ATH434, a promising iron-targeting compound for treating iron regulation disorders.

Autor:	Pall AE; De partment of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48201, USA., Bond S; Alterity Therapeutics Limited, Melbourne, 3000, Australia., Bailey DK; Department of Biochemistry, University of Buffalo, Buffalo, NY14203, USA., Stoj CS; Department of Biochemistry, Chemistry and Physics, Niagara University, Lewiston, NY 14109, USA., Deschamps I; Department of Biochemistry, Chemistry and Physics, Niagara University, Lewiston, NY 14109, USA., Huggins P; Alterity Therapeutics Limited, Melbourne, 3000, Australia., Parsons J; Alterity Therapeutics Limited, Melbourne, 3000, Australia., Bradbury MJ; Alterity Therapeutics Limited, Newark, CA 94560, USA., Kosman DJ; Department of Biochemistry, University of Buffalo, Buffalo, NY14203, USA., Stemmler TL; De partment of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48201, USA.
Jazyk:	angličtina
Zdroj:	Metallomics : integrated biometal science [Metallomics] 2024 Oct 04; Vol. 16 (10).
DOI:	10.1093/mtomcs/mfae044
Abstrakt:	Cytotoxic accumulation of loosely bound mitochondrial Fe2+ is a hallmark of Friedreich's Ataxia (FA), a rare and fatal neuromuscular disorder with limited therapeutic options. There are no clinically approved medications targeting excess Fe2+ associated with FA or the neurological disorders Parkinson's disease and Multiple System Atrophy. Traditional iron-chelating drugs clinically approved for systemic iron overload that target ferritin-stored Fe3+ for urinary excretion demonstrated limited efficacy in FA and exacerbated ataxia. Poor treatment outcomes reflect inadequate binding to excess toxic Fe2+ or exceptionally high affinities (i.e. ≤10-31) for non-pathologic Fe3+ that disrupts intrinsic iron homeostasis. To understand previous treatment failures and identify beneficial factors for Fe2+-targeted therapeutics, we compared traditional Fe3+ chelators deferiprone (DFP) and deferasirox (DFX) with additional iron-binding compounds including ATH434, DMOG, and IOX3. ATH434 and DFX had moderate Fe2+ binding affinities (Kd's of 1-4  µM), similar to endogenous iron chaperones, while the remaining had weaker divalent metal interactions. These compounds had low/moderate affinities for Fe3+(0.46-9.59 µM) relative to DFX and DFP. While all compounds coordinated iron using molecular oxygen and/or nitrogen ligands, thermodynamic analyses suggest ATH434 completes Fe2+ coordination using H2O. ATH434 significantly stabilized bound Fe2+ from ligand-induced autooxidation, reducing reactive oxygen species (ROS) production, whereas DFP and DFX promoted production. The comparable affinity of ATH434 for Fe2+ and Fe3+ position it to sequester excess Fe2+ and facilitate drug-to-protein iron metal exchange, mimicking natural endogenous iron binding proteins, at a reduced risk of autooxidation-induced ROS generation or perturbation of cellular iron stores. (© The Author(s) 2024. Published by Oxford University Press.)
Databáze:	MEDLINE
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