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

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Author(s)

  • Daniël Lahav
  • Bing Liu
  • Richard J. B. H. N. van den Berg
  • Adrianus M. C. H. van den Nieuwendijk
  • Tom Wennekes
  • Amar T. Ghisaidoobe
  • Imogen Breen
  • Maria J. Ferraz
  • Chi-Lin Kuo
  • Liang Wu
  • Paul P. Geurink
  • Huib Ovaa
  • Gijsbert A. van der Marel
  • Mario van der Stelt
  • Rolf G. Boot
  • Gideon J. Davies
  • Johannes M. F. G. Aerts
  • Herman S. Overkleeft

Department/unit(s)

Publication details

JournalJournal of the American Chemical Society
DateAccepted/In press - 22 Sep 2017
DateE-pub ahead of print - 22 Sep 2017
DatePublished (current) - 11 Oct 2017
Issue number40
Volume139
Number of pages6
Pages (from-to)14192-14197
Early online date22/09/17
Original languageEnglish

Abstract

Human nonlysosomal 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.

Bibliographical note

© 2017 American Chemical Society

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