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    A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of Sirtuin 2 Deacetylase

    Taylor, D.M. and Balabadra, U. and Xiang, Z. and Woodman, B. and Meade, S. and Amore, A. and Maxwell, M.M. and Reeves, S. and Bates, G.P. and Luthi-Carter, R. and Lowden, Philip A.S. and Kazantsev, A.G. (2011) A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of Sirtuin 2 Deacetylase. ACS Chemical Biology 6 (6), pp. 540-546. ISSN 1554-8929.

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    Abstract

    Sirtuin 2 (SIRT2) deacetylase-dependent inhibition mediates neuroprotective reduction of cholesterol biosynthesis in an in vitro Huntington’s disease model. This study sought to identify the first brain-permeable SIRT2 inhibitor and to characterize its cholesterol-reducing properties in neuronal models. Using biochemical sirtuin deacetylation assays, we screened a brain-permeable in silico compound library, yielding 3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide as the most potent and selective SIRT2 inhibitor. Pharmacokinetic studies demonstrated brain-permeability but limited metabolic stability of the selected candidate. In accordance with previous observations, this SIRT2 inhibitor stimulated cytoplasmic retention of sterol regulatory element binding protein-2 and subsequent transcriptional downregulation of cholesterol biosynthesis genes, resulting in reduced total cholesterol in primary striatal neurons. Furthermore, the identified inhibitor reduced cholesterol in cultured naïve neuronal cells and brain slices from wild-type mice. The outcome of this study provides a clear opportunity for lead optimization and drug development, targeting metabolic dysfunctions in CNS disorders where abnormal cholesterol homeostasis is implicated.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 09 Jan 2013 13:43
    Last Modified: 06 Dec 2016 10:37
    URI: http://eprints.bbk.ac.uk/id/eprint/5720

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