Nanoparticle Conjugation Stabilizes and Multimerizes β-Hairpin Peptides To Effectively Target PD-1/PD-L1 β-Sheet-Rich Interfaces
Nanoparticle Conjugation Stabilizes and Multimerizes β-Hairpin Peptides To Effectively Target PD-1/PD-L1 β-Sheet-Rich Interfaces
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DOI：
10.1021/jacs.9b10160
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发表时间：
2020-01-29
影响因子：
15
通讯作者：
Hong, Seungpyo
中科院分区：
文献类型：
--
作者：
Jeong, Woo-jin;Bu, Jiyoon;Hong, Seungpyo
β-发夹肽作为富含β折叠的蛋白质表面的拮抗剂具有巨大的潜力，其宽而平坦的几何形状通常是小分子“不可成药的”。在此，我们介绍了一种肽-树枝状大分子缀合物（PDC）方法，该方法通过分子间力和排除体积效应来稳定肽的β-发夹结构，并利用多价结合效应。由于协同优势，与游离肽相比，基于从工程化程序性死亡 1 (PD-1) 蛋白分离的 β-发夹肽的 PDC 对其结合对应物程序性死亡配体 1 (PD-L1) 表现出显着更高的亲和力（亲和力）（高达 5 个数量级）。具有高选择性的增强结合动力学在体外转化为改善的免疫检查点抑制效果，其水平与全尺寸单克隆抗体相当（如果不是更好）。结果证明了 PDC 系统作为一类针对富含 β 链的蛋白质表面（例如 PD-1 和 PD-L-1）的新型抑制剂的潜力，展示了其作为新的癌症免疫治疗平台的潜力。
beta-Hairpin peptides present great potential as antagonists against beta-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 beta-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 beta-hairpin peptide isolated from an engineered programmed death-1 (PD-1) protein showed significantly higher affinity (avidity) to their binding counterpart, programmed deathligand 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 beta-strand-rich protein surfaces, such as PD-1 and PD-L-1, displaying its potential as a new cancer immunotherapy platform.