Aberrant N-linked glycosylation is a prominent feature of cancers. Perturbance of oligosaccharide structure on cell surfaces directly affects key processes in tumor development and progression. In spite of the critical role played by N-linked glycans in tumor biology, the discovery of small molecules that specifically disturbs the N-linked glycans is still under investigation. To identify more saccharide-structure-perturbing compounds, a repurposed drug screen by using a library consisting of 1530 FDA-approved drugs was performed. Interestingly, an antipsychotic drug, penfluridol, was identified as being able to decrease cell surface Wheat germ agglutinin (WGA) staining. In the presence of penfluridol, cell membrane glycoproteins PD-L1 shifted to a lower molecular weight. Further studies demonstrated that penfluridol treatment caused an accumulation of high-mannose oligosaccharides, especially Man5-7GlcNAc2 glycan structures. Mechanistically, this effect is due to direct targeting of MAN1A1 mannosidase, a Golgi enzyme involved in N-glycan maturation. Moreover, we found that altered glycosylation of PD-L1 caused by penfluridol disrupted interactions between PD-1 and PD-L1, resulting in activation of T-cell tumor immunity. In a mouse xenograft and glioma model, penfluridol enhanced the anti-tumor effect of the anti-PD-L1 antibody in vivo. Overall, these findings revealed an important biological activity of the antipsychotic drug penfluridol as an inhibitor of glycan processing and proposed a repurposed use of penfluridol in anti-tumor therapy through activation of T-cell immunity.

中文翻译：

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抗精神病药物五氟利多抑制 N 连接糖蛋白加工并增强 T 细胞介导的肿瘤免疫

异常的 N-连接糖基化是癌症的一个显着特征。细胞表面寡糖结构的扰动直接影响肿瘤发生和进展的关键过程。尽管 N 连接聚糖在肿瘤生物学中发挥着关键作用，但特异性干扰 N 连接聚糖的小分子的发现仍在研究中。为了识别更多干扰糖结构的化合物，我们使用由 1530 种 FDA 批准的药物组成的库进行了重新用途的药物筛选。有趣的是，一种抗精神病药物五氟利多被认为能够减少细胞表面小麦胚芽凝集素 (WGA) 染色。在五氟利多存在的情况下，细胞膜糖蛋白 PD-L1 转变为较低的分子量。进一步的研究表明，五氟利多处理导致高甘露糖寡糖的积累，尤其是 Man5-7GlcNAc2 聚糖结构。从机制上讲，这种效应是由于直接靶向 MAN1A1 甘露糖苷酶（一种参与 N-聚糖成熟的高尔基体酶）所致。此外，我们发现五氟利多引起的 PD-L1 糖基化改变破坏了 PD-1 和 PD-L1 之间的相互作用，从而激活 T 细胞肿瘤免疫。在小鼠异种移植和神经胶质瘤模型中，五氟利多增强了抗 PD-L1 抗体的体内抗肿瘤作用。总体而言，这些发现揭示了抗精神病药物五氟利多作为聚糖加工抑制剂的重要生物活性，并提出通过激活 T 细胞免疫在抗肿瘤治疗中重新利用五氟利多。