Zhang Mingming, Yang Wanzhen, Liu Na, Tu Jie, Lin Jingsheng, Dong Guoqiang, Zhao Dongmei, Sheng Chunquan
The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
J Med Chem. 2025 Jan 23;68(2):1668-1681. doi: 10.1021/acs.jmedchem.4c02305. Epub 2025 Jan 4.
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 exhibited potent and antifungal activity against 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.
侵袭性念珠菌病因其高发病率和死亡率而引起全球关注。目前的抗真菌药物受到治疗效果不佳、显著的肝肾毒性以及耐药性发展的限制。在此，我们基于抗真菌协同作用设计了第一代羊毛甾醇14α-去甲基酶（CYP51）/热休克蛋白90（Hsp90）双重抑制剂。其中，双重抑制剂对[具体真菌名称未给出]表现出强效抗真菌活性，并有效抑制重要的真菌毒力因子（如菌丝、生物膜）。因此，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方面显示出巨大潜力。
