Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity

  1. Keisuke Kitakaze
  2. Shusuke Taniuchi
  3. Eri Kawano
  4. Yoshimasa Hamada
  5. Masato Miyake
  6. Miho Oyadomari
  7. Hirotatsu Kojima
  8. Hidetaka Kosako
  9. Tomoko Kuribara
  10. Suguru Yoshida
  11. Takamitsu Hosoya
  12. Seiichi Oyadomari  Is a corresponding author
  1. Tokushima University, Japan
  2. The University of Tokyo, Japan
  3. Tokyo Medical and Dental University (TMDU), Japan

Abstract

The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Here, we identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen. Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. Finally, IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, our data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Keisuke Kitakaze

    Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4852-1257
  2. Shusuke Taniuchi

    Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Eri Kawano

    Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Yoshimasa Hamada

    Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Masato Miyake

    Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Miho Oyadomari

    Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Hirotatsu Kojima

    Drug Discovery Initiative (DDI), The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Hidetaka Kosako

    Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Tomoko Kuribara

    Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Suguru Yoshida

    Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5888-9330
  11. Takamitsu Hosoya

    Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  12. Seiichi Oyadomari

    Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
    For correspondence
    oyadomar@tokushima-u.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6766-1485

Funding

Japan Agency for Medical Research and Development (JP18nk0101336)

  • Seiichi Oyadomari

Japan Agency for Medical Research and Development (JP17am0101086)

  • Hirotatsu Kojima

Platform Project for Supporting Drug Discovery and Life Science Research, Basis for Supporting Innovative Drug Discovery and Life Science Research (JP18am0101098)

  • Takamitsu Hosoya

a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (16H05222)

  • Seiichi Oyadomari

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Matthew D Shoulders, Massachusetts Institute of Technology, United States

Publication history

  1. Received: November 1, 2018
  2. Accepted: November 24, 2019
  3. Accepted Manuscript published: December 17, 2019 (version 1)
  4. Version of Record published: December 19, 2019 (version 2)

Copyright

© 2019, Kitakaze et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Keisuke Kitakaze
  2. Shusuke Taniuchi
  3. Eri Kawano
  4. Yoshimasa Hamada
  5. Masato Miyake
  6. Miho Oyadomari
  7. Hirotatsu Kojima
  8. Hidetaka Kosako
  9. Tomoko Kuribara
  10. Suguru Yoshida
  11. Takamitsu Hosoya
  12. Seiichi Oyadomari
(2019)
Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity
eLife 8:e43302.
https://doi.org/10.7554/eLife.43302

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