CYP51 as drug targets for fungi and protozoan parasites: past, present and future

Abstract

The efficiency of treatment of human infections with the unicellular eukaryotic pathogens such as fungi and protozoa remains deeply unsatisfactory. For example, the mortality rates from nosocomial fungemia in critically ill, immunosuppressed or post-cancer patients often exceed 50%. A set of six systemic clinical azoles [sterol 14α-demethylase (CYP51) inhibitors] represents the first-line antifungal treatment. All these drugs were discovered empirically, by monitoring their effects on fungal cell growth, though it had been proven that they kill fungal cells by blocking the biosynthesis of ergosterol in fungi at the stage of 14α-demethylation of the sterol nucleus. This review briefs the history of antifungal azoles, outlines the situation with the current clinical azole-based drugs, describes the attempts of their repurposing for treatment of human infections with the protozoan parasites that, similar to fungi, also produce endogenous sterols, and discusses the most recently acquired knowledge on the CYP51 structure/function and inhibition. It is our belief that this information should be helpful in shifting from the traditional phenotypic screening to the actual target-driven drug discovery paradigm, which will rationalize and substantially accelerate the development of new, more efficient and pathogen-oriented CYP51 inhibitors.

Thiazolidinone-Related Heterocyclic Compounds as Potential Antitrypanosomal Agents

“…This enzyme is involved in the ergosterol biosynthesis, taking part in the production of components of the plasma membranes and serving as precursors for regulatory molecules that modulate growth, division, differentiation, and development processes [77,78]. Fungicides as well as clinically used antifungal azoles inhibit CYP51 that along with the resemblance of sterol biosynthesis in trypanosomatids to such in fungi [79], makes lanosterol 14α-demethylase an attractive target for the design of antitrypanosomal agents.…”

Advances in preclinical approaches to Chagas disease drug discovery

“…Similarly, the structures of sterol 14 α-demethylases from the fungal organisms Aspergillus fumigatus [39,40] and Candida albicans [41], and from humans [42] were characterized. Also, the sterol 14 αdemethylase of Trypanosoma brucei and Leishmania infantum were characterized and their structures were solved in a ligand-free form and in complexes with different inhibitors and their structures were compared with the counterpart enzyme in T. cruzi and fungal organisms [43][44][45].…”

“…However, rigorous PK/PD analysis is essential to translate the results of preclinical in vivo studies such as those with novel T. cruzi sterol 14 α-demethylase inhibitors VNI and VFV. The demonstrated drugability of the T. cruzi 14 α-demethylase is facilitating the design of new pharmacophores that do not affect the human counterpart, with high efficacy in curing T. cruzi infections in rodent experimental models and presenting excellent PKs [45]. However, Tc24SMT is the only enzyme in the biosynthesis of ergosterol in T. cruzi with no human counterpart and is a prime target for intervention.…”

Parasite, Compartments, and Molecules: Trick versus Treatment on Chagas Disease

“…T. cruzi and related trypanosomatids have a strict requirement for endogenous sterols (ergosterol and analogs) for survival that cannot be replaced by cholesterol found in the host. Thus, the biosynthesis of sterols is a major target in the drug development for Chagas disease [84]. Among enzymes of the sterol metabolism, squalene synthase (SQS) and C14α-sterol demethylase (CYP51) have been intensively investigated as drug targets (Figure 5).…”

“…This enzyme catalyzes the oxidative removal of the 14α-methyl group from of catalyzing the oxidative removal of the 14α-methyl group from sterol precursors such as lanosterol or eburicol, via a repetitive three-step process that uses NADPH and oxygen to produce 4,4-dimethyl-5α-cholesta-8,14,24-trien-3β-ol [83]. CYP51s are the most conserved cytochrome P450 enzymes [84]. Series of azoles originally developed for the treatment of fungal infections targets this enzyme leading to accumulation of lanosterol and other sterol intermediates and displaying activity in vitro and in vivo against T. cruzi [95][96][97].…”