Media in the Netherlands and abroad reported extensively about the drug research led by Leiden chemist Mario van der Stelt. In this research, Van der Stelt shows which unwanted side-effects a French drug candidate has.

On Friday May 3rd 2013 NWO has announced that Dr. Mario van der Stelt, Division of Bio-Organic Synthesis (LIC) and Dr. Laura Heitman, Division of Medicinal Chemistry (LACDR), have been awarded with an ECHO-STIP grant for their project, entitled: “Novel target engagement biomarkers for better drug ca…

Grants awarded to molecular physiology research

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Cancer is the leading cause of death in the Netherlands, and, with over 100 different types of cancer, it’s not a simple disease. Today, skin, breast, lung, prostate and colon cancer are the most diagnosed forms. Therefore, the discovery and development of new drugs has the ability to significantly…

Multiple Sclerosis, Parkinson’s and Alzheimer’s disease are the most common neurodegenerative disorders. Unfortunately, no effective treatments are currently available to halt the progression of these neuroinflammatory diseases [1].

Activity-based protein profiling (ABPP, also termed chemical proteomics), is one of the pillars of chemical biology, and at LED3 we have taken it to the next level. ABPP allows the assessment of protein function in live cells and tissues, which means that the activity of a complete protein family can…

The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a lipase that degrades a specific endocannabinoid. On the basis of this activity, BIA 10-2474 was being developed as a potential treatment for anxiety and pain. In a phase 1 trial of the drug, one subject died, and four others suffered…

The cannabinoid receptor type 2 (CB2R) is associated with several inflammatory diseases with an unmet medical need (e.g. Alzheimers, multiple sclerosis, reumatoid arthritis). Development of new chemical biology strategies to study this protein is essential to aid future development of drugs for these…

The aim of the research described in this thesis was to use structure-based design to optimise multiple properties of aryl sulfoxide monoacylglycerol lipase inhibitors as anti-inflammatory analgesics.

Molecular Physiology is a research group at the Leiden Institute of Chemistry dedicated to the design, synthesis and application of chemical tools to study important biological and biomedical questions. The group is headed by Prof. Dr. Mario van der Stelt and includes the research lines of Assistant…

This thesis explored the molecular pharmacological mechanisms of targeting CB2R via investigation of novel drug discovery concepts such as target binding kinetics, allosteric modulation and biased signaling.

This thesis describes the use of an activity-based proteomics method to study the endocannabinoid system.

N-acylethanolamines (NAEs), including N-arachidonoylethanolamine (anandamide, AEA), N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA), are signaling lipids that play an important role in different physiological process.

The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have…

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

Chemical tools to monitor drug-target engagement of endogenously expressed protein kinases are highly desirable for preclinical target validation in drug discovery. Here, we describe a chemical genetics strategy to selectively study target engagement of endogenous kinases.

Endocannabinoids are lipid messengers that modulate various physiological functions by activating the cannabinoid CB1 and CB2 receptors. While the metabolism of endocannabinoids and their action at the CB receptors is fairly well studied, the molecular mechanisms governing their release and transport…

The disease acute myeloid leukemia (AML) is characterized by fast progression and low survival rates.

Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo.

Research and education at the Leiden Institute of Chemistry is overseen by the Institute Board. The Board and representatives of the two research themes form the Management Team. The Scientific Council (WERA), the Institute Council (I-Raad) and the platform for PhDs and post-doctoral co-workers (LIC73)…

Diacylglycerol lipases (DAGLα and DAGLβ) are responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain and peripheral tissues. Selective DAGLβ inhibitors have been proposed as a potential treatment for inflammatory diseases with reduced potential for central…

Vancomycin is a last-resort antibiotic for the treatment of many Gram-positive bacterial infections, while remaining inactive against Gram-negative strains.

The endocannabinoid receptors CB1R and CB2R are involved in a plethora of processes, and consequently are involved in many pathological conditions. Their wide distribution makes the CBRs both an interesting therapeutic target and hard to study.

The spindle-assembly checkpoint (SAC) is a safety mechanism which secures accurate chromosome segregation during mitosis.

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

Global healthcare is on the verge of an antibiotic availability crisis as bacteria have evolved resistance to nearly all known antibacterials. Identifying new antibiotics that operate via novel modes-of-action is therefore of high priority.

Do objectively correct solutions to ethical dilemmas exist? Or is ethics always a matter of your opinion against my opinion? How do you know what to do? What kind of thing is ethics anyway? Can you be an expert in ethics?

Phospholipase A/acyltransferase 3 (PLAAT3) and PLAAT4 are enzymes involved in the synthesis of bioactive lipids. Despite sequential and structural similarities, the two enzymes differ in activity and specificity.

Drug development is a time- and resource-consuming process that starts with the discovery and validation of a (protein) target that contributes to pathogenesis or disease progression.

Synthesis and application of chemical biology tools to study immunomodulatory signaling lipids.

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

Monoacylglycerol lipase (MAGL) is the principal enzyme responsible for hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibition provides several potential therapeutic opportunities, including anti-nociceptive, anti-inflammatory and anti-cancer activity.

This thesis describes the development and optimization of the first molecular tools to study the enzyme PLA2G4E.

Vitamin A or retinol is essential in embryonic development, the visual cycle and the immune system.

Dit rapport maakt deel uit van het project Receptenboek burgerparticipatie in opdracht van de Rijksdienst voor het Cultureel Erfgoed (RCE) en met steun van het Fonds voor Cultuurparticipatie.

On 12 April 2022 Alok Oak successfully defended a doctoral thesis and graduated.

N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids.

China wordt steeds assertiever in zijn relaties met andere landen, maar achter dit beeld gaat een opmerkelijk diverse maatschappij en politieke realiteit schuil die tal van aanknopingspunten biedt voor samenwerking en verdere integratie van China in de wereld. In China een gids voor de 21e eeuw past…

Kinase inhibitors are key therapeutic agents, particularly in oncology, yet their clinical efficacy is often hampered by off-target effects and limited understanding of their cellular target profiles.

Neurodegenerative diseases pose a large medical and societal challenge. The etiology of these diseases is still poorly understood, which makes drug discovery for these diseases difficult.

This thesis advances our understanding of lipid uptake, a vital first step in lipid metabolism, by developing innovative click chemistry-based tools to study how immune cells internalize lipids.

An overview of awards and prizes granted to our staff and students in 2017, as well as special appointments and royal distinctions.

Less than 1 in 10 drug candidates that enter phase 1 clinical trials actually gets approved for human use.

In the last decades, activity-based protein profiling (ABPP) has emerged as a powerful chemical tool that may aid the ever-challenging drug discovery process.

In this thesis an activity-based probe was discovered that could visualize the activity of PLAATs. With an optimized gel-based ABPP assay in hand, screening of a compound library led to the discovery of alpha-ketoamides as a hit for PLAAT3.

In this thesis, the discovery and optimization is described of chemical tools to study the N-acylethanolamine (NAE) biosynthetic pathway.