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 language | English |
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Pages (from-to) | 5045-5048 |
Number of pages | 4 |
Journal | Journal of the American Chemical Society |
Volume | 140 |
Issue number | 15 |
DOIs | |
Publication status | Published - 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.
Funders | Funder number |
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NWO-CW | |
Netherlands Organization for Scientific Research | |
Seventh Framework Programme | 322942, 290836 |
Sanofi Genzyme | mx-13587 |
European Research Council |