Journal
PARASITOLOGY
Volume 145, Issue 14, Pages 1820-1836Publisher
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S0031182018000562
Keywords
Amoeba; antifungal azoles; crystal structure; CYP51; inhibition; Leishmania; sterol 14 alpha-demethylase; sterol biosynthesis; Trypanosoma brucei; Trypanosoma cruzi
Categories
Funding
- National Institutes of Health [R01 GM067871]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM067871] Funding Source: NIH RePORTER
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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 14 alpha-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 14 alpha-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.
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