澳大利亚昆士兰大学Conan K. Wang团队报道了用于癌症免疫治疗的PD-1:PD-L1相互作用高效肽抑制剂的合理设计。相关研究成果发表在2021年10月18日出版的《美国化学会杂志》。

肽有潜力发展成为免疫检查点抑制剂，但其靶界面难以抑制。

该文中，研究人员探索了一种模拟PD-1结合表面设计抑制剂的方法。模拟天然PD-1会产生一个没有活性的模拟物。然而，模拟亲和力优化的PD-1导致肽模拟物MOPD-1显示出与PD-L1的纳摩尔亲和力，并可在基于蛋白质和细胞的分析中抑制PD-1:PD-L1相互作用。利用核磁共振波谱和X射线晶体学进行诱变和结构表征表明，来自高亲和力PD-1的结合残基对MOPD-1的生物活性至关重要。

此外，MOPD-1在人血清中极为稳定，并在体内抑制肿瘤生长，表明其在肿瘤免疫治疗中具有潜在的应用前景。使用该文所述的模拟方法成功设计PD-1:PD-L1抑制剂说明了在设计抑制剂之前更加重视优化目标界面的价值，并且是一种可用于设计其他复杂蛋白质-蛋白质相互作用的肽抑制剂的方法。

附：英文原文

Title: Rational Design of Potent Peptide Inhibitors of the PD-1:PD-L1 Interaction for Cancer Immunotherapy

Author: Huawu Yin, Xiuman Zhou, Yen-Hua Huang, Gordon J. King, Brett M. Collins, Yanfeng Gao, David J. Craik, Conan K. Wang

Issue&Volume: October 18, 2021

Abstract: Peptides have potential to be developed into immune checkpoint inhibitors, but the target interfaces are difficult to inhibit. Here, we explored an approach to mimic the binding surface of PD-1 to design inhibitors. Mimicking native PD-1 resulted in a mimetic with no activity. However, mimicking an affinity-optimized PD-1 resulted in the peptide mimetic MOPD-1 that displayed nanomolar affinity to PD-L1 and could inhibit PD-1:PD-L1 interactions in both protein- and cell-based assays. Mutagenesis and structural characterization using NMR spectroscopy and X-ray crystallography revealed that binding residues from the high affinity PD-1 are crucial for the bioactivity of MOPD-1. Furthermore, MOPD-1 was extremely stable in human serum and inhibited tumor growth in vivo, suggesting it has potential for use in cancer immunotherapy. The successful design of an inhibitor of PD-1:PD-L1 using the mimicry approach described herein illustrates the value of placing greater emphasis on optimizing the target interface before inhibitor design and is an approach that could have broader utility for the design of peptide inhibitors for other complex protein–protein interactions.

DOI: 10.1021/jacs.1c08132

Source: https://pubs.acs.org/doi/10.1021/jacs.1c08132