Candida albicans Lanosterol 14α-demethylase: Structural insights into its molecular mechanisms and mode of inhibition by azole antifungals

Abstract

During the past three decades azole compounds have been developed as medical and agricultural agents to combat fungal diseases. During the 1980s they were introduced as orally active compounds in medicine and the number of such azole drugs is likely to expand in the near future. They act by inhibiting cytochrome P450 14α- demethylase (CYP51), a key enzyme in the fungal ergosterol biosynthesis. Azole antifungals now represent a successful strategy for antifungal development. A universal step in the biosynthesis of membrane sterols and steroid hormones is the oxidative removal of the 14α-methyl group from sterol precursors by sterol 14α-demethylase (CYP51). This enzyme is a primary target in treatment of fungal infections in organisms ranging from humans to plants, and development of more potent and selective CYP51 inhibitors (azoles) is an important biological objective. However, their clinical value has been limited by their relatively high risk of toxicity, the emergence of drug resistance, pharmacokinetic deficiencies, and/or insufficiencies in their antifungal activities. Despite recent developments, there is still need for genuinely broad-spectrum and low-toxicity azole antifungal agents. In this review molecular basis of how azoles interact with their target enzyme is discussed. Indeed, the understanding of the molecular basis of such interaction will help in the design of more active CYP51 inhibitors.