Rational design of a covalent ACE2 decoy receptor that broadly neutralizes SARS-CoV-2 variants

Area of Science:

• Virology
• Biochemistry
• Drug Discovery

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution necessitates new antiviral strategies.
• Covalent binding enhances therapeutic protein efficacy but can be hindered by viral mutations.
• Existing vaccines and therapies face challenges from emerging SARS-CoV-2 variants.

Purpose of the Study:

• To develop a broadly neutralizing covalent angiotensin-converting enzyme 2-Fc (ACE2-Fc) decoy against SARS-CoV-2.
• To utilize rational design integrating functional genomics and structural information.
• To target conserved residues on the viral receptor-binding domain (RBD) for enhanced efficacy.

Main Methods:

• Engineered ACE2-Fc constructs with non-canonical amino acid-fluorosulfate-L-tyrosine (FSY).
• Targeted tyrosine 473 (Y473) on the SARS-CoV-2 RBD for covalent bond formation.
• Tested covalent ACE2-Fc constructs (E23FSY, T27FSY) against wild-type and Omicron BA.5 variants.

Main Results:

• Engineered constructs formed specific covalent bonds with Y473 on the RBD.
• Covalent capture remained effective against the Omicron BA.5 RBD.
• E23FSY and T27FSY showed enhanced potency against D614G and Omicron variants in pseudovirus assays.

Conclusions:

• Targeting evolutionarily constrained residues on the viral RBD with covalent decoys is effective.
• This strategy yields potent, broad-spectrum covalent inhibitors against rapidly evolving viruses like SARS-CoV-2.
• The developed covalent ACE2-Fc decoys offer a promising approach for combating viral escape variants.