A Rationally Designed Complex Replenishes the Transferrin Iron Pool Directly and with High Specificity

Many forms of anemia are caused or complicated by pathologic restriction of iron (Fe). Chronic inflammation and certain genetic mutations decrease the activity of ferroportin, the only Fe-exporter protein, so that endogenously recycled or nutritionally absorbed Fe cannot be exported to the extracell...

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Bibliographic Details
Published in:	Journal of the American Chemical Society Vol. 145; no. 12; pp. 6871 - 6879
Main Authors:	Sargun, Artur, Fisher, Allison L., Wolock, Anna S., Phillips, Sydney, Sojoodi, Mozhdeh, Khanna, Soumya, Babitt, Jodie L., Gale, Eric M.
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 29-03-2023
Subjects:	Anemia Anemia, Iron-Deficiency Animals Inflammation Iron - metabolism Mice Transferrin
Online Access:	Get full text
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Summary:	Many forms of anemia are caused or complicated by pathologic restriction of iron (Fe). Chronic inflammation and certain genetic mutations decrease the activity of ferroportin, the only Fe-exporter protein, so that endogenously recycled or nutritionally absorbed Fe cannot be exported to the extracellular Fe carrier protein transferrin for delivery to the bone marrow. Diminished ferroportin activity renders anemia correction challenging as Fe administered intravenously or through nutritional supplementation is trafficked through the ferroportin-transferrin axis. Utilizing judicious application of coordination chemistry principles, we designed an Fe complex (Fe-BBG) with solution thermodynamics and Fe dissociation kinetics optimized to replenish the transferrin-Fe pool rapidly, directly, and with precision. Fe-BBG is unreactive under conditions designed to force redox cycling and production of reactive oxygen species. The BBG ligand has a low affinity for divalent metal ions and does not compete for binding of other endogenously present ions including Cu and Zn. Treatment with Fe-BBG confers anemia correction in a mouse model of iron-refractory iron-deficiency anemia. Repeated exposure to Fe-BBG did not cause adverse clinical chemistry changes or trigger the expression of genes related to oxidative stress or inflammation. Fe-BBG represents the first entry in a promising new class of transferrin-targeted Fe replacement drugs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0002-7863 1520-5126
DOI:	10.1021/jacs.3c00123