@article{9c1e963a7af8497eb83997c2246c7d61,
title = "Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals",
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.",
author = "Grillo, {Anthony S.} and SantaMaria, {Anna M.} and Kafina, {Martin D.} and Cioffi, {Alexander G.} and Huston, {Nicholas C.} and Murui Han and Seo, {Young Ah} and Yien, {Yvette Y.} and Christopher Nardone and Menon, {Archita V.} and James Fan and Svoboda, {Dillon C.} and Anderson, {Jacob B.} and Hong, {John D.} and Nicolau, {Bruno G.} and Kiran Subedi and Gewirth, {Andrew A.} and Marianne Wessling-Resnick and Jonghan Kim and Paw, {Barry H.} and Burke, {Martin D.}",
note = "Funding Information: We gratefully acknowledge A. Ringel for assistance with zebrafish experiments and A. Li for assistance with octanol/water partition coefficients. We thank J. Hou, K. Muraglia, and R. Chorghade for independently repeating the results shown in Fig. 1C; fig. S2, A to C; Fig. 3, A and B; and fig. S9M. We further acknowledge D. Kosman and C. Philpott for providing yeast strains, L. Zon for the Tg(globinLCR:eGFP) transgenic zebrafish line, W. Boulanger for the generous gift of comenic acid, and J. Katzenellenbogen for use of a liquid scintillation counter. We thank M. Garrick, L. Garrick, and M. Fleming for helpful discussions. We thank D. Gray and the George L. Clark X-Ray Facility for x-ray analysis, M. Sivaguru and the Carl R. Woese Institute for Genomic Biology for assistance with confocal microscopy, B. Pilas and the Roy J. Carver Biotechnology Center for help with flow cytometry, and the University of Illinois School of Chemical Sciences microanalysis facility for ICP-MS and optical emission spectrometry. Support was provided by NIH through grants GM118185 (to M.D.B.), K01 DK106156 and F32 DK098866 (to Y.Y.Y.), R01 DK070838 and P01 HL032262 (to B.H.P.), K99ES024340 (to Y.A.S.), R01ES0146380 and R01DK064750 (to M.W.-R.), and R21EB023025 (to J.K.). M.D.B. also thanks the Howard Hughes Medical Institute (HHMI) for funding. A.S.G. was a NSF Graduate Fellow. J.B.A. was supported by the HHMI Exceptional Research Opportunities Program. M.D.B. and A.S.G. are inventors on patent application 62/101,706, submitted by the University of Illinois at Urbana-Champaign, which covers the use of small-molecule iron transporters to treat deficiencies of iron-transport proteins. Additional data reported in this paper are available in the supplementary materials. Crystallographic data for Fe(Hino)3 are available free of charge from the Cambridge Crystallographic Data Centre under reference CCDC 1536565. Publisher Copyright: {\textcopyright} 2017, American Association for the Advancement of Science. All rights reserved.",
year = "2017",
month = may,
day = "12",
doi = "10.1126/science.aah3862",
language = "English (US)",
volume = "356",
pages = "608--616",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6338",
}