Identification of a chemical chaperone for mitigating protein aggregation and proteotoxicity during endoplasmic reticulum stress

Abstract

Molecular chaperones are proteins that assist the conformational folding or unfolding of proteins to prevent aggregate into non-functional structures. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is called ER stress. The cell has an adaptive system against ER stress called the unfolded protein response (UPR) that prevents the aggregation of unfolded and incompletely folded proteins. Failure of the UPR has serious pathological consequences, including diabetes, neurodegenerative diseases, and cancer. Chemical chaperones are small compounds that support protein folding and suppress aggregation, and gathering attention as potential therapeutic strategies for ER stress-related diseases. Although several chemical chaperones have shown therapeutic benefits, due to limitations including high concentration treatment of currently known chemical chaperones, identifying novel chemical chaperones is desirable. In this study, we performed a high-throughput screen with a UPR signalling reporter cell and identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones. IBTs directly bound to secreted or membrane proteins and inhibited protein aggregation during ER stress. Furthermore, IBTs significantly prevented cell death caused by chemically induced ER stress and by an aggression-prone mutant prion protein. These results indicate that IBTs are chemical chaperones that strongly suppresses protein aggregation during ER stress, and is expected to be applied to therapeutic research for various ER stress-related diseases.