Blocking of the PD-1/PD-L1 Interaction by a D-Peptide Antagonist for Cancer Immunotherapy

• Published in: Angewandte Chemie 2015-09, Vol.127 (40), p.11926-11930
• Main Authors: Chang, Hao-Nan, Liu, Bei-Yuan, Qi, Yun-Kun, Zhou, Yang, Chen, Yan-Ping, Pan, Kai-Mai, Li, Wen-Wen, Zhou, Xiu-Man, Ma, Wei-Wei, Fu, Cai-Yun, Qi, Yuan-Ming, Liu, Lei, Gao, Yan-Feng
• Format: Article
• Language: eng ; ger
• Subjects: Affinity; Antikörper; Blocking; Cancer; Cell death; Cellular; Chemische Proteinsynthese; Chemistry; Krebsimmuntherapie; Ligands; Palladium; Pathways; Protein-Protein-Wechselwirkung; Proteins; Tumortherapeutika
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201506225

Blockade of the protein–protein interaction between the transmembrane protein programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror‐image phage display, we developed the first hydrolysis‐resistant D‐peptide antagonists to target the PD‐1/PD‐L1 pathway. The optimized compound DPPA‐1 could bind PD‐L1 at an affinity of 0.51 μM in vitro. A blockade assay at the cellular level and tumor‐bearing mice experiments indicated that DPPA‐1 could also effectively disrupt the PD‐1/PD‐L1 interaction in vivo. Thus D‐peptide antagonists may provide novel low‐molecular‐weight drug candidates for cancer immunotherapy. Chemische Proteinsynthese und Spiegelbild‐Phagendisplay wurden zur Entwicklung eines proteolyseresistenten D‐Peptid‐Antagonisten (DPPA‐1) kombiniert, der auf PD‐L1 (den Liganden von PD‐1, dem Protein 1 des programmierten Zelltods) zielt. DPPA‐1 hemmt die Protein‐Protein‐Wechselwirkung zwischen PD‐1 und PD‐L1 auf der Zellebene. IgV=Immunglobulin‐artige Variable.