A5002249713- Receptor Mechanisms and Signaling
- Innovative Microfluidic and Catalytic Techniques Innovation
- Computational Drug Discovery Methods
- Neuroscience and Neuropharmacology Research
- Drug Transport and Resistance Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Click Chemistry and Applications
- Neuropeptides and Animal Physiology
- Biotin and Related Studies
- Protein Interaction Studies and Fluorescence Analysis
- Lipid Membrane Structure and Behavior
- Carbohydrate Chemistry and Synthesis
- Retinoids in leukemia and cellular processes
- T-cell and B-cell Immunology
- HIV Research and Treatment
- Neurotransmitter Receptor Influence on Behavior
- Biochemical Analysis and Sensing Techniques
- Protein purification and stability
- Advanced biosensing and bioanalysis techniques
- Chemokine receptors and signaling
- Analytical Chemistry and Chromatography
- Pharmacological Receptor Mechanisms and Effects
- Molecular spectroscopy and chirality
- Gene Regulatory Network Analysis
Thorlabs (Germany)
2024
Sanofi (Belgium)
2023
Centre for Human Drug Research
2015-2018
Leiden University
2011-2018
Abstract CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with long residence time on the human CCR2, is effective inhibiting development atherosclerosis mouse disease model. First, radioligand binding assays were performed...
In 2017, the free and open-source software Open Systems Pharmacology (OSP) was launched. Since then, OSP has evolved from a small community into diverse network of stakeholders committed to advancing solutions for model-informed drug development (MIDD). this context, first Community Conference hosted by Novartis in Basel, Switzerland, on October 7-8, 2024, which gathered over 100 attendees more than 40 institutions. This perspective synthesizes key insights conference.
Background: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit efficacy solid tumors. Optimizing biodistribution is key overcoming these challenges. Methods: A physiologically based pharmacokinetic (PBPK) model was developed...
The reactivity of a variety mannopyranosyl uronic acid donors was assessed in set competition experiments, which two (S)-tolyl mannosyl were made to compete for limited amount promoter (NIS/TfOH). These experiments revealed that the mannuronic is significantly higher than expected based on electron-withdrawing capacity C-5 carboxylic ester function. A 4-O-acetyl-β-(S)-tolyl donor found have similar as per-O-benzyl-α-(S)-tolyl mannose.
The selection of the most suitable animal species and subsequent translation concentration-effect relationship to humans are critical steps for accurate assessment pro-arrhythmic risk candidate molecules. objective this investigation was assess quantitatively differences in QTc prolonging effects moxifloxacin between cynomolgus monkeys, dogs humans. impact interspecies is also illustrated a new molecule. Pharmacokinetic data ECG recordings from pre-clinical protocols monkeys phase I trial...
The influence of drug-target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as "rebinding" or "diffusion-limited binding". This gives rise a decreased decline complex concentration result locally higher that arises which leads prolonged exposure drug. phenomenon has been approximated steady-state approximation, assuming target. Recently, rate-limiting step approximation published. However, comparison between both...
Selectivity is an important attribute of effective and safe drugs, prediction in vivo target tissue selectivity would likely improve drug development success rates. However, a lack understanding the underlying (pharmacological) mechanisms availability directly applicable predictive methods complicates selectivity. We explore value combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) to predict influence dissociation constant...
Target binding kinetics influence the time course of drug effect (pharmacodynamics) both (i) directly, by affecting target occupancy, driven pharmacokinetics drug, competition with endogenous ligands and turnover, (ii) indirectly, signal transduction homeostatic feedback. For dopamine D2 receptor antagonists, it has been hypothesized that fast cause fewer side effects, because part dynamics dopaminergic system is preserved displacement these antagonists.Target antagonists after antagonist...
Abstract An important question in drug discovery is how to overcome the significant challenge of high attrition rates due lack efficacy and safety. A missing link understanding determinants for relation between drug-target binding kinetics signal transduction, particularly physiological context (multiple) endogenous ligands. We hypothesized that kinetic parameters both ligand play a crucial role determining cellular responses, using NK1 receptor as model system. demonstrated antagonists (DFA...
Drug–target binding kinetics (as determined by association and dissociation rate constants, kon koff) can be an important determinant of the drug action. However, effect compartment model is used most frequently instead a target to describe hysteresis. Here we investigate when drug–target should in lieu model. The utility (EC), (TB) combined compartment–target (EC–TB) were tested on either plasma (ECPL, TBPL EC–TBPL) or brain extracellular fluid (ECF) (ECECF, TBECF EC–TBECF) morphine...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
Abstract A ribosyltriazole ring‐fused cyclooctyne was prepared and converted into the corresponding phosphoramidite, which applied in automated synthesis of DNA RNA oligomers. Ensuing strain‐promoted alkyne–azide cycloaddition obtained oligonucleotides to fluorescent azides yielded oligonucleotide conjugates.