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A Modular Ionophore Platform for Liver-Directed Copper Supplementation in Cells and Animals

  • Timothy A. Su
    Timothy A. Su
    Department of Chemistry, University of California, Berkeley, California 94720, United States
  • Diyala S. Shihadih
    Diyala S. Shihadih
    Department of Nutritional Sciences & Toxicology, University of California, Berkeley, California 94720, United States
  • Wendy Cao
    Wendy Cao
    Department of Chemistry, University of California, Berkeley, California 94720, United States
    More by Wendy Cao
  • Tyler C. Detomasi
    Tyler C. Detomasi
    Department of Chemistry, University of California, Berkeley, California 94720, United States
  • Marie C. Heffern
    Marie C. Heffern
    Department of Chemistry, University of California, Berkeley, California 94720, United States
  • Shang Jia
    Shang Jia
    Department of Chemistry, University of California, Berkeley, California 94720, United States
    More by Shang Jia
  • Andreas Stahl*
    Andreas Stahl
    Department of Nutritional Sciences & Toxicology, University of California, Berkeley, California 94720, United States
    *[email protected]
  • , and 
  • Christopher J. Chang*
    Christopher J. Chang
    Department of Chemistry, University of California, Berkeley, California 94720, United States
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, United States
    Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, United States
    Howard Hughes Medical Institute, University of California, Berkeley, California 94720, United States
    *[email protected]
Cite this: J. Am. Chem. Soc. 2018, 140, 42, 13764–13774
Publication Date (Web):October 15, 2018
https://doi.org/10.1021/jacs.8b08014
Copyright © 2018 American Chemical Society

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    Abstract

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    Copper deficiency is implicated in a variety of genetic, neurological, cardiovascular, and metabolic diseases. Current approaches for addressing copper deficiency rely on generic copper supplementation, which can potentially lead to detrimental off-target metal accumulation in unwanted tissues and subsequently trigger oxidative stress and damage cascades. Here we present a new modular platform for delivering metal ions in a tissue-specific manner and demonstrate liver-targeted copper supplementation as a proof of concept of this strategy. Specifically, we designed and synthesized an N-acetylgalactosamine-functionalized ionophore, Gal-Cu(gtsm), to serve as a copper-carrying “Trojan Horse” that targets liver-localized asialoglycoprotein receptors (ASGPRs) and releases copper only after being taken up by cells, where the reducing intracellular environment triggers copper release from the ionophore. We utilized a combination of bioluminescence imaging and inductively coupled plasma mass spectrometry assays to establish ASGPR-dependent copper accumulation with this reagent in both liver cell culture and mouse models with minimal toxicity. The modular nature of our synthetic approach presages that this platform can be expanded to deliver a broader range of metals to specific cells, tissues, and organs in a more directed manner to treat metal deficiency in disease.

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