Kitakaze, Keisuke Tokushima University|Kawasaki Medical School
Taniuchi, Shusuke Tokushima University
Kawano, Eri Tokushima University
Kojima, Hirotatsu The University of Tokyo
Kuribara, Tomoko Tokyo Medical and Dental University
Yoshida, Suguru Tokyo Medical and Dental University
Hosoya, Takamitsu Tokyo Medical and Dental University
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.
eLife Sciences Publications
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