文献类型：期刊文献

英文题名：Drug Repurposing of ACT001 to Discover Novel Promising Sulfide Prodrugs with Improved Safety and Potent Activity for Neutrophil-Mediated Antifungal Immunotherapy

作者：Lu, Xiangran[1];Wang, Rongrong[1];Yu, Yao[1];Wei, Jinlian[2];Xu, Yixiang[2];Zhou, Luoyifan[2];Mao, Fei[2];Li, Jian[1,2,3,4];Li, Xiaokang[2];Jia, Xinming[1]

机构：[1]Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Clin Med Sci & Tech Innovat Ctr, Shanghai 200092, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn,Shanghai Frontiers S, Shanghai 200237, Peoples R China;[3]Dali Univ, Coll Pharm, Yunnan Key Lab Screening & Res Antipathogen Plant, Dali 671000, Peoples R China;[4]Hainan Univ, Coll Pharm, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Peoples R China

年份：2024

卷号：67

期号：7

起止页码：5783

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001190737900001)】；

基金：This work was supported by the National Key Research and Development Program of China (2022YFC2303000, 2021YFC2300400, and 2021YFA0804904), the National Natural Science Foundation of China (31970889, 22037002, 82173689, and 31972169), the Innovation Program of Shanghai Municipal Education Commission (201901070007E00022), the Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci & Tech 03-28, China), the Key fund for basic research of Shanghai Science and Technology Commission (20JC1417700), the Shanghai laboratory animal research fund (21140903300), the Outstanding Research Project of Shanghai Municipal Health Commission (20224Z0020), and the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (2060204).

语种：英文

摘要：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.