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Instruments / Technical Area	Publication Details	Published
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 I04-Macromolecular Crystallography	New irreversible α- l -Iduronidase inhibitors and activity-based probes Marta Artola , Chi-lin Kuo , Stephen Mcmahon , Verena Oehler , Thomas Hansen , Martijn Van Der Lienden , Xu He , Hans Van Den Elst , Bogdan I. Florea , Allison R. Kermode , Gijsbert A. Van Der Marel , Tracey M. Gloster , Jeroen D. C. Codée , Herman S. Overkleeft , Johannes M. F. G. Aerts Chemistry - A European Journal 42 DOI: 10.1002/chem.201804662 Diamond Proposal Number(s): [14980] Open Access Show Abstract ▼ Abstract: Cyclophellitol aziridines are potent irreversible inhibitors of retaining glycosidases and versatile intermediates in the synthesis of activity‐based glycosidase probes (ABPs). Direct 3‐amino‐2‐(trifluoromethyl)quinazolin‐4(3H)‐one‐mediated aziridination of l‐ido‐configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of α‐l‐iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type I (MPS I). The iduronidase ABPs react covalently and irreversibly in an activity‐based manner with human recombinant α‐l‐iduronidase (rIDUA, Aldurazyme®). The structures of IDUA when complexed with the inhibitors in a non‐covalent transition state mimicking form and a covalent enzyme‐bound form provide insights into its conformational itinerary. Inhibitors 1–3 adopt a half‐chair conformation in solution (4H3 and 3H4), as predicted by DFT calculations, which is different from the conformation of the Michaelis complex observed by crystallographic studies. Consequently, 1–3 may need to overcome an energy barrier in order to switch from the 4H3 conformation to the transition state (2, 5B) binding conformation before reacting and adopting a covalent 5S1 conformation. rIDUA can be labeled with fluorescent Cy5 ABP 2, which allows monitoring of the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS I patients.	Nov 2018
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
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 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 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	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

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