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.

中文翻译：

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纳米粒子共轭稳定和多聚化 β-发夹肽以有效靶向 PD-1/PD-L1 富含β-片层的界面

β-发夹肽作为对抗富含 β-折叠的蛋白质表面的拮抗剂具有巨大的潜力，其中宽而平坦的几何形状通常与小分子“不可成药”。在此，我们介绍了一种肽-树枝状大分子偶联物 (PDC) 方法，该方法通过分子间作用力和排除体积效应稳定肽的 β-发夹结构，并利用多价结合效应。由于协同优势，基于从工程程序性死亡 1 (PD-1) 蛋白中分离出的 β-发夹肽的 PDC 对其结合对应物程序性死亡配体 1 (PD-1) 显示出显着更高的亲和力（亲合力） -L1)，与游离肽相比（最多 5 个数量级）。具有高选择性的增强结合动力学被转化为改进的体外免疫检查点抑制作用，与全尺寸单克隆抗体相当（如果不是更好）的水平。结果证明了 PDC 系统作为一类新型抑制剂的潜力，靶向富含 β 链的蛋白质表面，如 PD-1 和 PD-L1，显示其作为新的癌症免疫治疗平台的潜力。