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

TL;DR

Scientists designed iron chelators that target mitochondria in parasites, showing strong antiparasitic effects with high selectivity.

Contribution

A modular design approach for mitochondrion-targeted iron chelators with selective antiparasitic activity is introduced.

Findings

MitoDFX effectively targets Trypanosoma spp. and Toxoplasma gondii with high selectivity.

Mitochondrial targeting, not iron chelation alone, drives antiparasitic effects.

MitoDFX is a promising repurposed drug with potential safety for human use.

Abstract

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.

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