2. Academic Validation
  3. Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals

Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals

  • Science. 2017 May 12;356(6338):608-616. doi: 10.1126/science.aah3862.
Anthony S Grillo 1,  Anna M SantaMaria 2,  Martin D Kafina 3,  Alexander G Cioffi 2,  Nicholas C Huston 3,  Murui Han 4,  Young Ah Seo 5,  Yvette Y Yien 3,  Christopher Nardone 2,  Archita V Menon 4,  James Fan 1,  Dillon C Svoboda 2,  Jacob B Anderson 1,  John D Hong 1,  Bruno G Nicolau 1,  Kiran Subedi 1,  Andrew A Gewirth 1,  Marianne Wessling-Resnick 6,  Jonghan Kim 7,  Barry H Paw 8 9 10,  Martin D Burke 11 2 12
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 2 Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 3 Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • 5 Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
  • 6 Department of Genetic and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. wessling@hsph.harvard.edu j.kim@neu.edu bpaw@rics.bwh.harvard.edu mdburke@illinois.edu.
  • 7 Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA. wessling@hsph.harvard.edu j.kim@neu.edu bpaw@rics.bwh.harvard.edu mdburke@illinois.edu.
  • 8 Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. wessling@hsph.harvard.edu j.kim@neu.edu bpaw@rics.bwh.harvard.edu mdburke@illinois.edu.
  • 9 Division of Hematology-Oncology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 10 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 11 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. wessling@hsph.harvard.edu j.kim@neu.edu bpaw@rics.bwh.harvard.edu mdburke@illinois.edu.
  • 12 Carle-Illinois College of Medicine, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA.
PMID: 28495746 DOI: 10.1126/science.aah3862
Abstract

Multiple human diseases ensue from a hereditary or acquired deficiency of iron-transporting protein function that diminishes transmembrane iron flux in distinct sites and directions. Because other iron-transport proteins remain active, labile iron gradients build up across the corresponding protein-deficient membranes. Here we report that a small-molecule natural product, hinokitiol, can harness such gradients to restore iron transport into, within, and/or out of cells. The same compound promotes gut iron absorption in DMT1-deficient rats and ferroportin-deficient mice, as well as hemoglobinization in DMT1- and mitoferrin-deficient zebrafish. These findings illuminate a general mechanistic framework for small molecule-mediated site- and direction-selective restoration of iron transport. They also suggest that small molecules that partially mimic the function of missing protein transporters of iron, and possibly other ions, may have potential in treating human diseases.

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