Engineered ACE2 receptor traps potently neutralize SARS-CoV-2.

Area of Science:

• Virology
• Biochemistry
• Protein Engineering

Background:

• SARS-CoV-1 and SARS-CoV-2 infections utilize the viral spike protein to bind the human ACE2 receptor, facilitating cell entry.
• Developing effective therapeutics against these viruses requires targeting this critical interaction.

Approach:

• A stepwise engineering strategy was employed to create affinity-optimized, enzymatically inactivated ACE2 variants.
• Computational design and a two-stage flexible protein backbone process improved ACE2-RBD binding affinity up to 12-fold.
• Further affinity maturation via random mutagenesis and yeast surface display increased binding 14-fold, resulting in a variant with 170-fold higher affinity.

Key Points:

• The highest affinity ACE2 variant demonstrated a 170-fold increase in binding to the SARS-CoV-2 receptor binding domain (RBD).
• Incorporating the ACE2 collectrin domain and an Fc fusion enhanced stability and avidity.
• Optimized ACE2 receptor traps neutralized SARS-CoV-2 pseudotyped and authentic viruses with IC50 values in the 10-100 ng/ml range.

Conclusions:

• Engineered ACE2 receptor traps provide a potent strategy for combating SARS-CoV-2 and other ACE2-utilizing coronaviruses.
• This approach offers a potential advantage as viral resistance may also hinder viral entry.
• Predesigned receptor traps can accelerate therapeutic responses for future viral threats with known entry mechanisms.