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A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites

Hayward, Jenni A ; Makota, F Victor ; Cihalova, Daniela ; Leonard, Rachel A ; Rajendran, Esther ; Zwahlen, Soraya M ; Shuttleworth, Laura ; Wiedemann, Ursula ; Spry, Christina ; Saliba, Kevin J ; Maier, Alexander G ; van Dooren, Giel G Soldati-Favre, Dominique

PLoS pathogens, 2023-07, Vol.19 (7), p.e1011517-e1011517 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites
Autor: Hayward, Jenni A ; Makota, F Victor ; Cihalova, Daniela ; Leonard, Rachel A ; Rajendran, Esther ; Zwahlen, Soraya M ; Shuttleworth, Laura ; Wiedemann, Ursula ; Spry, Christina ; Saliba, Kevin J ; Maier, Alexander G ; van Dooren, Giel G
Soldati-Favre, Dominique
Assuntos: Animals ; Auranofin ; Bacterial infections ; Biology and Life Sciences ; Biosynthesis ; Cytochrome ; Cytochrome b ; Dehydrogenases ; Diagnosis ; Disease ; Drug resistance ; Electron Transport ; Electron transport chain ; Electron Transport Complex III ; Health aspects ; Humans ; Inhibitors ; Kinases ; Libraries ; Malaria ; Medicine and Health Sciences ; Oxidation ; Parasite resistance ; Parasites ; Pathogens ; Plasmodium falciparum ; Proteins ; Protons ; Protozoa ; Pyrimethamine ; Research and Analysis Methods ; Risk factors ; Therapeutic targets ; Toxicity ; Toxoplasma ; Toxoplasmosis ; Toxoplasmosis - parasitology ; Vaccines ; Vector-borne diseases
É parte de: PLoS pathogens, 2023-07, Vol.19 (7), p.e1011517-e1011517
Notas: new_version
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Current address: The Francis Crick Institute, London, United Kingdom
Current address: Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
Current address: Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
The authors have declared that no competing interests exist.
Descrição: Apicomplexans are widespread parasites of humans and other animals, and include the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). Existing anti-apicomplexan therapies are beset with issues around drug resistance and toxicity, and new treatment options are needed. The mitochondrial electron transport chain (ETC) is one of the few processes that has been validated as a drug target in apicomplexans. To identify new inhibitors of the apicomplexan ETC, we developed a Seahorse XFe96 flux analyzer approach to screen the 400 compounds contained within the Medicines for Malaria Venture 'Pathogen Box' for ETC inhibition. We identified six chemically diverse, on-target inhibitors of the ETC in T. gondii, at least four of which also target the ETC of Plasmodium falciparum. Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. MMV688853 belongs to a compound class, the aminopyrazole carboxamides, that were shown previously to target a kinase with a key role in parasite invasion of host cells. Our data therefore reveal that MMV688853 has dual targets in apicomplexans. We further developed our approach to pinpoint the molecular targets of these inhibitors, demonstrating that all target Complex III of the ETC, with MMV688853 targeting the ubiquinone reduction (Qi) site of the complex. Most of the compounds we identified remain effective inhibitors of parasites that are resistant to Complex III inhibitors that are in clinical use or development, indicating that they could be used in treating drug resistant parasites. In sum, we have developed a versatile, scalable approach to screen for compounds that target the ETC in apicomplexan parasites, and used this to identify and characterize novel inhibitors.
Editor: United States: Public Library of Science
Idioma: Inglês

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A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites

Hayward, Jenni A ; Makota, F Victor ; Cihalova, Daniela ; Leonard, Rachel A ; Rajendran, Esther ; Zwahlen, Soraya M ; Shuttleworth, Laura ; Wiedemann, Ursula ; Spry, Christina ; Saliba, Kevin J ; Maier, Alexander G ; van Dooren, Giel G Soldati-Favre, Dominique

United States: Public Library of Science

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