Blockade of immune checkpoint PD-1/PD-L1 facilitates the rescue of immune escapes of tumor cells. Though various monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenges of protein–protein interaction (PPI) blocker design. In this work, we adopted the skeleton of natural cyclopeptidic antibiotics gramicidin S as the start point for PD-1/PD-L1 inhibitor exploring and discovered a series of novel cyclopeptides that could interfere with the PPI of PD-1/PD-L1 based on several rounds of structural design and optimization. The representative active cyclopeptide 66 can bind two PD-L1 and efficiently block the PD-1/PD-L1 interaction, recruit the immune cells to the tumor cells, enhance their killing against tumor cells by promoting the release of granzyme B and perforin, and display significant CD8+ T cell-dependent tumor suppression activity in vivo.

中文翻译：

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基于天然环肽骨架的程序性死亡配体1抑制剂作为癌症治疗的免疫调节剂的设计和发现。

阻断免疫检查点PD-1 / PD-L1有助于挽救肿瘤细胞的免疫逃逸。尽管各种单克隆抗体已被批准用于临床治疗，但小分子抑制剂的开发仍落后于抗体，部分原因是蛋白质间相互作用（PPI）阻断剂设计面临挑战。在这项工作中，我们以天然环肽抗生素短杆菌肽S的骨架作为PD-1 / PD-L1抑制剂探索的起点，并发现了一系列可能干扰PD-1 / PD-L1的PPI的新型环肽在几轮结构设计和优化上。代表性的活性环肽66可以结合两个PD-L1并有效阻止PD-1 / PD-L1相互作用，将免疫细胞募集到肿瘤细胞，通过促进粒酶B和穿孔素的释放来增强其对肿瘤细胞的杀伤力，并展示出重要的CD8 + T细胞依赖的体内抑癌活性。