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Identification of a small molecule that selectively activates alpha-synuclein translational expression.


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2011 Feb 4 [updated 2011 Feb 15].


Alpha-synuclein is a protein implicated in the pathogenesis of neurodegenerative alpha-synucleinopathies including Parkinson’s disease (PD), the most prevalent movement disorder in humans. Evidence suggests that misregulation of alpha-synuclein translation plays a clear role in the pathology of this disease. We report the outcome of a high-throughput chemical library screen to identify novel, nontoxic, and selective small-molecule activators of alpha-synuclein expression, which will aid understanding of the role of alpha-synuclein in PD and other neurodegenerative diseases. Of the 303,224-screened compounds, 22 hits were identified as activators of alpha-synuclein expression and subsequently validated to confirm their activation activity and selectivity. One of these compounds (ML163) displayed greater than 100-fold selective activation of alpha-synuclein expression compared with a related system and is inactive in a control system at the highest tested dose. Our results indicate that ML163 has a drug-like structure with no obvious chemical liabilities, excellent solubility, and stability in aqueous conditions. This new probe should be very useful in future cell-based investigations and in vivo studies of alpha-synuclein expression.

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