Search results

(1 - 20 of 390)

Pages

Ruijgrok, G.; Wu, D.; Overkleeft, H.S.; Codee, J.D.C. 2023

Synthesis and application of bacterial exopolysaccharides

Article / Letter to editor

open access

Chen, Y.; Nieuwendijk, A.M.C.H. van den; Wu, L.; Moran, E.; Skoulikopoulou, F.; Riet, V. van; ... ; Armstrong, Z.W.B. 2023

Molecular basis for inhibition of heparanases and β-glucuronidases by siastatin B

Article / Letter to editor

open access

Borlandelli, V.B.; Offen, W.; Moroz, O.; Nin-Hill, A.; Mcgregor, N.; Binkhorst, L.; ... ; Overkleeft, H.S. 2023

β-l-arabinofurano-cyclitol aziridines are covalent broad-spectrum inhibitors and activity-based probes for retaining β-l-arabinofuranosidases

Article / Letter to editor

open access

McGregor, N.G.S.; Boer, C. de; Foucart, Q.P.O.; Beenakker, T.; Offen, W.A..; Codee, J.D.C.; ... ; Davies, G.J. 2023

A multiplexing activity-based protein-profiling platform for dissection of a native bacterial xyloglucan-degrading system

Article / Letter to editor

open access

Males, A.; Kok, K.; Nin-Hill, A.; Koster, N. de; Beukel, S. van den; Beenakker, T.J.M.; ... ; Artola Perez de Azanza, M.E. 2023

Trans-cyclosulfamidate mannose-configured cyclitol allows isoform-dependent inhibition of GH47 α-d-mannosidases through a bump–hole strategy

Article / Letter to editor

open access

Wijngaarden, S.; Yang, C.; Vela-Rodríguez, C.; Lehtiö, L.; Overkleeft, H.S.; Paschal, B.M.; Filippov, D.V. 2023

Synthetic dual cysteine-ADP ribosylated peptides from the androgen receptor are recognized by the DTX3L/PARP9 complex

Article / Letter to editor

open access

Androgen signaling in prostate cancer cells involves multisite cysteine ADP-ribosylation of the androgen receptor (AR) by PARP7. The AR modification is read by ADP-ribosyl binding macrodomains in... Show moreAndrogen signaling in prostate cancer cells involves multisite cysteine ADP-ribosylation of the androgen receptor (AR) by PARP7. The AR modification is read by ADP-ribosyl binding macrodomains in PARP9, but the reason that multiple cysteines are modified is unknown. Here, we use synthetic peptides to show that dual ADP-ribosylation of closely spaced cysteines mediates recognition by the DTX3L/PARP9 complex. Mono and dual ADP-ribosylated cysteine peptides were prepared using a novel solid-phase synthetic strategy utilizing a key, Boc-protected, ribofuranosylcysteine building block. This synthetic strategy allowed us to synthesize fluorescently labeled peptides containing a dual ADP-ribosylation motif. It was found that the DTX3L/PARP9 complex recognizes the dual ADP-ribosylated AR peptide (Kd = 80.5 nM) with significantly higher affinity than peptides with a single ADP-ribose. Moreover, oligomerization of the DTX3L/PARP9 complex proved crucial for ADP-ribosyl-peptide interaction since a deletion mutant of the complex that prevents its oligomer formation dramatically reduced peptide binding. Our data show that features of the substrate modification and the reader contribute to the efficiency of the interaction and imply that multivalent interactions are important for AR-DTX3L/PARP9 assembly. Show less

Minnee, H.; Rack, J.G.M.; Marel, G.A. van der; Overkleeft, H.S.; Codée, J.D.C.; Ahel, I.; Filippov, D.V. 2023

Solid-phase synthesis and biological evaluation of peptides ADP-Ribosylated at histidine

Article / Letter to editor

open access

The transfer of an adenosine diphosphate (ADP) ribose moiety to a nucleophilic side chain by consumption of nicotinamide adenine dinucleotide is referred to as ADP-ribosylation, which allows for... Show moreThe transfer of an adenosine diphosphate (ADP) ribose moiety to a nucleophilic side chain by consumption of nicotinamide adenine dinucleotide is referred to as ADP-ribosylation, which allows for the spatiotemporal regulation of vital processes such as apoptosis and DNA repair. Recent mass-spectrometry based analyses of the "ADP-ribosylome" have identified histidine as ADP-ribose acceptor site. In order to study this modification, a fully synthetic strategy towards α-configured N(τ)- and N(π)-ADP-ribosylated histidine-containing peptides has been developed. Ribofuranosylated histidine building blocks were obtained via Mukaiyama-type glycosylation and the building blocks were integrated into an ADP-ribosylome derived peptide sequence using fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase peptide synthesis. On-resin installation of the ADP moiety was achieved using phosphoramidite chemistry, and global deprotection provided the desired ADP-ribosylated oligopeptides. The stability under various chemical conditions and resistance against (ADP-ribosyl) hydrolase-mediated degradation has been investigated to reveal that the constructs are stable under various chemical conditions and non-degradable by any of the known ADP-ribosylhydrolases. Show less

Reichart, N.J.; Steiger, A.K.; Fossen, E.M. van; McClure, R.; Overkleeft, H.S.; Wright, A.T. 2023

Selection and enrichment of microbial species with an increased lignocellulolytic phenotype from a native soil microbiome by activity-based probing

Article / Letter to editor

open access

Multi-omic analyses can provide information on the potential for activity within a microbial community but often lack specificity to link functions to cell, primarily offer potential for function... Show moreMulti-omic analyses can provide information on the potential for activity within a microbial community but often lack specificity to link functions to cell, primarily offer potential for function or rely on annotated databases. Functional assays are necessary for understanding in situ microbial activity to better describe and improve microbiome biology. Targeting enzyme activity through activity-based protein profiling enhances the accuracy of functional studies. Here, we introduce a pipeline of coupling activity-based probing with fluorescence-activated cell sorting, culturing, and downstream activity assays to isolate and examine viable populations of cells expressing a function of interest. We applied our approach to a soil microbiome using two activity-based probes to enrich for communities with elevated activity for lignocellulose-degradation phenotypes as determined by four fluorogenic kinetic assays. Our approach efficiently separated and identified microbial members with heightened activity for glycosyl hydrolases, and by expanding this workflow to various probes for other function, this process can be applied to unique phenotype targets of interest. Show less

Kuo, C.L.; Su, Q.; Nieuwendijk, A.M.C.H. van den; Beenakker, T.J.M.; Offen, W.A.; Willems, L.I.; ... ; Aerts, J.M.F.G. 2023

The development of a broad-spectrum retaining β-exo-galactosidase activity-based probe.

Article / Letter to editor

open access

Acid β-galactosidase (GLB1) and galactocerebrosidase (GALC) are retaining exo-β-galactosidases involved in lysosomal glycoconjugate metabolism. Deficiency of GLB1 may result in the lysosomal... Show moreAcid β-galactosidase (GLB1) and galactocerebrosidase (GALC) are retaining exo-β-galactosidases involved in lysosomal glycoconjugate metabolism. Deficiency of GLB1 may result in the lysosomal storage disorders GM1 gangliosidosis, Morquio B syndrome, and galactosialidosis, and deficiency of GALC may result in Krabbe disease. Activity-based protein profiling (ABPP) is a powerful technique to assess the activity of retaining glycosidases in relation to health and disease. This work describes the use of fluorescent and biotin-carrying activity-based probes (ABPs) to assess the activity of both GLB1 and GALC in cell lysates, culture media, and tissue extracts. The reported ABPs, which complement the growing list of retaining glycosidase ABPs based on configurational isomers of cyclophellitol, should assist in fundamental and clinical research on various β-galactosidases, whose inherited deficiencies cause debilitating lysosomal storage disorders. Show less

Gelder, M.A.; Zanden, S.Y. van der; Vriends, M.B.L.; Wagensveld, R.A.; Marel, G.A. van der; Codee, J.D.C.; ... ; Neefjes, J.J.C. 2023

Re-exploring the anthracycline chemical space for better anti-cancer compounds

Article / Letter to editor

open access

The anthracycline anti-cancer drugs are intensely usedin the clinicto treat a wide variety of cancers. They generate DNA double strandbreaks, but recently the induction of chromatin damage was... Show moreThe anthracycline anti-cancer drugs are intensely usedin the clinicto treat a wide variety of cancers. They generate DNA double strandbreaks, but recently the induction of chromatin damage was introducedas another major determinant of anti-cancer activity. The combinationof these two events results in their reported side effects. Whileour knowledge on the structure-activity relationship of anthracyclineshas improved, many structural variations remain poorly explored. Therefore,we here report on the preparation of a diverse set of anthracyclineswith variations within the sugar moiety, amine alkylation pattern,saccharide chain and aglycone. We assessed the cytotoxicity in vitro in relevant human cancer cell lines, and the capacityto induce DNA- and chromatin damage. This coherent set of data allowedus to deduce a few guidelines on anthracycline design, as well asdiscover novel, highly potent anthracyclines that may be better toleratedby patients. Show less

Gelder, M.A. van; Zanden, S.Y. van der; Vriends, M.B.L.; Wagensveld, R.A.; Marel, G.A. van der; Codee, J.D.C.; ... ; Neefjes, J.J.C. 2023

Re-exploring the anthracycline chemical space for better anti-cancer compounds

Article / Letter to editor

open access

The anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the induction of chromatin damage was... Show moreThe anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the induction of chromatin damage was introduced as another major determinant of anti-cancer activity. The combination of these two events results in their reported side effects. While our knowledge on the structure–activity relationship of anthracyclines has improved, many structural variations remain poorly explored. Therefore, we here report on the preparation of a diverse set of anthracyclines with variations within the sugar moiety, amine alkylation pattern, saccharide chain and aglycone. We assessed the cytotoxicity in vitro in relevant human cancer cell lines, and the capacity to induce DNA- and chromatin damage. This coherent set of data allowed us to deduce a few guidelines on anthracycline design, as well as discover novel, highly potent anthracyclines that may be better tolerated by patients. Show less

Uddin, M.J.; Overkleeft, H.S.; Lentz, C.S. 2023

Activity-based protein profiling in methicillin-resistant staphylococcus aureus reveals the broad reactivity of a carmofur-derived probe

Article / Letter to editor

open access

Activity-based protein profiling is a powerful chemoproteomic technique to detect active enzymes and identify targets and off-targets of drugs. Here, we report the use of carmofur- and activity... Show moreActivity-based protein profiling is a powerful chemoproteomic technique to detect active enzymes and identify targets and off-targets of drugs. Here, we report the use of carmofur- and activity-based probes to identify biologically relevant enzymes in the bacterial pathogen Staphylococcus aureus. Carmofur is an anti-neoplastic prodrug of 5-fluorouracil and also has antimicrobial and anti-biofilm activity. Carmofur probes were originally designed to target human acid ceramidase, a member of the NTN hydrolase family with an active-site cysteine nucleophile. Here, we first profiled the targets of a fluorescent carmofur probe in live S. aureus under biofilm-promoting conditions and in liquid culture, before proceeding to target identification by liquid chromatography/mass spectrometry. Treatment with a carmofur-biotin probe led to enrichment of 20 enzymes from diverse families awaiting further characterization, including the NTN hydrolase-related IMP cyclohydrolase PurH. However, the probe preferentially labeled serine hydrolases, thus displaying a reactivity profile similar to that of carbamates. Our results suggest that the electrophilic N-carbamoyl-5-fluorouracil scaffold could potentially be optimized to achieve selectivity towards diverse enzyme families. The observed promiscuous reactivity profile suggests that the clinical use of carmofur presumably leads to inactivation of a number human and microbial enzymes, which could lead to side effects and/or contribute to therapeutic efficacy. Show less

Gracht, D. van der; Rowland, R.J.; Roig-Zamboni, V.; Guimaraes Da Lomba Ferraz, M.J.; Louwerse, G.A.M.; Geurink, P.P.; ... ; Artola Perez de Azanza, M.E. 2023

Fluorescence polarisation activity-based protein profiling for the identification of deoxynojirimycin-type inhibitors selective for lysosomal retaining alpha- and beta-glucosidases

Article / Letter to editor

open access

Lysosomal exoglycosidases are responsible for processing endocytosed glycans from the non-reducing end to produce the corresponding monosaccharides. Genetic mutations in a particular lysosomal... Show moreLysosomal exoglycosidases are responsible for processing endocytosed glycans from the non-reducing end to produce the corresponding monosaccharides. Genetic mutations in a particular lysosomal glycosidase may result in accumulation of its particular substrate, which may cause diverse lysosomal storage disorders. The identification of effective therapeutic modalities to treat these diseases is a major yet poorly realised objective in biomedicine. One common strategy comprises the identification of effective and selective competitive inhibitors that may serve to stabilize the proper folding of the mutated enzyme, either during maturation and trafficking to, or residence in, endo-lysosomal compartments. The discovery of such inhibitors is greatly aided by effective screening assays, the development of which is the focus of the here-presented work. We developed and applied fluorescent activity-based probes reporting on either human GH30 lysosomal glucosylceramidase (GBA1, a retaining & beta;-glucosidase) or GH31 lysosomal retaining & alpha;-glucosidase (GAA). FluoPol-ABPP screening of our in-house 358-member iminosugar library yielded compound classes selective for either of these enzymes. In particular, we identified a class of N-alkyldeoxynojirimycins that inhibit GAA, but not GBA1, and that may form the starting point for the development of pharmacological chaperone therapeutics for the lysosomal glycogen storage disease that results from genetic deficiency in GAA: Pompe disease. Show less

Gracht, D. van der; Rowland, R.J.; Roig-Zamboni, V.; Ferraz, M.J.; Louwerse, M.; Geurink, P.P.; ... ; Artola, M. 2023

Fluorescence polarisation activity-based protein profiling for the identification of deoxynojirimycin-type inhibitors selective for lysosomal retaining alpha- and beta-glucosidases

Article / Letter to editor

open access

Lysosomal exoglycosidases are responsible for processing endocytosed glycans from the non-reducing end to produce the corresponding monosaccharides. Genetic mutations in a particular lysosomal... Show moreLysosomal exoglycosidases are responsible for processing endocytosed glycans from the non-reducing end to produce the corresponding monosaccharides. Genetic mutations in a particular lysosomal glycosidase may result in accumulation of its particular substrate, which may cause diverse lysosomal storage disorders. The identification of effective therapeutic modalities to treat these diseases is a major yet poorly realised objective in biomedicine. One common strategy comprises the identification of effective and selective competitive inhibitors that may serve to stabilize the proper folding of the mutated enzyme, either during maturation and trafficking to, or residence in, endo-lysosomal compartments. The discovery of such inhibitors is greatly aided by effective screening assays, the development of which is the focus of the here-presented work. We developed and applied fluorescent activity-based probes reporting on either human GH30 lysosomal glucosylceramidase (GBA1, a retaining β-glucosidase) or GH31 lysosomal retaining α-glucosidase (GAA). FluoPol-ABPP screening of our in-house 358-member iminosugar library yielded compound classes selective for either of these enzymes. In particular, we identified a class of N-alkyldeoxynojirimycins that inhibit GAA, but not GBA1, and that may form the starting point for the development of pharmacological chaperone therapeutics for the lysosomal glycogen storage disease that results from genetic deficiency in GAA: Pompe disease. Show less

Minnee, H.; Chung, H.W.; Rack, J.G.M.; Marel, G.A. van der; Overkleeft, H.S.; Codee, J.D.C.; ... ; Filippov, D.V. 2023

Four of a kind: a complete collection of ADP-ribosylated histidine isosteres using Cu(I)- and Ru(II)-catalyzed click chemistry

Article / Letter to editor

open access

Adenosine diphosphateribosylation (ADP-ribosylation) is a crucialpost-translational modification involved in important regulatory mechanismsof numerous cellular pathways including histone... Show moreAdenosine diphosphateribosylation (ADP-ribosylation) is a crucialpost-translational modification involved in important regulatory mechanismsof numerous cellular pathways including histone maintenance and DNAdamage repair. To study this modification, well-defined ADP-ribosylatedpeptides, proteins, and close analogues thereof have been invaluabletools. Recently, proteomics studies have revealed histidine residuesto be ADP-ribosylated. We describe here the synthesis of a completeset of triazole-isosteres of ADP-ribosylated histidine to serve asprobes for ADP-ribosylating biomachinery. By exploiting Cu(I)- andRu(II)-catalyzed click chemistry between a propargylglycine buildingblock and an & alpha;- or & beta;-configured azidoribose, we have successfullyassembled the & alpha;- and & beta;-configured 1,4- and 1,5-triazoles,mimicking N(& tau;)- and N(& pi;)-ADP-ribosylated histidine, respectively.The ribosylated building blocks could be incorporated into a peptidesequence using standard solid-phase peptide synthesis and transformedon resin into the ADP-ribosylated fragments to provide a total offour ADP-ribosyl triazole conjugates, which were evaluated for theirchemical and enzymatic stability. The 1,5-triazole analogues mimickingthe N(& pi;)-substituted histidines proved susceptible to base-inducedepimerization and the ADP-ribosyl & alpha;-1,5-triazole linkage couldbe cleaved by the (ADP-ribosyl)hydrolase ARH3. Show less

Wang, Z.; Poveda, A.; Zhang, Q.; Unione, L.; Overkleeft, H.S.; Marel, G.A. van der; ... ; Codee, J.D.C. 2023

Total synthesis and structural studies of zwitterionic Bacteroides fragilis polysaccharide A1 fragments

Article / Letter to editor

open access

Zwitterionic polysaccharides (ZPSs) are exceptional carbohydrates,carrying both positively charged amine groups and negatively chargedcarboxylates, that can be loaded onto MHC-II molecules to... Show moreZwitterionic polysaccharides (ZPSs) are exceptional carbohydrates,carrying both positively charged amine groups and negatively chargedcarboxylates, that can be loaded onto MHC-II molecules to activateT cells. It remains enigmatic, however, how these polysaccharidesbind to these receptors, and to understand the structural featuresresponsible for this "peptide-like" behavior, well-definedZPS fragments are required in sufficient quantity and quality. Wehere present the first total synthesis of Bacteroidesfragilis PS A1 fragments encompassing up to 12 monosaccharides,representing three repeating units. Key to our successful syntheseshas been the incorporation of a C-3,C-6-silylidene-bridged "ring-inverted"galactosamine building block that was designed to act as an apt nucleophileas well as a stereoselective glycosyl donor. Our stereoselective synthesisroute is further characterized by a unique protecting group strategy,built on base-labile protecting groups, which has allowed the incorporationof an orthogonal alkyne functionalization handle. Detailed structuralstudies have revealed that the assembled oligosaccharides take upa bent structure, which translates into a left-handed helix for largerPS A1 polysaccharides, presenting the key positively charged aminogroups to the outside of the helix. The availability of the fragmentsand the insight into their secondary structure will enable detailedinteraction studies with binding proteins to unravel the mode of actionof these unique oligosaccharides at the atomic level. Show less

Ofman, T.P.; Marel, G.A. van der; Codée, J.D.C.; Overkleeft, H.S. 2023

Design and synthesis of exocyclic cyclitol aziridines as potential mechanism-based glycosidase inactivators

Article / Letter to editor

open access

Cyclophellitol aziridines have found wide application as mechanism-based, covalent, and irreversible inhibitors of retaining glycosidases. These compounds, like their parent compound,... Show moreCyclophellitol aziridines have found wide application as mechanism-based, covalent, and irreversible inhibitors of retaining glycosidases. These compounds, like their parent compound, cyclophellitol (a natural product retaining beta-glucosidase inactivator), make use of the mechanism of action of retaining glycosidases, which process their substrate through the formation of a transient covalent intermediate. In contrast, inverting glycosidases, the other main family of glycosyl hydrolases, do not employ such a covalent intermediate, and, as a consequence, useful scaffolds for mechanism-based inhibitor design have yet to be discovered. In this work, we explore chemistries that allow for the construction of cyclitol aziridines with the aziridine electrophile attached in an exocyclic fashion, more distal from the anomeric carbon - thus putatively closer to an inverting glycosidase active site nucleophile. The developed chemistries have allowed for the synthesis of a focused library of differently N-substituted, alpha-and beta-glucopyranose configured cyclitol aziridines for future evaluation as inhibitors or inactivators of alpha-and beta-glucosidases alike. Show less

Zhou, X.; Besse, A.; Peter, J.; Steinhardt, M.J.; Vogt, C.; Nerreter, S.; ... ; Rasche, L. 2023

High-dose carfilzomib achieves superior anti-tumor activity over lowdose and recaptures response in relapsed/refractory multiple myeloma resistant to low-dose carfilzomib by co-inhibiting the β2 and β1 subunits of the proteasome complex

Article / Letter to editor

open access

The optimal carfilzomib dosing is a matter of debate. We analyzed the inhibition profiles of proteolytic proteasome subunits β5, β2 and β1 after low-dose (20/27 mg/m2) versus high-dose (≥36 mg/m2)... Show moreThe optimal carfilzomib dosing is a matter of debate. We analyzed the inhibition profiles of proteolytic proteasome subunits β5, β2 and β1 after low-dose (20/27 mg/m2) versus high-dose (≥36 mg/m2) carfilzomib in 103 pairs of peripheral blood mononuclear cells from patients with relapsed/refractory (RR) multiple myeloma (MM). β5 activity was inhibited (median inhibition >50%) in vivo by 20 mg/m2, whereas β2 and β1 were co-inhibited only by 36 and 56 mg/m2, respectively. Co-inhibition of β2 (P=0.0001) and β1 activity (P=0.0005) differed significantly between high-dose and low-dose carfilzomib. Subsequently, high-dose carfilzomib showed significantly more effective proteasome inhibition than low-dose drug in vivo (P=0.0003). We investigated the clinical data of 114 patients treated with carfilzomib combinations. High-dose carfilzomib demonstrated a higher overall response rate (P=0.03) and longer progression-free survival (PFS) (P=0.007) than low-dose carfilzomib. Therefore, we escalated the carfilzomib dose to ≥ 36 mg/m2 in 16 patients who progressed during low-dose carfilzomib-containing therapies. High-dose carfilzomib recaptured response (≥ partial remission) in 9 (56%) patients with a median PFS of 4.4 months. Altogether, we provide the first in vivo evidence in RRMM patients that the molecular activity of high-dose carfilzomib differs from that of low-dose carfilzomib by co-inhibition of β2 and β1 proteasome subunits and, consequently, high-dose carfilzomib achieves a superior anti-MM effect than low-dose and recaptures response in RRMM being resistant to low-dose carfilzomib. The optimal carfilzomib dose should be ≥ 36 mg/m2 to reach a sufficient anti-tumor activity, while the balance between efficacy and tolerability should be considered in each patient. Show less

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

Other

metadata only

This article corrects the following:

Xylose-Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase
- Volume 22Issue 21ChemBioChem
- pages: 3090-3098
- First Published online: September 13,...

This article corrects the following:

Xylose-Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase
- Volume 22Issue 21ChemBioChem
- pages: 3090-3098
- First Published online: September 13, 2021

Show less

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

Leiden University Scholarly Publications

Your Search

Enabled Filters

Sort Options

Refine Results

Resource Type

Availability

Creation Date

Faculty

Collection

Topic

Author

Language

Search results

Pages

Pages