A5046375428- Chemical Synthesis and Analysis
- DNA and Nucleic Acid Chemistry
- Advanced biosensing and bioanalysis techniques
- Immunotherapy and Immune Responses
- Glycosylation and Glycoproteins Research
- Immune Response and Inflammation
- Click Chemistry and Applications
- RNA Interference and Gene Delivery
- Carbohydrate Chemistry and Synthesis
- RNA and protein synthesis mechanisms
- Electron Spin Resonance Studies
- Radiopharmaceutical Chemistry and Applications
- Calcium signaling and nucleotide metabolism
- Bacteriophages and microbial interactions
- Lanthanide and Transition Metal Complexes
- Advanced NMR Techniques and Applications
- Antimicrobial Peptides and Activities
- PARP inhibition in cancer therapy
- vaccines and immunoinformatics approaches
- Metal complexes synthesis and properties
- Organophosphorus compounds synthesis
- Ferrocene Chemistry and Applications
- Peptidase Inhibition and Analysis
- Toxin Mechanisms and Immunotoxins
- Enzyme Catalysis and Immobilization
Leiden University
2015-2024
Railenium
2019
Netherlands Metabolomics Centre
2015-2016
Wageningen University & Research
2008
Radboud University Nijmegen
2007
University of St Andrews
2007
University of Udine
2005
Adaptive resistance of myeloma to proteasome inhibition represents a clinical challenge, whose biology is poorly understood. Proteasome mutations were implicated as underlying mechanism, while an alternative hypothesis based on low activation status the unfolded protein response was recently suggested (IRE1/XBP1-low model). We generated bortezomib- and carfilzomib-adapted, highly resistant multiple cell clones (AMO-BTZ, AMO-CFZ), which we analyzed in combined quantitative functional...
Abstract Chemical conjugates comprising synthetic Toll-like receptor ligands (TLR-L) covalently bound to antigenic long peptides (SLP) are attractive vaccine modalities, which can induce robust CD8+ T-cell immune responses. Previously, we have shown that the mechanism underlying power of TLR-L SLP is improved delivery antigen together with a dendritic cell activation signal. In present study, expanded approach tumor-specific CD4+ as well responses and in vivo studies two nonrelated...
A model method: strategy that combines a knowledge-based in silico design approach and the development of novel activity-based probes (ABPs) for detection endogenous diacylglycerol lipase-α (DAGL-α) is presented. This resulted rapid identification new DAGL-α inhibitors with high selectivity brain proteome. ABPP=activity-based protein profiling.
Heparan sulfate proteoglycans (HSPGs) mediate essential interactions throughout the extracellular matrix (ECM), providing signals that regulate cellular growth and development. Altered HSPG composition during tumorigenesis strongly aids cancer progression. Heparanase (HPSE) is principal enzyme responsible for heparan catabolism markedly up-regulated in aggressive cancers. HPSE overactivity degrades HSPGs within ECM, facilitating metastatic dissemination releasing mitogens drive...
A procedure is presented for copper(I)-catalyzed [3+2] cycloaddition of nucleosides and nucleotides in near-quantitative yield. Azido-alkyne was applied the preparation a range adenosine dimers derivatives with versatile functionality, as well smooth condensation two oligonucleotide strands. The described technology may find valuable application synthesis conjugates.
Abstract The post‐translational modification of proteins that is known as adenosine diphosphate ribosylation (ADPr) regulates a wide variety important biological processes, such DNA‐damage repair and cellular metabolism. This also involved in carcinogenesis the process aging. Therefore, better understanding function ADP‐ribosylation crucial for development novel therapeutics. To facilitate elucidation biology ADPr, availability well‐defined fragments poly(ADP‐ribose) essential. Herein we...
Dendritic cells (DCs) are important initiators of adaptive immunity, and they possess a multitude Pattern Recognition Receptors (PRR) to generate an adequate T cell mediated immunity against invading pathogens. PRR ligands frequently conjugated tumor-associated antigens in vaccination strategy enhance the immune response toward such antigens. One these PPRs, DC-SIGN, member C-type lectin receptor (CLR) family, has been extensively targeted with Lewis structures mannose glycans, often...
A new method for the construction of pyrophosphates is reported based on coupling a sugar phosphate and nucleoside phosphoramidite. The in situ formed phosphate−phosphite intermediate was subsequently oxidized with tBuOOH. Three UDP-N-acetylglucosamine derivatives were prepared using this one-pot procedure good yields.
Novel transition metal catalysts based on oligonucleotides can be easily obtained by functionalization of 5-iodouridine with phosphine ligands, resulting in good asymmetric induction palladium catalyzed allylic nucleophilic substitution.
The potency of human papillomavirus type 16 (HPV16)-encoded synthetic long peptides (SLP), conjugated to an optimized Toll-like receptor 2 ligand (TLR2-L), was assessed in ex vivo activation HPV16+ cancer patient-derived T cells. Two highly immunogenic SLP sequences derived from the oncogenic E6 protein HPV16 were selected and a Pam3CSK4-based TLR2-L under GMP conditions. Both conjugates able mature DCs vitro activate skin-derived antigen-presenting cells (APCs) upon intradermal injection...
Abstract The activation of CD8 + T‐cells requires the uptake exogenous polypeptide antigens and proteolytic processing these to octamer or nonamer peptides, which are loaded on MHC‐I complexes presented T‐cell. By using an azide as a bioorthogonal protecting group rather than ligation handle, masked were generated—antigens that not recognized by their cognate T‐cell unless they deprotected cell Staudinger reduction.
ADP-ribosylation (ADPr), as a post-translational modification, plays crucial role in DNA-repair, immunity and many other cellular physiological processes. Serine is the main acceptor for ADPr DNA damage response, whereas impact of less common ADPr-modifications cysteine threonine side chains clear. Generally, gaining molecular insights into recognition turn-over hampered by availability homogeneous, ADP-ribosylated material, such mono-ADP-ribosylated (MARylated) peptides. Here, new efficient...
Background Amplivant is a molecularly optimized Toll-like receptor 2 ligand that can be covalently conjugated to tumor peptide antigens. In preclinical models, amplivant-adjuvanted synthetic long peptides (SLPs) strongly enhanced antigen presentation by dendritic cells, T cell priming and induction of effective antitumor responses. The current study first-in-human trial investigate safety immunogenicity amplivant human papillomavirus (HPV) 16-SLP. Methods A dose escalation phase I...
The conjugation of a ribonucleic acid 16-mer with the cationic amphiphilic peptide penetratin and an anionic hyaluronan tetrasaccharide by means Cu-free "click" chemistry is reported. alkyne-functionalized was prepared automated solid-phase synthesis, using newly developed strained cyclooctyne phosphoramidite in final coupling. Cycloaddition alkyne functionalized RNA to azide containing biomolecules led clean conversion into corresponding nucleic conjugates.
Self-adjuvanting vaccines, wherein an antigenic peptide is covalently bound to immunostimulating agent, have been shown be promising tools for immunotherapy. Synthetic Toll-like receptor (TLR) ligands are ideal adjuvants covalent linking peptides or proteins. We here introduce a conjugation-ready TLR4 ligand, CRX-527, potent powerful lipid A analogue, in the generation of novel conjugate-vaccine modalities. Effective chemistry has developed synthesis ligand as well connection it antigen....
Dendritic cells (DCs) are armed with a multitude of Pattern Recognition Receptors (PRRs) to recognize pathogens and initiate pathogen-tailored T cell responses. In these responses, the maturation DCs is key, as well production cytokines that help accomplish DC-SIGN frequently exploited PRR can effectively be targeted mannosylated antigens enhance induction antigen-specific cells. The natural O-mannosidic linkage susceptible enzymatic degradation, its chemical sensitivity complicates...
Assembly of an immobilized tripeptide, platination, and subsequent deprotection release from the solid support are key steps in solid-phase peptide synthesis peptide–platinum(II) complex 1. This new methodology should be applicable for preparation a library platinum antitumor compounds by combinatorial approach.
New analogues (UPam) of triacylated lipopeptide Pam3CysSK4, a popular agonist Toll-like receptor 2 (TLR2), were designed making use the cocrystal structure TLR2 heterodimer (with TLR1) with Pam3CysSK4. Twenty-two UPam derivatives that feature an N-tetradecylcarbamyl chain to mimic native N-palmitoyl moiety and various small amino acids residues at penultimate N-terminal position prepared via solid-phase synthesis. In vitro evaluation immunostimulatory properties revealed new potent ligands.
Simultaneous triggering of Toll-like receptors (TLRs) and NOD-like (NLRs) has previously been shown to synergistically activate monocytes, dendritic cells, macrophages. We applied these properties in a T-cell vaccine setting by conjugating the NOD2-ligand muramyl-dipeptide (MDP) TLR2-ligand Pam3CSK4 synthetic peptide derived from model antigen. Stimulation human DCs with MDP-peptide-Pam3CSK4 conjugate led strongly increased secretion pro-inflammatory Th1-type cytokines chemokines. further...
Background Presently melanoma still lacks adequate treatment options for metastatic disease. While is exceptionally challenging to standard regimens, it suited with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation considered a favourable prognostic sign during intervention, we here aimed at the reverse approach of directly inducing vitiligo as shortcut effective anti-melanoma immunity. Methodology and Principal Findings We developed an simple use form by...
The amyloid β (A β) peptide is important in the context of Alzheimer's disease, since it one major components fibrils that constitute plaques. Agents can influence fibril formation are important, and those, membrane mimics particularly relevant, because hydrophobic part A suggests a possible activity peptide. We employed spin-label EPR to investigate aggregation process β1–40 presence sodium dodecyl sulfate (SDS) detergent as membrane-mimicking agent. In this work, effect SDS on studied...
The development of effective protecting group chemistry is an important driving force behind the progress in synthesis complex oligosaccharides. Automated solid-phase attractive technique for rapid assembly oligosaccharides, built up repetitive elements. fact that (harsh) reagents are used excess multiple reaction cycles makes this extra demanding on groups used. Here, a set oligorhamnan fragments reported using cyanopivaloyl (PivCN) ester to ensure neighboring participation during...
The transfection ability of nonviral gene therapy vehicles is generally hampered by untimely lysosomal degradation internalized DNA. In this study we describe the development a targeted lysosome disruptive element to facilitate escape DNA from compartment, thus enhancing efficacy, in cell-specific fashion. Two peptides (INF7 and JTS-1) were tested for their capacity disrupt liposomes. contrast JTS-1, INF7 induced rapid cholesterol-independent leakage (EC50, 1.3 μm). was therefore selected...
A single-stranded oligothymine peptide nucleic acid (PNA) was used as a template for the assembly of chiral oligo(p-phenylenevinylene) diaminotriazine derivative (OPV) in methylcyclohexane (MCH) revealing nanostructures which size is controlled by template.
Muramyl dipeptide (MDP) is the smallest peptidoglycan fragment capable of triggering innate immune system through interaction with intracellular NOD2 receptor. To develop synthetic vaccine modalities composed an antigenic entity (typically a small peptide) and molecular adjuvant well-defined activity, we previously assembled covalent MDP-antigen conjugates. Although these were found to be stimulating receptor processed by dendritic cells (DCs) leading effective antigen presentation, DC...