Discovery of Cyclic Peptide Inhibitors Targeting PD-L1 for Cancer Immunotherapy.
Discovery of Cyclic Peptide Inhibitors Targeting PD-L1 for Cancer Immunotherapy.
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DOI：
10.1021/acs.jmedchem.2c00539
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发表时间：
2022-09-22
影响因子：
7.3
通讯作者：
Li, Guangfu
中科院分区：
文献类型：
--
作者：
Cheng, Kun;Fetse, John;Zhao, Zhen;Liu, Hao;Mamani, Umar-Farouk;Mustafa, Bahaa;Adhikary, Pratik;Ibrahim, Mohammed;Liu, Yanli;Patel, Pratikkumar;Nakhjiri, Maryam;Alahmari, Mohammed;Li, Guangfu
阻断程序性细胞死亡配体-1(PD-L1)及其受体PD-1之间的相互作用在肿瘤免疫治疗中已显示出巨大的成功。多肽具有独特的特性，使其作为免疫检查点抑制剂具有显著优势。然而，不利的物理化学性质和蛋白质分解稳定性限制了生物活性多肽作为治疗剂的翻译。研究表明，环化可以提高线状多肽的生物活性和稳定性。在这项研究中，我们报告了使用大环扫描来发现具有更高生物活性的环状抗PD-L1多肽。这些环肽在PD-1/PD-L1阻断活性和体内抗肿瘤活性方面表现出高达34倍的提高。结果表明，大环化扫描是提高抗PD-L1线性多肽的血清稳定性和生物活性的有效方法。该策略也可用于其他生物活性多肽的优化，特别是蛋白质相互作用调节的生物活性多肽的优化。
Blockade of the interaction between programmed cell death ligand-1 (PD-L1) and its receptor PD-1 has shown great success in cancer immunotherapy. Peptides possess unique characteristics that give them significant advantages as immune checkpoint inhibitors. However, unfavorable physicochemical properties and proteolytic stability profiles limit the translation of bioactive peptides as therapeutic agents. Studies have revealed that cyclization improves the biological activity and stability of linear peptides. In this study, we report the use of macrocyclization scanning for the discovery of cyclic anti-PD-L1 peptides with improved bioactivity. The cyclic peptides demonstrated up to a 34-fold improvement in the PD-1/PD-L1 blocking activity and significant in vivo anti-tumor activity. Our results demonstrate that macrocyclization scanning is an effective way to improve the serum stability and bioactivity of the anti-PD-L1 linear peptide. This strategy can be employed in the optimization of other bioactive peptides, particularly those for protein-protein interaction modulation.
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