Development of Glycosylation-Modified DPPA-1 Compounds as Innovative PD-1/PD-L1 Blockers: Design, Synthesis, and Biological Evaluation

文献类型： 外文期刊

第一作者： Deng, Peng

作者： Deng, Peng;Dong, Xiaodan;Peng, Chune;Peng, Lizeng;Wu, Ziyuan;Mao, Longfei;Hou, Xixi;Guo, Jingjing;Zhao, Wenshan;Zhang, Zhe

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关键词： cancer immunotherapy; immune checkpoint; PD-1/PD-L1; peptide; glycosylation

期刊名称：MOLECULES （ 影响因子：4.6； 五年影响因子：4.9 ）

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年卷期： 2024 年 29 卷 8 期

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收录情况： SCI

摘要： In the context of peptide drug development, glycosylation plays a pivotal role. Accordingly, L-type peptides were synthesized predicated upon the PD-1/PD-L1 blocker (D)PPA-1. Subsequent glycosylation resulted in the production of two distinct glycopeptides, D-glu-(L)PPA-1 and D-gal-(L)PPA-1, by using D-glucose (D-glu) and D-galactose (D-gal), respectively, during glycosylation. Both glycopeptides significantly inhibited the interaction between PD-1 and PD-L1, and the measured half maximal inhibitory concentrations (IC50s) were 75.5 mu M and 101.9 mu M for D-glu-LPPA-1 and D-gal-LPPA-1, respectively. Furthermore, D-gal-LPPA-1 displayed a pronounced ability to restore T-cell functionality. In an MC38 tumor-bearing mouse model, D-gal-LPPA-1 demonstrated a significant inhibitory effect. Notably, D-gal-LPPA-1 substantially augmented the abundance and functionality of CD8(+) T cells in the tumor microenvironment. Additionally, in the lymph nodes and spleens, D-gal-LPPA-1 significantly increased the proportion of CD8(+) T cells secreting interferon-gamma (IFN-gamma). These strong findings position D-gal-LPPA-1 as a potent enhancer of the antitumor immune response in MC38 tumor-bearing mice, underscoring its potential as a formidable PD-1/PD-L1 blocking agent.

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