A5028277975- Cannabis and Cannabinoid Research
- Diet, Metabolism, and Disease
- Pancreatic function and diabetes
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Zebrafish Biomedical Research Applications
- Metabolomics and Mass Spectrometry Studies
- Peroxisome Proliferator-Activated Receptors
- Pharmacogenetics and Drug Metabolism
- Biochemical and Molecular Research
- Receptor Mechanisms and Signaling
- Ubiquitin and proteasome pathways
- Neurotransmitter Receptor Influence on Behavior
- Sleep and Wakefulness Research
- Monoclonal and Polyclonal Antibodies Research
- Adipose Tissue and Metabolism
- Protein Degradation and Inhibitors
- Alcohol Consumption and Health Effects
- Lymphoma Diagnosis and Treatment
- Animal testing and alternatives
- Forensic Toxicology and Drug Analysis
- Radiopharmaceutical Chemistry and Applications
- Peptidase Inhibition and Analysis
- Biotin and Related Studies
- Coffee research and impacts
AstraZeneca (United Kingdom)
2020-2024
Centre for Human Drug Research
2016-2020
Leiden University
2015-2020
Netherlands Metabolomics Centre
2019
A clue to a drug's neurotoxicity? The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), lipase that degrades specific endocannabinoid. On the basis of this activity, was being developed as potential treatment for anxiety and pain. In phase 1 trial drug, one subject died, four others suffered brain damage. As an initial step in investigating whether inhibition off-target proteins by might contribute its clinical neurotoxicity, van Esbroeck et al. used activity-based proteomic...
Personalized medicine, in modern drug therapy, aims at a tailored treatment accounting for inter-individual variations pharmacology to treat individuals effectively and safely. The variability response upon administration is caused by the interplay between patients' (patho)physiological status. Individual status may result from genetic polymorphisms, environmental factors (including current/past treatments), demographic characteristics, disease related factors. Identification quantification...
The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to in vivo MAT2a tool inhibitor is discussed. structure-based drug discovery approach, aided relative binding free energy calculations, resulted AZ'9567 (21), a potent vitro with excellent preclinical pharmacokinetic properties. This showed selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both and vivo, providing further evidence support the utility inhibitors...
Diacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of endocannabinoid 2-arachidonoylglycerol (2-AG). Selective reversible inhibitors required to study function DAGLs in neuronal cells an acute temporal fashion, but they currently lacking. Here, we describe identification a highly selective DAGL inhibitor using structure-guided chemoproteomics strategy characterize selectivity complex proteomes. Key success this approach is use comparative competitive...
Zebrafish larvae (Danio rerio) are increasingly used to translate findings regarding drug efficacy and safety from in vitro-based assays vertebrate species, including humans. However, the limited understanding of exposure this species hampers its implementation translational research. Using paracetamol as a paradigm compound, we present novel method characterize pharmacokinetic processes zebrafish larvae, by combining sensitive bioanalytical methods nonlinear mixed effects modeling. The...
The endocannabinoid system (ECS) controls energy balance by regulating both intake and expenditure. Endocannabinoid levels are elevated in obesity suggesting a potential causal relationship. This study aimed to elucidate the rate of dysregulation ECS, metabolic organs involved, diet-induced obesity. Eight groups age-matched male C57Bl/6J mice were randomized receive chow diet (control) or high fat (HFD, 45% calories derived from fat) ranging 1 day up 18 weeks before euthanasia. Plasma...
Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family RING finger E3 ubiquitin ligases, has been demonstrated to play central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via ubiquitin-mediated protein modulation. Thus, inhibition ligase activity can lead immune therapeutic potential immuno-oncology. Herein, we describe discovery...
Endocannabinoids, a class of lipid messengers, have emerged as crucial regulators synaptic communication in the CNS. Dysregulation these compounds has been implicated many brain disorders. Although some studies identified and quantified limited number target compounds, method that provides comprehensive quantitative information on endocannabinoids related N-acylethanolamines (NAEs) cerebrospinal fluid (CSF) is currently lacking, measurements are challenging due to low concentrations under...
Abstract Background/Objectives Endocannabinoids (ECs) are associated with obesity and ectopic fat accumulation, both of which play a role in the development cardiovascular disease (CVD) type 2 diabetes (T2D). The effect prolonged caloric restriction on ECs relation to distribution cardiac function is still unknown. Therefore, our aim was investigate this relationship obese T2D patients coronary artery (CAD). Subjects/Methods In prospective intervention study, CAD ( n = 27) followed 16 week...
Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics necessary reliable translation of results to higher vertebrates, including humans. Quantification clearance and distribution requires measurements blood concentrations. Additionally, measuring metabolites importance understand in this model organism mechanistically. We therefore mechanistically studied quantified zebrafish larvae, compared...
Zebrafish larvae are increasingly used in pharmacological and toxicological studies, but it is often overlooked that internal exposure to exogenous compounds, rather than the incubation medium concentration, driving observed effects. Moreover, as zebrafish larva a developing organism, continuous physiological changes impact pharmacokinetic or toxicokinetic processes like absorption elimination of influencing interpretation observations conclusions drawn from experiments at different larval...
The endocannabinoid 2-arachidonoylglycerol (2-AG) is involved in neuronal differentiation. This study aimed to identify the biosynthetic enzymes responsible for 2-AG production during retinoic acid (RA)-induced neurite outgrowth of Neuro-2a cells. First, we confirmed that RA stimulation cells increases and outgrowth. diacylglycerol lipase (DAGL) inhibitor DH376 blocked reduced Surprisingly, CRISPR/Cas9-mediated knockdown DAGLα DAGLβ did not reduce levels, suggesting another enzyme capable...
Bfl-1, a member of the Bcl-2 family proteins, plays crucial role in apoptosis regulation and has been implicated cancer cell survival resistance to venetoclax therapy. Due unique cysteine residue BH3 binding site, development covalent inhibitors targeting Bfl-1 represents promising strategy for treatment. Herein, optimization cellular tool from lead-like hit using structure based design is described. Informed by reversible X-ray fragment screen, establish interactions with key glutamic acid...
South Asians have a higher risk to develop obesity and related disorders compared white Caucasians. This is likely in part due their lower resting energy expenditure (REE) as with less energy-combusting brown adipose tissue (BAT). Since overactivation of the endocannabinoid system associated low BAT activity, we hypothesized that tone. Healthy lean Caucasian (n = 10) Asian men were cold-exposed activate BAT. Before after cooling, REE was assessed plasma collected for analysis...
Covalent inhibition is a valuable modality in drug discovery because of its potential ability decoupling pharmacokinetics from pharmacodynamics by prolonging the residence time on target interest. This increase occupancy limited only rate turnover. However, limitation such studies to translate vitro assessment appropriate cellulo engagement parameter covalent probes. Estimation parameters often impeded low-throughput nature current probe-free approaches. In this study, an ultra-performance...
The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists five members, which are involved in the Ca2+-independent production N-acylphosphatidylethanolamines (NAPEs). NAPEs lipid precursors for bioactive N-acylethanolamines (NAEs) that various physiological processes such as food intake, pain, inflammation, stress, anxiety. Recently, we identified α-ketoamides first pan-active PLAAT inhibitor scaffold reduced arachidonic acid levels PLAAT3-overexpressing U2OS...
Objective The study aimed to investigate whether markers of endocannabinoid signaling differed between men with overweight South Asian and white Caucasian descent. Methods We included ( n = 10) prediabetes aged 35 50 years. Plasma samples were analyzed for endocannabinoids, their congeners, lipids. In adipose tissue (WAT) skeletal muscle biopsies, mRNA expression genes involved in the system (ECS) was assessed using quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR)....
BFL1, a member of the antiapoptotic BCL2 family, has been relatively understudied compared to its counterparts despite evidence overexpression in various hematological malignancies. Across two articles, we describe development BFL1 vivo tools. The first article describes hit identification from covalent fragment library and subsequent evolution compound 6.22 This work reports structure-based optimization 6 into series inhibitors selective over other family members, with low nanomolar...
Abstract Covalent inhibition is a valuable modality in drug-discovery due to its potential ability decoupling pharmacokinetics from pharmacodynamics by prolonging the residence time of drug on target interest. This increase occupancy limited only rate turnover. However, limitation such studies translate in-vitro assessment appropriate in-cellulo engagement parameter covalent probes. Estimation parameters often impeded low-throughput nature current label-free approaches. In this study, an...