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    Dihydropyrimidine-thiones and clioquinol synergize to target beta-amyloid cellular pathologies through a metal-dependent mechanism

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    Date Issued
    2017-09-01
    Publisher Version
    10.1021/acschemneuro.7b00187
    Author(s)
    Tardiff, Daniel F.
    Brown, Lauren E.
    Yan, Xiaohui
    Trilles, Richard
    Jui, Nathan T.
    Barrasa, M. Inmaculada
    Caldwell, Kim A.
    Caldwell, Guy A.
    Schaus, Scott E.
    Lindquist, Susan
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    Permanent Link
    https://hdl.handle.net/2144/40468
    OA Version
    Accepted manuscript
    Citation (published version)
    Daniel F Tardiff, Lauren E Brown, Xiaohui Yan, Richard Trilles, Nathan T Jui, M Inmaculada Barrasa, Kim A Caldwell, Guy A Caldwell, Scott E Schaus, Susan Lindquist. 2017. "Dihydropyrimidine-Thiones and Clioquinol Synergize To Target beta-Amyloid Cellular Pathologies through a Metal-Dependent Mechanism." ACS CHEMICAL NEUROSCIENCE, Volume 8, Issue 9, pp. 2039 - 2055 (17). https://doi.org/10.1021/acschemneuro.7b00187
    Abstract
    The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer’s disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action. The bioactivity was distinct, however, from that of the 8-hydroxyquinoline clioquinol (CQ). These structurally dissimilar compounds strongly synergized at concentrations otherwise not competent to reduce toxicity. Cotreatment ameliorated Aβ toxicity by reducing Aβ levels and restoring functional vesicle trafficking. Notably, these low doses significantly reduced deleterious off-target effects caused by CQ on mitochondria at higher concentrations. Both single and combinatorial treatments also reduced death of neurons expressing Aβ in a nematode, indicating that DHPM-thiones target a conserved protective mechanism. Furthermore, this conserved activity suggests that expression of the Aβ peptide causes similar cellular pathologies from yeast to neurons. Our identification of a new cytoprotective scaffold that requires metal-binding underscores the critical role of metal phenomenology in mediating Aβ toxicity. Additionally, our findings demonstrate the valuable potential of synergistic compounds to enhance on-target activities, while mitigating deleterious off-target effects. The identification and prosecution of synergistic compounds could prove useful for developing AD therapeutics where combination therapies may be required to antagonize diverse pathologies.
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    • CAS: Chemistry: Scholarly Papers [120]
    • BU Open Access Articles [3670]


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