An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants

Area of Science:

• Biochemistry
• Virology
• Computational Biology

Background:

• SARS-CoV-2 variants pose a significant threat due to immune evasion.
• Existing humoral immunity may be less effective against new viral strains.
• Angiotensin converting enzyme 2 (ACE2) decoys are a potential therapeutic strategy.

Purpose of the Study:

• To engineer and evaluate ACE2 decoys with enhanced affinity for SARS-CoV-2 spike receptor binding domain (S RBD).
• To assess the efficacy of these decoys against SARS-CoV-2 variants.
• To identify a therapeutic option with sustained efficacy against evolving viral strains.

Main Methods:

• Molecular Dynamics (MD) simulations to predict ACE2 sequence substitutions for increased S RBD affinity.
• In vitro screening of candidate ACE2 decoys.
• Assessment of live SARS-CoV-2 neutralization by engineered decoys.
• MD simulations and in vitro testing to evaluate decoy efficacy against mutated S RBD variants.

Main Results:

• An ACE2(T27Y/H34A)-IgG1Fc fusion protein showed enhanced S RBD affinity and greater neutralization than wild-type ACE2.
• An ACE2 Triple Decoy, including an H374N substitution, maintained high affinity for mutated S RBD.
• The Triple Decoy demonstrated enhanced affinity for S RBD variants with N501Y or L452R mutations.
• The Triple Decoy exhibited the highest affinity for S RBD with combined E484K and N501Y mutations.

Conclusions:

• Engineered ACE2 decoys, particularly the Triple Decoy, show significant potential as therapeutics against SARS-CoV-2 variants.
• These decoys maintain high affinity for mutated spike proteins, including those with immune-evasive mutations.
• The developed ACE2 decoys represent a viable option for preventing or treating SARS-CoV-2 infections, with a high likelihood of efficacy against current and future variants.