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19 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography	Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors Thomas J. M. Beenakker , Dennis P. A. Wander , Wendy Offen , Marta Artola , Lluís Raich , Maria J. Ferraz , Kah-yee Li , Judith H. P. M. Houben , Erwin R. Van Rijssel , Thomas Hansen , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Johannes M. F. G. Aerts , Carme Rovira , Gideon J. Davies , Herman S. Overkleeft Journal Of The American Chemical Society DOI: 10.1021/jacs.7b01773 Diamond Proposal Number(s): [13587] Show Abstract ▼ Abstract: The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine—both covalent retaining β-glucosidase inhibitors—we postulated that the corresponding carba “cyclopropyl” analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the 4H3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4H3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (Ki = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4H3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.	May 2017
I02-Macromolecular Crystallography	Towards broad spectrum activity-based glycosidase probes: synthesis and evaluation of deoxygenated cyclophellitol aziridines Sybrin P. Schröder , Jasper W. Van De Sande , Wouter W. Kallemeijn , Chi-lin Kuo , Marta Artola , Eva J. Van Rooden , Jianbing Jiang , Thomas J. M. Beenakker , Bogdan I. Florea , Wendy Offen , Gideon Davies , Adriaan J. Minnaard , Johannes M. F. G. Aerts , Jeroen D. C. Codée , Gijsbert A. Van Der Marel , Herman S. Overkleeft Chemical Communications 3 DOI: 10.1039/C7CC07730K Diamond Proposal Number(s): [9948] Open Access Show Abstract ▼ Abstract: Activity-based protein profiling has emerged as a powerful tool for visualizing glycosidases in complex biological samples. Several configurational cyclophellitol isomers have been shown to display high selectivity as probes for glycosidases processing substrates featuring the same configuration. Here, a set of deoxygenated cyclophellitols are presented which enable inter-class profiling of β-glucosidases and β-galactosidases.	Nov 2017
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Activity-based probes for functional interrogation of retaining β-glucuronidases Liang Wu , Jianbing Jiang , Yi Jin , Wouter W. Kallemeijn , Chi-lin Kuo , Marta Artola , Wei Dai , Cas Van Elk , Marco Van Eijk , Gijsbert A. Van Der Marel , Jeroen D. C. Codee , Bogdan I. Florea , Johannes M. F. G. Aerts , Herman S. Overkleeft , Gideon J. Davies Nature Chemical Biology 268 DOI: 10.1038/nchembio.2395 Diamond Proposal Number(s): [9948, 13587] Show Abstract ▼ Abstract: Humans express at least two distinct β-glucuronidase enzymes that are involved in disease: exo-acting β-glucuronidase (GUSB), whose deficiency gives rise to mucopolysaccharidosis type VII, and endo-acting heparanase (HPSE), whose overexpression is implicated in inflammation and cancers. The medical importance of these enzymes necessitates reliable methods to assay their activities in tissues. Herein, we present a set of β-glucuronidase-specific activity-based probes (ABPs) that allow rapid and quantitative visualization of GUSB and HPSE in biological samples, providing a powerful tool for dissecting their activities in normal and disease states. Unexpectedly, we find that the supposedly inactive HPSE proenzyme proHPSE is also labeled by our ABPs, leading to surprising insights regarding structural relationships between proHPSE, mature HPSE, and their bacterial homologs. Our results demonstrate the application of β-glucuronidase ABPs in tracking pathologically relevant enzymes and provide a case study of how ABP-driven approaches can lead to discovery of unanticipated structural and biochemical functionality.	Jun 2017
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor Marta Artola , Liang Wu , Maria J. Ferraz , Chi-lin Kuo , Lluís Raich , Imogen Z. Breen , Wendy A. Offen , Jeroen D. C. Codée , Gijsbert A. Van Der Marel , Carme Rovira , Johannes M. F. G. Aerts , Gideon J. Davies , Herman S. Overkleeft Acs Central Science DOI: 10.1021/acscentsci.7b00214 Diamond Proposal Number(s): [13587] Open Access Show Abstract ▼ Abstract: The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors. Here we present the synthesis, conformational analysis, and application of novel 1,6-cyclophellitol cyclosulfates. We show that 1,6-epi-cyclophellitol cyclosulfate (α-cyclosulfate) is a rapidly reacting α-glucosidase inhibitor whose 4C1 chair conformation matches that adopted by α-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (β-cyclosulfate) reacts more slowly, likely reflecting its conformational restrictions. Selective glycosidase inhibitors are invaluable as mechanistic probes and therapeutic agents, and we propose cyclophellitol cyclosulfates as a valuable new class of carbohydrate mimetics for application in these directions.	Jul 2017
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	α- d -Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease Marta Artola , Christinne Hedberg , Rhianna J. Rowland , Lluís Raich , Kassiani Kytidou , Liang Wu , Amanda Schaaf , Maria Joao Ferraz , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Carme Rovira , Johannes M. F. G. Aerts , Gideon J. Davies , Herman S. Overkleeft Chemical Science 42 DOI: 10.1039/C9SC03342D Diamond Proposal Number(s): [13587] Open Access Show Abstract ▼ Abstract: Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α-D-galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with a recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy, a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α-D-gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally constrained competitive glycosidase inhibitors that act by mimicry of the Michaelis complex conformation. We found that D-galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α-D-galactosidase (agalsidase beta, Fabrazyme®) both in vitro and in cellulo.	Aug 2019
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish Marta Artola , Chi-lin Kuo , Lindsey T. Lelieveld , Rhianna J. Rowland , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Rolf G. Boot , Gideon J. Davies , Johannes M. F. G. Aerts , Herman S. Overkleeft Journal Of The American Chemical Society DOI: 10.1021/jacs.9b00056 Diamond Proposal Number(s): [13587] Open Access Show Abstract ▼ Abstract: 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 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 generation 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.	Mar 2019
I03-Macromolecular Crystallography	In vitro and in vivo comparative and competitive activity-based protein profiling of GH29 a-Lfucosidases Jianbing Jiang , Wouter W. Kallemeijn , Daniel W. Wright , Adrianus M. C. H. Van Den Nieuwendijk , Veronica Coco Rohde , Elisa Colomina Folch , Hans Van Den Elst , Bogdan I. Florea , Saskia Scheij , Wilma E. Donker-koopman , Marri Verhoek , Nan Li , Martin Schürmann , Daniel Mink , Rolf G. Boot , Jeroen D. C. Codée , Gijsbert A. Van Der Marel , Gideon J. Davies , Johannes M. F. G. Aerts , Herman S. Overkleeft Chemical Science 6 (5), 2782 - 2789 DOI: 10.1039/C4SC03739A Diamond Proposal Number(s): [7864, 9948] Show Abstract ▼ Abstract: GH29 a-L-fucosidases catalyze the hydrolysis of a-L-fucosidic linkages. Deficiency in human lysosomal a-Lfucosidase (FUCA1) leads to the recessively inherited disorder, fucosidosis. Herein we describe the development of fucopyranose-configured cyclophellitol aziridines as activity-based probes (ABPs) for selective in vitro and in vivo labeling of GH29 a-L-fucosidases from bacteria, mice and man. Crystallographic analysis on bacterial a-L-fucosidase confirms that the ABPs act by covalent modification f the active site nucleophile. Competitive activity-based protein profiling identified L-fuconojirimycin as the single GH29 a-L-fucosidase inhibitor from eight configurational isomers.	Jun 2015
I03-Macromolecular Crystallography	Gluco-1H-imidazole: a new class of azole-type β-glucosidase inhibitor Sybrin P. Schröder , Liang Wu , Marta Artola , Thomas Hansen , Wendy A. Offen , Maria J. Ferraz , Kah-yee Li , Johannes M. F. G. Aerts , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Gideon J. Davies , Herman S. Overkleeft Journal Of The American Chemical Society DOI: 10.1021/jacs.8b02399 Diamond Proposal Number(s): [13587] Show Abstract ▼ 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.	Mar 2018
I03-Macromolecular Crystallography	A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase Daniël Lahav , Bing Liu , Richard J. B. H. N. Van Den Berg , Adrianus M. C. H. Van Den Nieuwendijk , Tom Wennekes , Amar T. Ghisaidoobe , Imogen Breen , Maria J. Ferraz , Chi-lin Kuo , Liang Wu , Paul P. Geurink , Huib Ovaa , Gijsbert A. Van Der Marel , Mario Van Der Stelt , Rolf G. Boot , Gideon J. Davies , Johannes M. F. G. Aerts , Herman S. Overkleeft Journal Of The American Chemical Society DOI: 10.1021/jacs.7b07352 Diamond Proposal Number(s): [13587] Open Access Show Abstract ▼ Abstract: Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.	Sep 2017
I03-Macromolecular Crystallography	Glycosylated cyclophellitol-derived activity-based probes and inhibitors for cellulases Casper De Boer , Nicholas G. S. Mcgregor , Evert Peterse , Sybrin P. Schröder , Bogdan I. Florea , Jianbing Jiang , Jos Reijngoud , Arthur F. J. Ram , Gilles P. Van Wezel , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Herman S. Overkleeft , Gideon Davies Rsc Chemical Biology 25 DOI: 10.1039/D0CB00045K Diamond Proposal Number(s): [18598] Open Access Show Abstract ▼ Abstract: Cellulases and related β-1,4-glucanases are essential components of lignocellulose-degrading enzyme mixtures. The detection of β-1,4-glucanase activity typically relies on monitoring the breakdown of purified lignocellulose-derived substrates or synthetic chromogenic substrates, limiting the activities which can be detected and complicating the tracing of activity back to specific components within complex enzyme mixtures. As a tool for the rapid detection and identification of β-1,4-glucanases, a series of glycosylated cyclophellitol inhibitors mimicking β-1,4-glucan oligosaccharides have been synthesised. These compounds are highly efficient inhibitors of HiCel7B, a well-known GH7 endo-β-1,4-glucanase. An elaborated activity-based probe facilitated the direct detection and identification of β-1,4-glucanases within a complex fungal secretome without any detectable cross-reactivity with β-D-glucosidases. These probes and inhibitors add valuable new capacity to the growing toolbox of cyclophellitol-derived probes for the activity-based profiling of biomass-degrading enzymes.	Jul 2020

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