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

January 2, 2020
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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 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.

Process involving peptides

Published

Journal of the American Chemical Society
JACS Volume 142 Issue 4 cover

Cited by

This article is cited by 11 publications

  1. Gu, Z., Xu, S., Guo, Z., & Liu, Z. (2022). Rational development of molecularly imprinted nanoparticles for blocking PD-1/PD-L1 axis. Chemical science, 13(36), 10897–10903. https://doi.org/10.1039/d2sc03412c
  2. Poellmann, M. J., Rawding, P., Kim, D., Bu, J., Kim, Y., & Hong, S. (2022). Branched, dendritic, and hyperbranched polymers in liquid biopsy device design. Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology, 14(3), e1770. https://doi.org/10.1002/wnan.1770
  3. Rawding, P. A., Bu, J., Wang, J., Kim, D. W., Drelich, A. J., Kim, Y., & Hong, S. (2022). Dendrimers for cancer immunotherapy: Avidity-based drug delivery vehicles for effective anti-tumor immune response. Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology, 14(2), e1752. https://doi.org/10.1002/wnan.1752
  4. Jeong, W. J., Bu, J., Jafari, R., Rehak, P., Kubiatowicz, L. J., Drelich, A. J., Owen, R. H., Nair, A., Rawding, P. A., Poellmann, M. J., Hopkins, C. M., Král, P., & Hong, S. (2022). Hierarchically Multivalent Peptide-Nanoparticle Architectures: A Systematic Approach to Engineer Surface Adhesion. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 9(4), e2103098. https://doi.org/10.1002/advs.202103098
  5. Ershov, P. V., Mezentsev, Y. V., & Ivanov, A. S. (2022). Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions. Biomolecules, 12(1), 106. https://doi.org/10.3390/biom12010106