Journal article
The Exochelins of Pathogenic Mycobacteria: Unique, Highly Potent, Lipid- and Water-Soluble Hexadentate Iron Chelators with Multiple Potential Therapeutic Uses
Antioxidants & redox signaling, Vol.21(16), pp.2246-2261
12/01/2014
DOI: 10.1089/ars.2013.5789
PMCID: PMC4224048
PMID: 24684595
Abstract
Significance: Exochelins are lipid- and water-soluble siderophores of Mycobacterium tuberculosis with unique properties that endow them with exceptional pharmacologic utility. Exochelins can be utilized as probes to decipher the role of iron in normal and pathological states, and, since they rapidly cross cell membranes and chelate intracellular iron with little or no toxicity, exochelins are potentially useful for the treatment of a number of iron-dependent pathological phenomena. Recent Advances: In animal models, exochelins have been demonstrated to have promise for the treatment of transfusion-related iron overload, restenosis after coronary artery angioplasty, cancer, and oxidative injury associated with acute myocardial infarction and transplantation. Critical Issues: To be clinically effective, iron chelators should be able to rapidly enter cells and chelate iron at key intracellular sites. Desferri-exochelins, and other lipid-soluble chelators, can readily cross cell membranes and remove intracellular free iron; whereas deferoxamine, which is lipid insoluble, cannot do so. Clinical utility also requires that the chelators be nontoxic, which, we hypothesize, includes the capability to prevent iron from catalyzing free radical reactions which produce center dot OH or other reactive oxygen species. Lipid-soluble iron chelators currently available for clinical application are bidentate (deferiprone) or tridentate (desferasirox) molecules that do not block all six sites on the iron molecule capable of catalyzing free radical reactions. In contrast, desferriexochelins are hexadentate molecules, and by forming a one-to-one binding relationship with iron, they prevent free radical reactions. Future Directions: Clinical studies are needed to assess the utility of desferri-exochelins in the treatment of iron-dependent pathological disorders.
Details
- Title: Subtitle
- The Exochelins of Pathogenic Mycobacteria: Unique, Highly Potent, Lipid- and Water-Soluble Hexadentate Iron Chelators with Multiple Potential Therapeutic Uses
- Creators
- Lawrence D. Horwitz - University of Colorado HealthMarcus A. Horwitz - University of California, Los Angeles
- Resource Type
- Journal article
- Publication Details
- Antioxidants & redox signaling, Vol.21(16), pp.2246-2261
- DOI
- 10.1089/ars.2013.5789
- PMID
- 24684595
- PMCID
- PMC4224048
- NLM abbreviation
- Antioxid Redox Signal
- ISSN
- 1523-0864
- eISSN
- 1557-7716
- Publisher
- Mary Ann Liebert, Inc
- Number of pages
- 16
- Grant note
- AI33790; AI35725; HL077000; HL55291 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL055291 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01AI033790 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 12/01/2014
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984656604402771
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