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Title 

Discovery of (2-aminophenyl)methanol as a new molecular chaperone that rescues the localization of P123S mutant pendrin stably expressed in HEK293 cells

Authors 

W NabeyamaK IshiharaHyun Seung BanH WadaH Nakamura

Publisher 

Elsevier

Issue Date 

2017

Citation 

Bioorganic & Medicinal Chemistry

Keywords 

Hearing loss LocalizationMisfoldingMolecular chaperoneMorphological analysisP123S mutantPendrin

Abstract 

Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsight™. Morphological analysis of stained cells in each well of 96-well plates yielded six compounds in the compound library. Furthermore, fluorescence intensity analysis of the intracellular localization of P123S mutant pendrin in HEK293 cells using FLUOVIEW™ and cytotoxicity experiments revealed that (2-aminophenyl)methanol 8 is the most promising molecular chaperone to rescue P123S mutant pendrin: the plasma membrane (M)/cytoplasm (C) ratios are 1.5 and 0.9 at the concentrations of 0.3 and 0.1?mM, respectively, and a sustained effect was observed 12?h after removal of the compound from the cell medium. Because the M/C ratio of salicylate, which was previously discovered as a molecular chaperone of P123S mutant pendrin, was approximately 1 at 10?mM concentration and a sustained effect was not observed even at 6?h, (2-aminophenyl)methanol 8 was 100 times more potent and exhibited a longer sustained effect than salicylate. These findings suggest that (2-aminophenyl)methanol 8 is an attractive candidate for therapeutic agent for Pendred syndrome patients.

ISSN 

0968-0896

Link 

http://dx.doi.org/10.1016/j.bmc.2017.03.024

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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