Xylose‐Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase. (13th September 2021)

• Record Type: Journal Article
• Authors: Su, Qin; Schröder, Sybrin P.; Lelieveld, Lindsey T.; Ferraz, Maria J.; Verhoek, Marri; Boot, Rolf G.; Overkleeft, Herman S.; Aerts, Johannes M. F. G.; Artola, Marta; Kuo, Chi‐Lin
• Is Part Of: Chembiochem. Volume 22:Number 21(2021)
• Page Start: 3090
• Page End: 3098
• Publication Date: 2021-09-13
• Subjects: activity-based probe -- cyclophellitol -- conduritol B-epoxide -- Gaucher disease -- glucocerebrosidase -- xylose; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202100396
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Glucocerebrosidase (GBA), a lysosomal retaining β‐d ‐glucosidase, has recently been shown to hydrolyze β‐d ‐xylosides and to transxylosylate cholesterol. Genetic defects in GBA cause the lysosomal storage disorder Gaucher disease (GD), and also constitute a risk factor for developing Parkinson's disease. GBA and other retaining glycosidases can be selectively visualized by activity‐based protein profiling (ABPP) using fluorescent probes composed of a cyclophellitol scaffold having a configuration tailored to the targeted glycosidase family. GBA processes β‐d ‐xylosides in addition to β‐d ‐glucosides, this in contrast to the other two mammalian cellular retaining β‐d ‐glucosidases, GBA2 and GBA3. Here we show that the xylopyranose preference also holds up for covalent inhibitors: xylose‐configured cyclophellitol and cyclophellitol aziridines selectively react with GBA over GBA2 and GBA3 in vitro and in vivo, and that the xylose‐configured cyclophellitol is more potent and more selective for GBA than the classical GBA inhibitor, conduritol B‐epoxide (CBE). Both xylose‐configured cyclophellitol and cyclophellitol aziridine cause accumulation of glucosylsphingosine in zebrafish embryo, a characteristic hallmark of GD, and we conclude that these compounds are well suited for creating such chemically induced GD models. Abstract : New selective GBA inhibitor : We show that the β‐d ‐xylose configured epoxide and aziridine are potent selective inhibitors towards GBA in vitro and in vivo, and their selectivity and inhibitory effect towards GBA are superior to the widely used GBA inhibitor Conduritol B‐epoxide (CBE).