학술논문
Minimizing higher-order aggregation maximizes iron mobilization by small molecules
Document Type
Article
Author
Blake, Andrew D.; Chao, Jianhua; SantaMaria, Anna M.; Ekaputri, Stella; Green, Kelsie J.; Brown, Samantha T.; Rakowski, Christopher K.; Choi, Eun-Kyung; Aring, Luisa; Chen, Peng-Jui; Snead, Nicholas M.; Matje, Douglas M.; Geng, Tao; Octaviani, Angela; Bailey, Keith; Hollenbach, Stanley J.; Fan, Timothy M.; Seo, Young-Ah; Burke, Martin D.
Source
Nature Chemical Biology; 20240101, Issue: Preprints p1-12, 12p
Subject
Language
ISSN
15524450; 15524469
Abstract
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, hinokitiol3: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.