Nanoparticle Conjugation Stabilizes and Multimerizes ß-Hairpin Peptides To Effectively Target PD-1/PD-L1 ß-Sheet-Rich Interfaces.
J Am Chem Soc
; 142(4): 1832-1837, 2020 01 29.
Article
em En
| MEDLINE
| ID: mdl-31895555
ABSTRACT
ß-Hairpin peptides present great potential as antagonists against ß-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 ß-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 ß-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 ß-strand-rich protein surfaces, such as PD-1 and PD-L1, displaying its potential as a new cancer immunotherapy platform.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Nanopartículas
/
Antígeno B7-H1
/
Receptor de Morte Celular Programada 1
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2020
Tipo de documento:
Article