Neutrophil-mediated immunotherapy is a promising strategy for treating Candida albicans infection due to its potential in dealing with drug-resistant events. Our previous study found that ACT001 exhibited good antifungal immunotherapeutic activity by inhibiting PD-L1 expression in neutrophils, but its strong cytotoxicity and high BBB permeability hindered its antifungal application. To address these deficiencies, a series of novel sulfide derivatives were designed and synthesized based on a slow-release prodrug strategy. Among these derivatives, compound 16 exhibited stronger inhibition of PD-L1 expression, less cytotoxicity to neutrophils, and lower BBB permeability than ACT001. Compound 16 also significantly enhanced neutrophil-mediated antifungal immunity in C. albicans infected mice, with acceptable pharmacokinetic properties and good oral safety. Moreover, pharmacological mechanism studies demonstrated that ACT001 and compound 16 reduced PD-L1 expression in neutrophils by directly targeting STAT3. Briefly, this study provided a novel prototype compound 16 which exhibited great potential in neutrophil-mediated antifungal immunotherapy.

中文翻译：

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ACT001 的药物再利用，发现新型有前途的硫化物前药，其安全性更高，且具有中性粒细胞介导的抗真菌免疫治疗的有效活性

中性粒细胞介导的免疫疗法是治疗白色念珠菌感染的一种有前途的策略，因为它在处理耐药事件方面具有潜力。我们前期的研究发现ACT001通过抑制中性粒细胞PD-L1表达而表现出良好的抗真菌免疫治疗活性，但其较强的细胞毒性和高BBB通透性阻碍了其抗真菌应用。为了解决这些缺陷，基于缓释前药策略设计并合成了一系列新型硫化物衍生物。在这些衍生物中，化合物16比ACT001表现出更强的PD-L1表达抑制作用、更小的对中性粒细胞的细胞毒性以及更低的BBB通透性。化合物16还显着增强白色念珠菌感染小鼠中中性粒细胞介导的抗真菌免疫力，具有可接受的药代动力学特性和良好的口服安全性。此外，药理学机制研究表明，ACT001和化合物16通过直接靶向STAT3来降低中性粒细胞中的PD-L1表达。简而言之，这项研究提供了一种新型原型化合物16，它在中性粒细胞介导的抗真菌免疫治疗中表现出巨大的潜力。