Nanoparticle Conjugation Stabilizes and Multimerizes β-Hairpin Peptides To Effectively Target PD-1/PD-L1 β-Sheet-Rich Interfaces

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Abstract
β-hairpin peptides present great potential as antagonists against β-sheet-rich protein surfaces, of which wide and flat geometries are typically ‘undruggable’ with small molecules. Herein, we introduce a peptide-dendrimer conjugate (PDC) approach that stabilizes β-hairpin structure of the peptide via intermolecular forces and excluded volume ef-fect as well as exploits multivalent binding effect. Due to the synergistic advantages, the PDCs based on a β-hairpin peptide isolated from an engineered programmed death-1 (PD-1) protein showed significantly higher affinity (avidi-ty) to their binding counterpart, programmed death-ligand 1 (PD-L1), compared to free peptides (by up to 5 orders of magnitude). The enhanced binding kinetics with high selectivity was translated into an improved immune check-point inhibitory effect in vitro, at a level comparable to (if not better than) a full-size monoclonal antibody. The re-sults demonstrate the potential of the PDC system as a novel class of inhibitors targeting β-strand-rich protein surfac-es, such as PD-1 and PD-L1, displaying its potential as a new cancer immunotherapy platform.
Funding Information
  • National Institute of Biomedical Imaging and Bioengineering (1R21EB022374)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R01AR069541)
  • National Science Foundation (DMR-1808251)

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