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

Published online by Cambridge University Press:  12 April 2018

Galina I. Lepesheva ,
Laura Friggeri  and
Michael R. Waterman
Galina I. Lepesheva*
Affiliation:
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
Laura Friggeri
Affiliation:
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
Michael R. Waterman
Affiliation:
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
*
Author for correspondence: Galina I. Lepesheva, E-mail: [email protected]
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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.

Keywords

Amoebaantifungal azolescrystal structureCYP51inhibitionLeishmaniasterol 14α-demethylasesterol biosynthesisTrypanosoma bruceiTrypanosoma cruzi
Type
Review Article
Information
Parasitology , Volume 145 , Issue 14 , December 2018 , pp. 1820 - 1836
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Copyright
Copyright © Cambridge University Press 2018 

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