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

• Kitakaze, Keisuke

• Taniuchi, Shusuke

• Kawano, Eri

• Hamada, Yoshimasa

• Miyake, Masato

• Oyadomari, Miho

• Kojima, Hirotatsu

• Kosako, Hidetaka

• Kuribara, Tomoko

• Yoshida, Suguru

• Hosoya, Takamitsu

• Oyadomari, Seiichi

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.

Journal

• eLife

  eLife 8 e43302-, 2019-12-17

  eLife Sciences Publications

Keywords

• General Immunology and Microbiology
• General Biochemistry, Genetics and Molecular Biology
• General Medicine
• General Neuroscience

Details

• CRID: 1050569094120038656
• NII Article ID: 120006941114
• ISSN: 2050084X
• DOI: 10.7554/elife.43302
• Web Site: http://repo.lib.tokushima-u.ac.jp/115090
• Web Site: https://cdn.elifesciences.org/articles/43302/elife-43302-v2.pdf
• Web Site: https://cdn.elifesciences.org/articles/43302/elife-43302-v2.xml
• Web Site: https://elifesciences.org/articles/43302
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN