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

Woo jin Jeong, Jiyoon Bu, Yanxiao Han, Adam J. Drelich, Ashita Nair, Petr Král, Seungpyo Hong

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 the β-hairpin structure of the peptide via intermolecular forces and the excluded volume effect as well as exploits the multivalent binding effect. Because of 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 (avidity) to their binding counterpart, programmed death-ligand 1 (PD-L1), as compared to free peptides (by up to 5 orders of magnitude). The enhanced binding kinetics with high selectivity was translated into an improved immune checkpoint inhibitory effect in vitro, at a level comparable to (if not better than) that of a full-size monoclonal antibody. The results demonstrate the potential of the PDC system as a novel class of inhibitors targeting β-strand-rich protein surfaces, such as PD-1 and PD-L1, displaying its potential as a new cancer immunotherapy platform.

Original languageEnglish
Pages (from-to)1832-1837
Number of pages6
JournalJournal of the American Chemical Society
Volume142
Issue number4
DOIs
Publication statusPublished - 2020 Jan 29

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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