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

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.