文章基本信息

标题：Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase
本地全文：下载
作者：Evgeny Shlevkov ; Paramasivam Murugan ; Dan Montagna 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：1
页码：1-39
DOI：10.1016/j.isci.2021.103650
语种：English
出版社：Elsevier
摘要：SummaryPharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for the treatment of Parkinson’s disease. Here we identify several compounds that enhance the activity of wildtype Parkin in the presence of phospho-ubiquitin and act as positive allosteric modulators (PAMs). While these compounds activate Parkin in a series of biochemical assays, they do not act by thermally destabilizing Parkin and fail to enhance the Parkin translocation rate to mitochondria or to enact mitophagy in cell-based assays. We conclude that in the context of the cellular milieu the therapeutic window to pharmacologically activate Parkin is very narrow.Graphical abstractDisplay OmittedHighlights•A biochemical FRET-based HTS identified compounds that activate wildtype Parkin•A Ub-charging assay confirms results and suggests they act as PAMs to activate Parkin•Compounds do not enhance Parkin’s mito translocation or enhance mitophagy in cells•Data suggests a model of activation after the REP domain release, limiting pharmacologyChemistry; Biochemistry; Biochemistry Applications