Recently Designed Multivalent Spike Binders Cannot Bind Multivalently─How Do They Achieve Enhanced Avidity to...

Area of Science:

• Virology
• Immunology
• Biochemistry

Background:

• The SARS-CoV-2 trimeric spike protein is a key target for antibody mimics designed to neutralize the virus.
• Previous studies suggested enhanced binding avidity of multivalent constructs due to simultaneous binding to multiple sites on a single spike trimer.

Purpose of the Study:

• To investigate the mechanism behind the enhanced binding avidity observed in multivalent antibody mimics targeting the SARS-CoV-2 spike protein.
• To challenge the prevailing hypothesis of simultaneous multivalent binding within a single spike trimer.

Main Methods:

• Analysis of peptide linker lengths (15-20 amino acids) in multivalent constructs using a worm-like-chain model.
• Theoretical evaluation of the spatial constraints for simultaneous binding to a single spike trimer.

Main Results:

• The short peptide linkers (15-20 amino acids) are likely too short to span the binding sites within a single SARS-CoV-2 spike trimer.
• The observed enhanced avidity is more plausibly explained by a rebinding mechanism.

Conclusions:

• The enhanced binding avidity of multivalent antibody mimics against SARS-CoV-2 spike protein is unlikely to result from simultaneous binding to a single spike trimer.
• A rebinding mechanism offers a more viable explanation for the increased avidity of these constructs.