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Correctors of Protein Trafficking Defects Identified by a Novel High-Throughput Screening Assay

✍ Scribed by Graeme W. Carlile ; Renaud Robert ; Donglei Zhang; Katrina A. Teske; Yishan Luo; John W. Hanrahan; David Y. Thomas

Publisher
John Wiley and Sons
Year
2007
Tongue
English
Weight
713 KB
Volume
8
Category
Article
ISSN
1439-4227

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✦ Synopsis

Abstract

High‐throughput small‐molecule screens hold great promise for identifying compounds with potential therapeutic value in the treatment of protein‐trafficking diseases such as cystic fibrosis (CF) and nephrogenic diabetes insipidus (NDI). The approach usually involves expressing the mutant form of the gene in cells and assaying function in a multiwell format when cells are exposed to libraries of compounds. Although such functional assays are useful, they do not directly test the ability of a compound to correct defective trafficking of the protein. To address this we have developed a novel corrector‐screening assay for CF, in which the appearance of the mutant protein at the cell surface is measured. We used this assay to screen a library of 2000 compounds and have isolated several classes of trafficking correctors that had not previously been identified. This novel screening approach to protein‐trafficking diseases is robust and general, and could enable the selection of molecules that could be translated rapidly to a clinical setting.

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