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

Area of Science:

• Virology
• Immunology
• Biochemistry

Background:

• The SARS-CoV-2 spike (S) protein binds to the host cell receptor ACE2 to initiate viral entry.
• Soluble decoy receptors engineered from ACE2 ectodomain show potential for broad neutralization of SARS-associated viruses.
• The hypothesis that these decoys are broadly active against viral variants needs direct testing.

Approach:

• Engineered decoy receptor sACE2₂.v2.4 was tested for binding to SARS-associated viruses from human and bat hosts.
• Saturation mutagenesis of the S receptor-binding domain (RBD) was performed, followed by in vitro selection.
• The binding affinity of viral variants to both wild-type ACE2 and the engineered decoy was assessed.

Key Points:

• The engineered decoy receptor sACE2₂.v2.4 binds tightly to the S protein of SARS-associated viruses, even in regions of high sequence diversity.
• No S mutants were identified that could discriminate binding between wild-type ACE2 and the engineered decoy.
• The N501Y variant, which enhances binding to wild-type ACE2, remained tightly bound to the engineered decoy.

Conclusions:

• Resistance to engineered decoy receptors is likely to be rare.
• Engineered decoys demonstrate potential broad activity against SARS-associated betacoronaviruses, including future outbreaks.
• Decoy receptors offer a promising strategy for broad-spectrum antiviral therapy against coronaviruses.