A Brain-Permeable Small Molecule Reduces Neuronal Cholesterol by Inhibiting Activity of Sirtuin 2 Deacetylase
2011; American Chemical Society; Volume: 6; Issue: 6 Linguagem: Inglês
10.1021/cb100376q
ISSN1554-8937
AutoresDavid Taylor, Uma Balabadra, Zhongmin Xiang, Ben Woodman, Sarah Meade, Allison Amore, Michele M. Maxwell, Steven A. Reeves, Gillian P. Bates, Ruth Luthi‐Carter, Philip A. S. Lowden, Aleksey Kazantsev,
Tópico(s)Neuroscience and Neuropharmacology Research
ResumoSirtuin 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.
Referência(s)