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 can neutralize SARS-CoV-2 by blocking S protein binding.
• These decoys offer potential broad activity against viral variants due to their similarity to the natural receptor.

Purpose of the Study:

• To investigate the hypothesis that engineered decoy receptors are broadly active against SARS-associated betacoronaviruses.
• To determine if SARS-associated viruses can evolve resistance to soluble ACE2 decoy receptors.

Main Methods:

• Engineered a soluble decoy receptor, sACE2₂v2.4, with high affinity for the SARS-CoV-2 S protein.
• Tested the binding affinity of sACE2₂v2.4 against S proteins from human and bat SARS-associated viruses.
• Performed saturation mutagenesis on the S protein's receptor-binding domain and selected for mutants that could escape decoy binding.

Main Results:

• The engineered decoy receptor sACE2₂v2.4 demonstrated tight binding to S proteins from diverse SARS-associated viruses.
• The ACE2-binding surface of the S protein, a region of high sequence diversity, did not confer resistance to the decoy.
• No S protein mutants were identified that could discriminate between wild-type ACE2 and the engineered decoy receptor.

Conclusions:

• Engineered soluble ACE2 decoy receptors exhibit broad neutralizing activity against SARS-associated betacoronaviruses.
• Viral resistance to these engineered decoys is predicted to be rare.
• Decoy receptors hold promise for combating current and future outbreaks of SARS-related coronaviruses.