Alternative oxidase inhibitors: mitochondrion-targeting as a strategy for new drugs against pathogenic parasites and fungi

Ebiloma, G. U., Balogun, E. O., Cueto-Díaz, E. J., de Koning, H. P. and Dardonville, C. (2019) Alternative oxidase inhibitors: mitochondrion-targeting as a strategy for new drugs against pathogenic parasites and fungi. Medicinal Research Reviews, (doi:10.1002/med.21560) (PMID:30693533) (Early Online Publication)

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Abstract

The alternative oxidase (AOX) is a ubiquitous terminal oxidase of plants and many fungi, catalyzing the four‐electron reduction of oxygen to water alongside the cytochrome‐based electron transfer chain. Unlike the classical electron transfer chain, however, the activity of AOX does not generate adenosine triphosphate but has functions such as thermogenesis and stress response. As it lacks a mammalian counterpart, it has been investigated intensely in pathogenic fungi. However, it is in African trypanosomes, which lack cytochrome‐based respiration in their infective stages, that trypanosome alternative oxidase (TAO) plays the central and essential role in their energy metabolism. TAO was validated as a drug target decades ago and among the first inhibitors to be identified was salicylhydroxamic acid (SHAM), which produced the expected trypanocidal effects, especially when potentiated by coadministration with glycerol to inhibit anaerobic energy metabolism as well. However, the efficacy of this combination was too low to be of practical clinical use. The antibiotic ascofuranone (AF) proved a much stronger TAO inhibitor and was able to cure Trypanosoma vivax infections in mice without glycerol and at much lower doses, providing an important proof of concept milestone. Systematic efforts to improve the SHAM and AF scaffolds, aided with the elucidation of the TAO crystal structure, provided detailed structure‐activity relationship information and reinvigorated the drug discovery effort. Recently, the coupling of mitochondrion‐targeting lipophilic cations to TAO inhibitors has dramatically improved drug targeting and trypanocidal activity while retaining target protein potency. These developments appear to have finally signposted the way to preclinical development of TAO inhibitors.

Item Type:Articles
Additional Information:Funding from the Spanish Ministerio de Economia, Industria y Competitividad (grant SAF2015‐66690‐R) and theJapan Society for the Promotion of Science (JSPS grant 17F17420) is gratefully acknowledged.
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry and Ebiloma, Godwin Unekwuojo
Authors: Ebiloma, G. U., Balogun, E. O., Cueto-Díaz, E. J., de Koning, H. P., and Dardonville, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Medicinal Research Reviews
Publisher:Wiley
ISSN:0198-6325
ISSN (Online):1098-1128
Published Online:29 January 2019
Copyright Holders:Copyright © 2019 Wiley Periodicals Inc.
First Published:First published in Medicinal Research Reviews 2019
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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