Leiden University Scholarly Publications

Fan, J.; Hale V.L.; Lelieveld, L.T.; Whitworth, L.J.; Busch-Nentwich, E.M.; Troll, M.; ... ; Ramakrishnan, L. 2023

Gaucher disease protects against tuberculosis

Article / Letter to editor

open access

Su, Q.; Schroder, S.P.; Lelieveld, L.T.; Guimaraes Da Lomba Ferraz, M.J.; Verhoek, M.; Boot, R.G.; ... ; Kuo, C.-L. 2023

Corrigendum: Xylose-configured cyclophellitols as selective inhibitors for glucocerebrosidase

Article / Letter to editor

open access

2023-08-02T00:00:00Z

Kok, K.; Kuo, C.L.; Katzy, R.E.; Lelieveld, L.T.; Wu, L.; Roig-Zamboni, V.; ... ; Artola Perez de Azanza, M.E. 2022

1,6-epi-Cyclophellitol cyclosulfamidate is a bona fide lysosomal α-glucosidase stabilizer for the treatment of Pompe disease

Article / Letter to editor

open access

α-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as a new class of... Show moreα-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as a new class of reversible α-glucosidase inhibitors that displays enzyme inhibitory activity by virtue of its conformational mimicry of the substrate when bound in the Michaelis complex. The α-d-glc-configured cyclophellitol cyclosulfamidate 4 binds in a competitive manner the human lysosomal acid α-glucosidase (GAA), ER α-glucosidases, and, at higher concentrations, intestinal α-glucosidases, displaying an excellent selectivity over the human β-glucosidases GBA and GBA2 and glucosylceramide synthase (GCS). Cyclosulfamidate 4 stabilizes recombinant human GAA (rhGAA, alglucosidase alfa, Myozyme) in cell medium and plasma and facilitates enzyme trafficking to lysosomes. It stabilizes rhGAA more effectively than existing small-molecule chaperones and does so in vitro, in cellulo, and in vivo in zebrafish, thus representing a promising therapeutic alternative to Miglustat for Pompe disease. Show less

Su, Q.; Schröder, S.P.; Lelieveld, L.T.; Ferraz, M.J.; Verhoek, M.; Boot, R.G.; ... ; Kuo, C.L. 2021

Xylose-configured cyclophellitols as selective inhibitors for glucocerebrosidase

Article / Letter to editor

open access

Glucocerebrosidase (GBA), a lysosomal retaining beta-d-glucosidase, has recently been shown to hydrolyze beta-d-xylosides and to transxylosylate cholesterol. Genetic defects in GBA cause the... Show moreGlucocerebrosidase (GBA), a lysosomal retaining beta-d-glucosidase, has recently been shown to hydrolyze beta-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 beta-d-xylosides in addition to beta-d-glucosides, this in contrast to the other two mammalian cellular retaining beta-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. Show less

Aerts, J.M.F.G.; Kuo, C.L.; Lelieveld, L.T.; Boer, D.E.C.; Lienden, M.J.C. van der; Overkleeft, H.S.; Artola, M. 2019

Glycosphingolipids and lysosomal storage disorders as illustrated by gaucher disease

Article / Letter to editor

open access

Glycosphingolipids are important building blocks of the outer leaflet of the cell membrane. They are continuously recycled, involving fragmentation inside lysosomes by glycosidases. Inherited... Show moreGlycosphingolipids are important building blocks of the outer leaflet of the cell membrane. They are continuously recycled, involving fragmentation inside lysosomes by glycosidases. Inherited defects in degradation cause lysosomal glycosphingolipid storage disorders. The relatively common glycosphingolipidosis Gaucher disease is highlighted here to discuss new insights in the molecular basis and pathophysiology of glycosphingolipidoses reached by fundamental research increasingly using chemical biology tools. We discuss improvements in the detection of glycosphingolipid metabolites by mass spectrometry and review new developments in laboratory diagnosis and disease monitoring as well as therapeutic interventions. Show less

Artola, M.; Kuo, C.L.; Lelieveld, L.T.; Rowland, R.J.; Marel, G.A. van der; Codée, J.D.C.; ... ; Overkleeft, H.S. 2019

Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish

Article / Letter to editor

open access

Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and deficiency in GBA constitutes the largest known genetic risk factor for Parkinson's... Show moreGaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and deficiency in GBA constitutes the largest known genetic risk factor for Parkinson's disease. In the past, animal models of Gaucher disease have been generated by treatment with the mechanism-based GBA inhibitors, conduritol B epoxide (CBE) and cyclophellitol. Both compounds however also target other retaining glycosidases, rendering genera-tion and interpretation of such chemical knockout models complicated. Here we demonstrate that cyclophellitol derivatives carrying a bulky hydrophobic substituent at C8 are potent and selective GBA inhibitors and that an unambiguous Gaucher animal model can be readily generated by treatment of zebrafish with these. Show less

Kuo, C.L.; Kallemeijn, W.W.; Lelieveld, L.T.; Mirzaian, M.; Zoutendijk, I.; Vardi, A.; ... ; Artola, M. 2019

In vivo inactivation of glycosidases by conduritol B epoxide and cyclophellitol as revealed by activity-based protein profiling

Article / Letter to editor

open access

Glucocerebrosidase (GBA) is a lysosomal β-glucosidase degrading glucosylceramide. Its deficiency causes Gaucher disease (GD), a common lysosomal storage disorder. Carrying a genetic abnormality in... Show moreGlucocerebrosidase (GBA) is a lysosomal β-glucosidase degrading glucosylceramide. Its deficiency causes Gaucher disease (GD), a common lysosomal storage disorder. Carrying a genetic abnormality in GBA constitutes at present the largest genetic risk factor for Parkinson's disease (PD). Conduritol B epoxide (CBE), a mechanism-based irreversible inhibitor of GBA, is used to generate cell and animal models for investigations on GD and PD. However, CBE may have additional glycosidase targets besides GBA. Here, we present the first in vivo target engagement study for CBE, employing a suite of activity-based probes to visualize catalytic pocket occupancy of candidate off-target glycosidases. Only at significantly higher CBE concentrations, non-lysosomal glucosylceramidase (GBA2) and lysosomal α-glucosidase were identified as major off-targets in cells and zebrafish larvae. A tight, but acceptable window for selective inhibition of GBA in the brain of mice was observed. On the other hand, cyclophellitol, a closer glucose mimic, was found to inactivate with equal affinity GBA and GBA2 and therefore is not suitable to generate genuine GD-like models. This article is protected by copyright. All rights reserved. Show less