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A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Non-lysosomal Glucosylceramidase.

著者 Lahav D , Liu B , van den Berg RJBHN , van den Nieuwendijk AMCH , Wennekes T , Ghisaidoobe AT , Breen I , Ferraz MJ , Kuo CL , Wu L , Geurink PP , Ovaa H , van der Marel GA , van der Stelt M , Boot RG , Davies GJ , Aerts JMFG , Overkleeft HS
J Am Chem Soc.2017 Sep 22 ; ():.
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Human non-lysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA) and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.
PMID: 28937220 [PubMed - as supplied by publisher]
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