Minimizing higher-order aggregation maximizes iron mobilization by small molecules.

Autor: Blake AD; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Chao J; Ambys Medicines, South San Francisco, CA, USA., SantaMaria AM; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Ekaputri S; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Green KJ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Brown ST; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Rakowski CK; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Choi EK; Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA., Aring L; Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA., Chen PJ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Snead NM; Ambys Medicines, South San Francisco, CA, USA., Matje DM; Ambys Medicines, South San Francisco, CA, USA., Geng T; Ambys Medicines, South San Francisco, CA, USA., Octaviani A; Ambys Medicines, South San Francisco, CA, USA., Bailey K; Alnylam Pharmaceuticals, Inc., Cambridge, MA, USA., Hollenbach SJ; Ambys Medicines, South San Francisco, CA, USA., Fan TM; Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Seo YA; Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA. youngseo@umich.edu., Burke MD; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA. mdburke@illinois.edu.; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA. mdburke@illinois.edu.; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA. mdburke@illinois.edu.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. mdburke@illinois.edu.; Molecule Maker Lab Institute, Arnold and Mabel Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA. mdburke@illinois.edu.; Carle Illinois College of Medicine, Champaign, IL, USA. mdburke@illinois.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2024 Oct; Vol. 20 (10), pp. 1282-1293. Date of Electronic Publication: 2024 Apr 25.
DOI: 10.1038/s41589-024-01596-3
Abstrakt: The natural product hinokitiol mobilizes iron across lipid bilayers at low concentrations and restores hemoglobinization in iron transporter protein-deficient systems. But hinokitiol fails to similarly mobilize iron at higher concentrations, limiting its uses in chemical biology and medicine. Here we show that at higher concentrations, hinokitiol 3 :Fe(III) complexes form large, higher-order aggregates, leading to loss of transmembrane iron mobilization. Guided by this understanding and systematic structure-function studies enabled by modular synthesis, we identified FeM-1269, which minimally aggregates and dose-dependently mobilizes iron across lipid bilayers even at very high concentrations. In contrast to hinokitiol, FeM-1269 is also well-tolerated in animals at high doses for extended periods of time. In a mouse model of anemia of inflammation, FeM-1269 increases serum iron, transferrin saturation, hemoglobin and hematocrit. This rationally developed iron-mobilizing small molecule has enhanced potential as a molecular prosthetic for understanding and potentially treating iron transporter deficiencies.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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