2. Academic Validation
  3. Drug Repurposing of ACT001 to Discover Novel Promising Sulfide Prodrugs with Improved Safety and Potent Activity for Neutrophil-Mediated Antifungal Immunotherapy

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

  • J Med Chem. 2024 Apr 11;67(7):5783-5799. doi: 10.1021/acs.jmedchem.3c02453.
Xiangran Lu 1,  Rongrong Wang 1,  Yao Yu 1,  Jinlian Wei 2,  Yixiang Xu 2,  Luoyifan Zhou 2,  Fei Mao 2,  Jian Li 1 2 3 4,  Xiaokang Li 2,  Xinming Jia 1
Affiliations

Affiliations

  • 1 Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China.
  • 2 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 3 Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan, College of Pharmacy, Dali University, Dali 671000, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, China.
PMID: 38526960 DOI: 10.1021/acs.jmedchem.3c02453
Abstract

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.

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