccine resistance in SARS-CoV-2 emerges and becomes widespread
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