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

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Manno-epi-cyclophellitols enable activity-based protein profiling of human α-mannosidases and discovery of new golgi mannosidase II inhibitors Zachary Armstrong , Chi-Lin Kuo , Daniël Lahav , Bing Liu , Rachel Johnson , Thomas J. M. Beenakker , Casper De Boer , Chung-Sing Wong , Erwin R. Van Rijssel , Marjoke F. Debets , Bogdan I. Florea , Colin Hissink , Rolf G. Boot , Paul P. Geurink , Huib Ovaa , Mario Van Der Stelt , Gijsbert M. Van Der Marel , Jeroen D. C. Codée , Johannes M. F. G. Aerts , Liang Wu , Herman S. Overkleeft , Gideon Davies Journal Of The American Chemical Society DOI: 10.1021/jacs.0c03880 Diamond Proposal Number(s): [18598] Show Abstract ▼ Abstract: Golgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl residues from GlcNAcMan5GlcNAc2 to produce GlcNAcMan3GlcNAc2, the precursor for all complex N-glycans, including the branched N-glycans associated with cancer. Inhibitors of GMII are potential cancer therapeutics, but their usefulness is limited by off-target effects, which produce α-mannosidosis-like symptoms. Despite many structural and mechanistic studies of GMII, we still lack a potent and selective inhibitor of this enzyme. Here, we synthesized manno-epi-cyclophellitol epoxide and aziridines and demonstrate their covalent modification and time-dependent inhibition of GMII. Application of fluorescent manno-epi-cyclophellitol aziridine derivatives enabled activity-based protein profiling of α-mannosidases from both human cell lysate and mouse tissue extracts. Synthesized probes also facilitated a fluorescence polarization-based screen for dGMII inhibitors. We identified seven previously unknown inhibitors of GMII from a library of over 350 iminosugars and investigated their binding modalities through X-ray crystallography. Our results reveal previously unobserved inhibitor binding modes and promising scaffolds for the generation of selective GMII inhibitors.	Jul 2020
I04-Macromolecular Crystallography	Rational design of mechanism-based inhibitors and activity-based probes for the identification of retaining α-l-arabinofuranosidases Nicholas G. S. Mcgregor , Marta Artola , Alba Nin-Hill , Daniel Linzel , Mireille Haon , Jos Reijngoud , Arthur F. J. Ram , Marie-Noelle Rosso , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Gilles P. Van Wezel , Jean-Guy Berrin , Carme Rovira , Herman S. Overkleeft , Gideon J. Davies Journal Of The American Chemical Society DOI: 10.1021/jacs.9b11351 Diamond Proposal Number(s): [18598] Open Access Show Abstract ▼ Abstract: Identifying and characterizing the enzymes responsible for an observed activity within a complex eukaryotic catabolic system remains one of the most significant challenges in the study of biomass-degrading systems. The debranching of both complex hemicellulosic and pectinaceous polysaccharides requires the production of α-L-arabinofuranosidases among a wide variety of co-expressed carbohydrate-active enzymes. To selectively detect and identify α-L-arabinofuranosidases produced by fungi grown on complex biomass, potential covalent inhibitors and probes which mimic α-L-arabinofuranosides were sought. The conformational free energy landscapes of free α-L-arabinofuranose and several rationally designed covalent α-L-arabinofuranosidase inhibitors were analyzed. A synthetic route to these inhibitors was subsequently developed based on a key Wittig-Still rearrangement. Through a combination of kinetic measurements, intact mass spectrometry, and structural experiments, the designed inhibitors were shown to efficiently label the catalytic nucleophiles of retaining GH51 and GH54 α-L-arabinofuranosidases. Activity-based probes elaborated from an inhibitor with an aziridine warhead were applied to the identification and characterization of α-L-arabinofuranosidases within the secretome of A. niger grown on arabinan. This method was extended to the detection and identification of α-L-arabinofuranosidases produced by eight biomass-degrading basidiomycete fungi grown on complex biomass. The broad applicability of the cyclophellitol-derived activity-based probes and inhibitors presented here make them a valuable new tool in the characterization of complex eukaryotic carbohydrate-degrading systems and in the high-throughput discovery of α-L-arabinofuranosidases.	Feb 2020
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
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Dynamic and functional profiling of xylan-degrading enzymes in Aspergillus secretomes using activity-based probes Sybrin P. Schröder , Casper De Boer , Nicholas G. S. Mcgregor , Rhianna J. Rowland , Olga Moroz , Elena Blagova , Jos Reijngoud , Mark Arentshorst , David Osborn , Marc D. Morant , Eric Abbate , Mary A. Stringer , Kristian B. R. M. Krogh , Lluís Raich , Carme Rovira , Jean-Guy Berrin , Gilles P. Van Wezel , Arthur F. J. Ram , Bogdan I. Florea , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Keith S. Wilson , Liang Wu , Gideon J. Davies , Herman S. Overkleeft Acs Central Science DOI: 10.1021/acscentsci.9b00221 Diamond Proposal Number(s): [13587] Show Abstract ▼ Abstract: Plant polysaccharides represent a virtually unlimited feedstock for the generation of biofuels and other commodities. However, the extraordinary recalcitrance of plant polysaccharides toward breakdown necessitates a continued search for enzymes that degrade these materials efficiently under defined conditions. Activity-based protein profiling provides a route for the functional discovery of such enzymes in complex mixtures and under industrially relevant conditions. Here, we show the detection and identification of β-xylosidases and endo-β-1,4-xylanases in the secretomes of Aspergillus niger, by the use of chemical probes inspired by the β-glucosidase inhibitor cyclophellitol. Furthermore, we demonstrate the use of these activity-based probes (ABPs) to assess enzyme–substrate specificities, thermal stabilities, and other biotechnologically relevant parameters. Our experiments highlight the utility of ABPs as promising tools for the discovery of relevant enzymes useful for biomass breakdown.	May 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	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] Open Access 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
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
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

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