서영아 (University of Michigan)

한빛사논문

조회288

University of Michigan

CV File 778 kb

Nat. Chem. Biol., Apr 25 2024, | https://doi.org/10.1038/s41589-024-01596-3 Minimizing higher-order aggregation maximizes iron mobilization by small molecules

Andrew D. Blake ¹, Jianhua Chao ², Anna M. SantaMaria ¹, Stella Ekaputri ¹, Kelsie J. Green ³, Samantha T. Brown ³, Christopher K. Rakowski ³, Eun-Kyung Choi ⁴, Luisa Aring ⁴, Peng-Jui Chen ³, Nicholas M. Snead ², Douglas M. Matje ², Tao Geng², Angela Octaviani ², Keith Bailey⁵, Stanley J. Hollenbach², Timothy M. Fan^6,7, Young-Ah Seo ⁴ & Martin D. Burke ^1,3,7,8,9,10

¹Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

²Ambys Medicines, South San Francisco, CA, USA.

³Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

⁴Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.

⁵Alnylam Pharmaceuticals, Inc., Cambridge, MA, USA.

⁶Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

⁷Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

⁸Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

⁹Molecule Maker Lab Institute, Arnold and Mabel Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

¹⁰Carle Illinois College of Medicine, Champaign, IL, USA.

Corresponding authors : Correspondence to Young-Ah Seo or Martin D. Burke.

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, 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.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-05-02)
연구진국외 연구진
분야 생명과학 > 생리학

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