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.