Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity
- Tokushima University, Japan
- The University of Tokyo, Japan
- 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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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.
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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Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity
eLife 8:e43302.
https://doi.org/10.7554/eLife.43302
