Modular Design of Mitochondrion-Targeted Iron Chelators Allows Highly Selective Antiparasitic Activity against Trypanosomes and Apicomplexan Parasites

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; Robert Sutak

doi:10.1021/acsinfecdis.5c00548

Article de revue

Modular Design of Mitochondrion-Targeted Iron Chelators Allows Highly Selective Antiparasitic Activity against Trypanosomes and Apicomplexan Parasites

Ronald Malych, Yann Bordat, Kristýna Klanicová, Dominik Arbon, Farnaz Zahedifard, Anna Šipková, Eliška Drncová, Viktoriya Levytska, Jan Mach, Laura Plutowski-Wrobel, …

ACS infectious diseases

22/12/2025

DOI: https://doi.org/10.1021/acsinfecdis.5c00548

PMID: 41428959

Résumé

Toxoplasma

iron chelators

Trypanosoma

drug repurposing

antiparasitic agents

mitochondrion

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 spp. and 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.

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Titre: Modular Design of Mitochondrion-Targeted Iron Chelators Allows Highly Selective Antiparasitic Activity against Trypanosomes and Apicomplexan Parasites
Créateurs - sans rôle: Ronald Malych - Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec 25250, Czech Republic
Yann Bordat - LPHI, University of Montpellier, CNRS, INSERM, Montpellier 34095, France
Kristýna Klanicová - Department of Organic Chemistry, Faculty of Science, Charles University, Prague 25250, Czech Republic
Dominik Arbon - Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec 25250, Czech Republic
Farnaz Zahedifard - Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec 25250, Czech Republic
Anna Šipková - Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec 25250, Czech Republic
Eliška Drncová - Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec 25250, Czech Republic
Viktoriya Levytska - Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, BC CAS, Branišovská 1160/31, České Budějovice 37005, Czech Republic
Jan Mach - Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec 25250, Czech Republic
Laura Plutowski-Wrobel - Centre for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg 69120, Germany
Marta Machado - Graduate Program in Areas of Basic and Applied Biology, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto 4050-313, Portugal
Jan Štursa - Laboratory of Clinical Pathophysiology, Diabetes Centre, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague 140 21, Czech Republic
Jaroslav Truksa - Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec 25250, Czech Republic
Markus Ganter - Centre for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg 69120, Germany
Daniel Sojka - Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, BC CAS, Branišovská 1160/31, České Budějovice 37005, Czech Republic
Martin Zoltner - Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec 25250, Czech Republic
Sébastien Besteiro - Inserm
Lukáš Werner - Laboratory of Clinical Pathophysiology, Diabetes Centre, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague 140 21, Czech Republic
Robert Sutak - Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec 25250, Czech Republic
Détails de publication: ACS infectious diseases
Identifiants: 99147732009311
Unité académique: Laboratory of Pathogens and Host Immunity - LPHI
Langue: English
Type de ressource: Journal article