Assessment of Partially Deoxygenated Deoxynojirimycin Derivates as Glucosylceramide Synthase Inhibitors : Letter

R.J.B.H.N. Berg, T. Wennekes, A. Ghisaidoobe, W.E. Donker-Koopman, A. Strijland, R.G. Boot, G.A. van der Marel, J.M.F.G. Aerts, H.S. Overkleeft

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Scopus)

Abstract

Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies, including type 2 diabetes. The clinical drug N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with Zavesca) for other glycoprocessing enzymes, in particular those hydrolases that act on glucosylceramide.
Original languageEnglish
Pages (from-to)519-522
JournalACS Medicical Chemistry Letters
Volume2
Issue number7
DOIs
Publication statusPublished - 2011

Keywords

  • chiral building-block
  • glycolipid biosynthesis
  • insulin sensitivity
  • nonlysosomal glucosylceramidase
  • glycosyltransferase inhibitors
  • 1-deoxynojirimycin derivatives
  • n-butyldeoxynojirimycin
  • asymmetric-synthesis
  • storage disorders
  • gaucher disease

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