Please use this identifier to cite or link to this item:
https://doi.org/10.1002/pro.33
DC Field | Value | |
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dc.title | Discovery of amyloid-beta aggregation inhibitors using an engineered assay for intracellular protein folding and solubility | |
dc.contributor.author | Lee, L.L. | |
dc.contributor.author | Ha, H. | |
dc.contributor.author | Chang, Y.-T. | |
dc.contributor.author | Delisa, M.P. | |
dc.date.accessioned | 2014-06-23T05:36:52Z | |
dc.date.available | 2014-06-23T05:36:52Z | |
dc.date.issued | 2009-02 | |
dc.identifier.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 | |
dc.identifier.issn | 09618368 | |
dc.identifier.uri | http://scholarbank.nus.edu.sg/handle/10635/75965 | |
dc.description.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. | |
dc.description.uri | http://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1002/pro.33 | |
dc.source | Scopus | |
dc.subject | Aggregation | |
dc.subject | Alzheimer's disease | |
dc.subject | Chemical biology | |
dc.subject | Chemical chaperone | |
dc.subject | Protein misfolding | |
dc.subject | Twin-arginine translocation | |
dc.type | Article | |
dc.contributor.department | CHEMISTRY | |
dc.description.doi | 10.1002/pro.33 | |
dc.description.sourcetitle | Protein Science | |
dc.description.volume | 18 | |
dc.description.issue | 2 | |
dc.description.page | 277-286 | |
dc.description.coden | PRCIE | |
dc.identifier.isiut | 000264941500003 | |
Appears in Collections: | Staff Publications |
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