title: Exploring functional cyclophellitol analogues as human retaining beta-glucosidase inhibitors.
abstract: The natural product, cyclophellitol and its aziridine analogue are potent mechanism-based retaining β-glucosidase inhibitors. In this paper we explore the inhibitory potency of a number of cyclophellitol analogues against the three human retaining β-glucosidases, GBA, GBA2 and GBA3. We demonstrate that N-alkyl cyclophellitol aziridine is at least equally potent in inhibiting the enzymes evaluated as its N-acyl congener, whereas the N-sulfonyl analogue is a considerably weaker inhibitor. Our results complement the literature on the inhibitory potency of cyclophellitol analogues and hold promise for the future design of more effective activity-based retaining glycosidase probes with respect to probe stability in physiological media.
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, the Netherlands. h.s.overkleeft@chem.leidenuniv.nl.
authors.forename: Kah-Yee
authors.initials: KY
authors.lastname: Li
authors.forename: Jianbing
authors.initials: J
authors.lastname: Jiang
authors.forename: Martin D
authors.initials: MD
authors.lastname: Witte
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Kallemeijn
authors.forename: Wilma E
authors.initials: WE
authors.lastname: Donker-Koopman
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Jeroen D C
authors.initials: JD
authors.lastname: Codée
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
mesh_terms: D003511:Cyclohexanols / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors*
chemical_list: D003511:Cyclohexanols; D004791:Enzyme Inhibitors; C063285:cyclophellitol; D001617:beta-Glucosidase