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

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-relat...

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Autores principales: Kitakaze, Keisuke, Taniuchi, Shusuke, Kawano, Eri, Hamada, Yoshimasa, Miyake, Masato, Oyadomari, Miho, Kojima, Hirotatsu, Kosako, Hidetaka, Kuribara, Tomoko, Yoshida, Suguru, Hosoya, Takamitsu, Oyadomari, Seiichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922633/
https://www.ncbi.nlm.nih.gov/pubmed/31843052
http://dx.doi.org/10.7554/eLife.43302
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author Kitakaze, Keisuke
Taniuchi, Shusuke
Kawano, Eri
Hamada, Yoshimasa
Miyake, Masato
Oyadomari, Miho
Kojima, Hirotatsu
Kosako, Hidetaka
Kuribara, Tomoko
Yoshida, Suguru
Hosoya, Takamitsu
Oyadomari, Seiichi
author_facet Kitakaze, Keisuke
Taniuchi, Shusuke
Kawano, Eri
Hamada, Yoshimasa
Miyake, Masato
Oyadomari, Miho
Kojima, Hirotatsu
Kosako, Hidetaka
Kuribara, Tomoko
Yoshida, Suguru
Hosoya, Takamitsu
Oyadomari, Seiichi
author_sort Kitakaze, Keisuke
collection PubMed
description 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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spelling pubmed-69226332019-12-23 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 eLife Biochemistry and Chemical Biology 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, Ltd 2019-12-17 /pmc/articles/PMC6922633/ /pubmed/31843052 http://dx.doi.org/10.7554/eLife.43302 Text en © 2019, Kitakaze et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Kitakaze, Keisuke
Taniuchi, Shusuke
Kawano, Eri
Hamada, Yoshimasa
Miyake, Masato
Oyadomari, Miho
Kojima, Hirotatsu
Kosako, Hidetaka
Kuribara, Tomoko
Yoshida, Suguru
Hosoya, Takamitsu
Oyadomari, Seiichi
Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity
title Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity
title_full Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity
title_fullStr Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity
title_full_unstemmed Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity
title_short Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity
title_sort cell-based hts identifies a chemical chaperone for preventing er protein aggregation and proteotoxicity
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922633/
https://www.ncbi.nlm.nih.gov/pubmed/31843052
http://dx.doi.org/10.7554/eLife.43302
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