Engineered High-Affinity ACE2 Peptide Mitigates ARDS and Death Induced by Multiple SARS-CoV-2 Variants

Area of Science:

• Virology
• Immunology
• Biochemistry

Background:

• COVID-19 therapeutics are urgently needed due to vaccine hesitancy and emerging SARS-CoV-2 variants.
• Existing monoclonal antibodies have variable efficacy against different SARS-CoV-2 variants.
• Engineered ACE2 peptides with enhanced binding to the Spike protein are being explored for broad therapeutic benefit.

Approach:

• Molecular dynamics simulations were used to analyze an engineered soluble ACE2 peptide (sACE2 2 .v2.4-IgG1).
• The study investigated the peptide's binding affinity to the SARS-CoV-2 Spike protein from the WA-1/2020 isolate and multiple variants (Alpha, Beta, Gamma, Delta).
• In vivo efficacy was assessed in K18-hACE2 mice, evaluating protection against lung injury and survival after infection.

Key Points:

• Three amino acid substitutions in sACE2 2 .v2.4-IgG1 significantly increased its affinity for the SARS-CoV-2 Spike protein.
• The peptide demonstrated high binding affinity to both the original SARS-CoV-2 strain and key variants of concern.
• Prophylactic and therapeutic administration in mice prevented acute lung vascular injury and edema, crucial features of ARDS.

Conclusions:

• This study demonstrates the in vivo efficacy of an ACE2 decoy peptide against multiple SARS-CoV-2 variants for the first time.
• The engineered peptide sACE2 2 .v2.4-IgG1 shows significant therapeutic potential for treating COVID-19.
• The findings support the development of broadly effective therapeutics against SARS-CoV-2 and its future variants.