Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy
Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy
复制标题
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免疫调节剂的设计和发现
DOI：
10.1021/acs.jmedchem.0c01262
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发表时间：
2020-10-08
影响因子：
7.3
通讯作者：
Bu, Xianzhang
中科院分区：
文献类型：
--
作者：
Sun, Haixia;Chen, Daoyuan;Bu, Xianzhang
阻断免疫检查点PD-1/PD-L1有助于拯救肿瘤细胞的免疫逃逸。虽然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落后于抗体，部分原因是蛋白质-蛋白质相互作用（PPI）阻断剂设计的挑战。本研究以天然环肽类抗生素短杆菌肽S的骨架为研究起点，通过多轮结构设计和优化，发现了一系列能够干扰PD-1/PD-L1的PPI的新型环肽。具有代表性的活性环肽66可以结合两个PD-L1并有效阻断PD-1/PD-L1相互作用，将免疫细胞募集到肿瘤细胞，通过促进颗粒酶B和穿孔素的释放来增强其对肿瘤细胞的杀伤，并在体内显示出显著的CD 8 + T细胞依赖性肿瘤抑制活性。
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.