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Gluco-1H-imidazole: a new class of azole-type β-glucosidase inhibitor

DOI: 10.1021/jacs.8b02399 DOI Help

Authors: Sybrin P. Schröder (Leiden Institute of Chemistry, Leiden University) , Liang Wu (The University of York) , Marta Artola (Leiden Institute of Chemistry, Leiden University) , Thomas Hansen (Leiden Institute of Chemistry, Leiden University) , Wendy A. Offen (University of York) , Maria J. Ferraz (Leiden Institute of Chemistry, Leiden University) , Kah-yee Li (Leiden Institute of Chemistry, Leiden University) , Johannes M. F. G. Aerts (Leiden Institute of Chemistry, Leiden University) , Gijsbert A. Van Der Marel (Leiden Institute of Chemistry, Leiden University) , Jeroen D. C. Codée (Leiden Institute of Chemistry, Leiden University) , Gideon J. Davies (University of York) , Herman S. Overkleeft (Leiden Institute of Chemistry, Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of The American Chemical Society

State: Published (Approved)
Published: March 2018
Diamond Proposal Number(s): 13587

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.

Subject Areas: Chemistry


Instruments: I03-Macromolecular Crystallography