A Multivalent DNA Nanoparticle/Peptide Hybrid Molecular Modality for the Modulation of Protein-Protein Interactions...

Area of Science:

• Immunology
• Molecular Biology
• Biotechnology

Background:

• Immunotherapy shows limited efficacy in solid tumors due to immune evasion within the tumor microenvironment.
• Targeting protein-protein interactions (PPIs) is crucial for immune activation but challenging for nonenzymatic PPIs.
• The IL-33/ST2 signaling axis contributes to tumor tolerance and immunotherapy resistance.

Purpose of the Study:

• To develop a novel molecular modality for targeting protein-protein interactions.
• To create a prototype targeting the IL-33/ST2 signaling axis to enhance anti-tumor immunity.

Main Methods:

• Designed a synthetic, multivalent molecular platform using small interfering peptides on a DNA scaffold.
• Developed peptides mimicking hotspot residues of IL-33/ST2 co-receptor interactions.
• Utilized cell models to assess binding affinity, signal transduction inhibition, and selectivity.

Main Results:

• The DNA-scaffolded peptide molecule effectively binds IL-33/ST2 with a binding affinity (Kd) of 110 nM.
• The molecule abrogates IL-33/ST2 signal transduction in cellular models at high nanomolar concentrations.
• Demonstrated exquisite selectivity for the target complex over similar protein-protein interactions.

Conclusions:

• The synthetic molecular modality offers a promising strategy for targeting challenging protein-protein interactions.
• This approach effectively disrupts the IL-33/ST2 pathway, a key mediator of tumor tolerance.
• The developed platform holds potential for improving immunotherapy outcomes in solid tumors.