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|Title:||Discovery of amyloid-beta aggregation inhibitors using an engineered assay for intracellular protein folding and solubility||Authors:||Lee, L.L.
|Issue Date:||Feb-2009||Citation:||Lee, L.L., Ha, H., Chang, Y.-T., Delisa, M.P. (2009-02). Discovery of amyloid-beta aggregation inhibitors using an engineered assay for intracellular protein folding and solubility. Protein Science 18 (2) : 277-286. ScholarBank@NUS Repository. https://doi.org/10.1002/pro.33||Abstract:||Genetic and biochemical studies suggest that Alzheimer's disease (AD) is caused by a series of events initiated by the production and subsequent aggregation of the Alzheimer's amyloid β peptide (Aβ), the so-called amyloid cascade hypothesis. Thus, a logical approach to treating AD is the development of small molecule inhibitors that either block the proteases that generate Aβ from its precursor (β- and γ-secretases) or interrupt and/or reverse Aβ aggregation. To identify potent inhibitors of Aβ aggregation, we have developed a high-throughput screen based on an earlier selection that effectively paired the folding quality control feature of the Escherichia coli Tat protein export system with aggregation of the 42-residue AD pathogenesis effecter Aβ42. Specifically, a tripartite fusion between the Tat-dependent export signal ssTorA, the Aβ42 peptide and the β-lactamase (Bla) reporter enzyme was found to be export incompetent due to aggregation of the Aβ 42 moiety. Here, we reasoned that small, cell-permeable molecules that inhibited Aβ 42 aggregation would render the ssTorA-Aβ42-Bla chimera competent for Tat export to the periplasm where Bla is active against β-lactam antibiotics such as ampicillin. Using a fluorescence-based version of our assay, we screened a library of triazine derivatives and isolated four nontoxic, cell-permeable compounds that promoted efficient Tat-dependent export of ssTorA-Aβ42-Bla. Each of these was subsequently shown to be a bona fide inhibitor of Aβ42 aggregation using a standard thioflavin T fibrillization assay, thereby highlighting the utility of our bacterial assay as a useful screen for antiaggregation factors under physiological conditions. © 2008 The Protein Society.||Source Title:||Protein Science||URI:||http://scholarbank.nus.edu.sg/handle/10635/75965||ISSN:||09618368||DOI:||10.1002/pro.33|
|Appears in Collections:||Staff Publications|
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