Discovery of High Affinity Cyclic Peptide Ligands for Human ACE2 with SARS-CoV-2 Entry Inhibitory Activity

Area of Science:

• Biochemistry
• Virology
• Drug Discovery

Background:

• Effective antiviral development is crucial for managing the COVID-19 pandemic.
• SARS-CoV-2 entry into host cells relies on the spike protein binding to ACE2.
• Inhibiting this spike-ACE2 interaction is a key antiviral strategy.

Purpose of the Study:

• To develop novel therapeutics by targeting the human ACE2 receptor's spike-binding interface.
• To identify potent cyclic peptide ligands that inhibit the SARS-CoV-2 spike-ACE2 interaction.

Main Methods:

• Utilized mRNA display technology for cyclic peptide library selection.
• Performed two rounds of display selection to isolate ACE2-binding peptides.
• Characterized the affinity and neutralizing capacity of identified peptide binders.

Main Results:

• Identified potent cyclic peptide binders of human ACE2 with picomolar to nanomolar affinities.
• Two selected cyclic peptides demonstrated neutralization of SARS-CoV-2 entry into host cells.
• Validated ACE2 as a viable therapeutic target for antiviral development.

Conclusions:

• Targeting the ACE2 receptor presents a promising strategy for developing anti-SARS-CoV-2 therapeutics.
• The identified cyclic peptides show potential for broad-spectrum antiviral activity against SARS-like betacoronaviruses.
• This approach offers an alternative to directly targeting viral proteins for therapeutic intervention.