Lanosterol 14α-Demethylase (CYP51)/Heat Shock Protein 90 (Hsp90) Dual Inhibitors for the Treatment of Invasive Candidiasis

Invasive candidiasis has attracted global attention with a high incidence and mortality. Current antifungal drugs are limited by unfavorable therapeutic efficacy, significant hepatorenal toxicity, and the development of drug resistance. Herein, we designed the first generation of lanosterol 14α-demethylase (CYP51)/heat shock protein 90 (Hsp90) dual inhibitors on the basis of antifungal synergism. Among them, dual inhibitor MM4 exhibited potent in vitro and in vivo antifungal activity against Candida albicans and effectively inhibited important fungal virulence factors (e.g., hyphae, biofilm). Therefore, CYP51/Hsp90 dual inhibitors show great promise in the development of novel antifungal drugs to combat invasive candidiasis.侵袭性念珠菌病（Invasive candidiasis）因高发病率与高死亡率受到全球关注。当前抗真菌药物存在治疗效果欠佳、肝肾毒性显著以及耐药性滋生等局限性。本研究基于抗真菌协同作用，设计了首款羊毛甾醇14α-去甲基酶（lanosterol 14α-demethylase，CYP51）/热休克蛋白90（heat shock protein 90，Hsp90）双重抑制剂。其中，双重抑制剂MM4对白色念珠菌（Candida albicans）展现出强效的体内外抗真菌活性，且可有效抑制关键真菌毒力因子（如菌丝、生物被膜）。综上，CYP51/Hsp90双重抑制剂在开发对抗侵袭性念珠菌病的新型抗真菌药物领域具备巨大应用前景。