Gluco-1 H -imidazole: A New Class of Azole-Type β-Glucosidase Inhibitor

Sybrin P. Schröder, Liang Wu, Marta Artola, Thomas Hansen, Wendy A. Offen, Maria J. Ferraz, Kah Yee Li, Johannes M.F.G. Aerts, Gijsbert A. Van Der Marel, Jeroen D.C. Codée, Gideon J. Davies, Herman S. Overkleeft*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1H-imidazoles. Here, we present gluco-1H-imidazole, a gluco-azole bearing a 1H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors.

Original languageEnglish
Pages (from-to)5045-5048
Number of pages4
JournalJournal of the American Chemical Society
Volume140
Issue number15
DOIs
Publication statusPublished - 18 Apr 2018

Funding

We thank The Netherlands Organization for Scientific Research (NWO-CW ChemThem grant to J.M.F.G.A. and H.S.O.), the European Research Council (ERC-2011-AdG-290836 “Chembiosphing” to H.S.O., and ERC-2012-AdG-322942 “Glycopoise” to G.J.D.), Sanofi Genzyme (research grant to J.M.F.G.A. and H.S.O. and postdoctoral contract to M.A.) and Diamond Light Source (beamline I03, proposal number mx-13587) for provision of data collection facilities. G.J.D. thanks the Royal Society for the Ken Murray Research Professorship.

FundersFunder number
NWO-CW
Netherlands Organization for Scientific Research
Seventh Framework Programme322942, 290836
Sanofi Genzymemx-13587
European Research Council

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