A Rationally Designed Complex Replenishes the Transferrin Iron Pool Directly and with High Specificity.
J Am Chem Soc
; 145(12): 6871-6879, 2023 03 29.
Article
en En
| MEDLINE
| ID: mdl-36920018
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Anemia Ferropénica
/
Anemia
Límite:
Animals
Idioma:
En
Revista:
J Am Chem Soc
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos