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Modular design of mitochondrion-targeted iron chelators allows highly selective antiparasitic activity against trypanosomes and apicomplexan parasites

Parasitic protozoa exhibit a high demand for iron, with mitochondrial iron metabolism representing a vulnerable target for chemotherapeutic intervention. We recently demonstrated that mitochondrial targeting of the iron chelator deferoxamine (DFO) via triphenylphosphonium (TPP) conjugation enhances...

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Main Authors: Malych, Ronald (Author) , Bordat, Yann (Author) , Klanicová, Kristýna (Author) , Arbon, Dominik (Author) , Zahedifard, Farnaz (Author) , Šipková, Anna (Author) , Drncová, Eliška (Author) , Levytska, Viktoriya (Author) , Mach, Jan (Author) , Plutowski-Wrobel, Laura (Author) , Machado, Marta (Author) , Štursa, Jan (Author) , Truksa, Jaroslav (Author) , Ganter, Markus (Author) , Sojka, Daniel (Author) , Zoltner, Martin (Author) , Besteiro, Sébastien (Author) , Werner, Lukáš (Author) , Sutak, Robert (Author)
Format: Article (Journal)
Language:English
Published: December 22, 2025
In: ACS infectious diseases
Year: 2026, Volume: 12, Issue: 1, Pages: 119-127
ISSN:2373-8227
DOI:10.1021/acsinfecdis.5c00548
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1021/acsinfecdis.5c00548
Verlag, kostenfrei, Volltext: https://pubs.acs.org/doi/10.1021/acsinfecdis.5c00548
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Author Notes:Ronald Malych, Yann Bordat, Kristýna Klanicová, Dominik Arbon, Farnaz Zahedifard, Anna Šipková, Eliška Drncová, Viktoriya Levytska, Jan Mach, Laura Plutowski-Wrobel, Marta Machado, Jan Štursa, Jaroslav Truksa, Markus Ganter, Daniel Sojka, Martin Zoltner, Sébastien Besteiro, Lukáš Werner, and Robert Sutak
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Summary:Parasitic protozoa exhibit a high demand for iron, with mitochondrial iron metabolism representing a vulnerable target for chemotherapeutic intervention. We recently demonstrated that mitochondrial targeting of the iron chelator deferoxamine (DFO) via triphenylphosphonium (TPP) conjugation enhances its antiparasitic efficacy. To expand upon this strategy, mitochondrially targeted derivatives of DFO and deferasirox (DFX) were synthesized and evaluated for their activity against important human parasites. The DFX derivative mitoDFX was effective against Trypanosoma spp. and Toxoplasma gondii with remarkable selectivity. The fact that mitoDFX is a promising anticancer agent, which is likely safe to use in the context of human health, highlights the potential for drug repurposing in parasitology. Structure-activity relationship (SAR) studies and iron distribution analyses in trypanosomes revealed that mitochondrial targeting of the compounds, rather than iron chelation per se, is the main driver of the antiparasitic effects, underscoring the critical role of phosphonium salts in bioactivity.
Item Description:Gesehen am 30.03.2026
Physical Description:Online Resource
ISSN:2373-8227
DOI:10.1021/acsinfecdis.5c00548

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