A5048769374- Receptor Mechanisms and Signaling
- RNA Interference and Gene Delivery
- Neuropeptides and Animal Physiology
- Advanced biosensing and bioanalysis techniques
- Lipid Membrane Structure and Behavior
- Monoclonal and Polyclonal Antibodies Research
- Nanoparticle-Based Drug Delivery
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- HER2/EGFR in Cancer Research
- Analytical Chemistry and Chromatography
- Peroxisome Proliferator-Activated Receptors
- Peptidase Inhibition and Analysis
- Drug Transport and Resistance Mechanisms
- Diabetes Treatment and Management
- Immunotherapy and Immune Responses
- Pharmacological Effects and Assays
- Advanced Biosensing Techniques and Applications
- Spectroscopy and Quantum Chemical Studies
- Immune Response and Inflammation
- Invertebrate Taxonomy and Ecology
- Bacterial Genetics and Biotechnology
- Synthesis of β-Lactam Compounds
- Neuroscience and Neuropharmacology Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Technical University of Denmark
2018-2025
University of Southern Denmark
2013-2023
University of Cambridge
2022
Lundbeck Foundation
2015-2016
University of Glasgow
2014
Lundbeck (Denmark)
2013
UiT The Arctic University of Norway
1998
Analysis of the roles short chain fatty acid receptor, free 3 receptor (FFA3), has been severely limited by low potency its endogenous ligands, crossover function these on closely related 2 and a dearth FFA3-selective synthetic ligands. From series hexahydroquinolone-3-carboxamides, we demonstrate that 4-(furan-2-yl)-2-methyl-5-oxo-<i>N</i>-(<i>o</i>-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide is selective moderately potent positive allosteric modular (PAM)-agonist FFA3 receptor....
A human epidermal growth factor receptor 2 (HER2)-specific nanobody called 2Rs15d, containing a His3LysHis6 segment at the C-terminus, was recombinantly produced. Subsequent site-selective acylation on C-terminally activated lysine residue allowed installation of cytotoxin monomethyl auristatin E-functionalized cathepsin B-sensitive payload to provide highly homogenous nanobody–drug conjugate (NBC), which demonstrated high potency and selectivity for HER2-positive breast cancer models.
The free fatty acid receptor 1 (FFA1/GPR40) is a potential target for treatment of type 2 diabetes. Although several potent agonists have been described, there remains strong need suitable tracers to interrogate ligand binding this receptor. We address by exploring fluorophore-tethering known FFA1 agonists. This led the development 4, high affinity tracer with favorable and polarity-dependent fluorescent properties. A close ideal overlap between emission spectrum NanoLuciferase tag...
Ligands with improved potency and selectivity for free fatty acid receptor 2 (FFA2R) have become available, we here characterize the neutrophil responses induced by one such agonist (Cmp1) antagonist (CATPB). Cmp1 triggered an increase in cytosolic concentration of Ca2+, neutrophils were then desensitized to acetate, a naturally occurring FFA2R agonist. The CATPB selectively inhibited or acetate. activated superoxide anion secretion at low level naive blood neutrophils. This response was...
Free fatty acid receptor 2 (FFA2/GPR43) is a for short-chain acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses potential target treatment various metabolic diseases. By bioisosteric replacement the central pyrrolidine core previously disclosed FFA2 agonist with synthetically more tractable thiazolidine, we were able rapidly synthesize screen analogues modified at both 2- 3-positions on thiazolidine core. Herein, report SAR...
The free fatty acid receptor 2 (FFA2/GPR43) is considered a potential target for treatment of metabolic and inflammatory diseases. Here we describe the development first fluorescent tracer FFA2 intended as tool assessment thermodynamic kinetic binding parameters unlabeled ligands. Starting with known azetidine antagonist, used carboxylic moiety not to be critical interaction attachment point nitrobenzoxadiazole (NBD) fluorophore. This led 4 (TUG-1609), favorable spectroscopic properties high...
Lipid nanoparticles (LNPs) constitute a facile and scalable approach for delivery of payloads to human cells. LNPs are relatively immunologically inert can be produced in cost effective manner. However, targeting across the blood-brain barrier (BBB) has proven challenging. In an effort target composed ionizable cationic lipid (DLin-MC3-DMA), cholesterol, phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG...
Tetra-divinylpyrimidine (TetraDVP) linkers offer a method for the generation of antibody conjugates with modular cargo loading and excellent stability via all-in-one disulfide bridging.
Abstract Free Fatty Acid Receptor 2 is a GPCR activated by short chain fatty acids produced in high levels the lower gut microbial fermentation of non-digestible carbohydrates. A major challenge studying this receptor that mouse ortholog does not have significant affinity for antagonists are able to block human receptor. Docking exemplar from two chemical series homology models both and suggested single lysine - arginine variation at extracellular face might provide basis antagonist...
The feasibility of exploiting secretory phospholipase A2 (sPLA2) enzymes, which are overexpressed in tumors, to activate drug release from liposomes precisely at the tumor site has been demonstrated before. Although efficacy developed formulations was evaluated using vitro and vivo models, pattern sPLA2-assisted is unknown due lack a suitable bio-relevant model. We report here on development novel bioluminescence living-cell-based luciferase assay for monitoring sPLA2-triggered luciferin...
Hypercholesterolemia is a condition that characterized by very high levels of cholesterol in the blood and major correlating factor with heart disease. Indeed, low-density lipoprotein (LDL) have been causally linked to development atherosclerotic cardiovascular disease (ASCVD). A method specifically reduce long-term, stable manner could prove therapeutically relevant. Cholesterol removed from LDL receptor (LDLR) liver. Others we discovered long non-coding RNA (lncRNA; BM450697) functions as...
We herein describe the cell-specific release of alcohol-containing payloads via a sulfatase-sensitive linker in antibody-drug conjugates (ADCs). The shows efficient sulfatase-mediated and high stability human mouse plasma. In vitro evaluation demonstrates potent antigen dependent toxicity towards breast cancer cell lines.
Abstract The ability to manipulate and fuse nano-compartmentalized volumes addresses a demand for spatiotemporal control in the field of synthetic biology, example bottom-up construction (bio)chemical nanoreactors interrogation enzymatic reactions confined space. Herein, we mix entrapped sub-attoliter liposomes (~135 nm diameter) via lipid bilayer fusion, facilitated by hybridization membrane-anchored lipidated oligonucleotides. We report on an improved synthesis membrane-anchor...
Free fatty acid receptor 3 (FFA3, previously GPR41) is activated by short-chain acids, mediates health effects of the gut microbiota, and a therapeutic target for metabolic inflammatory diseases. The shortage well-characterized tool compounds has however impeded progress. Herein, we report structure–activity relationship an allosteric modulator series characterization physicochemical pharmacokinetic properties selected compounds, including previous new tools. Two representatives, 57...
Free fatty acid receptor 2 (FFA2) is a sensor for short-chain acids that has been identified as an interesting potential drug target treatment of metabolic and inflammatory diseases. Although several ligand series are known the receptor, there still need improved compounds. One most potent frequently used antagonists amide-substituted phenylbutanoic CATPB (1). We here report structure-activity relationship exploration this compound, leading to identification homologues with increased...
The free fatty acid receptor 2 (FFA2), also known as GPR43, mediates effects of short-chain acids and has attracted interest a potential target for treatment various metabolic inflammatory diseases. Herein, we report the results from bioisosteric replacement carboxylic group established FFA2 antagonist CATPB SAR investigations around these compounds, leading to discovery first high-potency antagonists, with preferred compound TUG-2304 (16l) featuring IC50 values 3–4 nM in both cAMP GTPγS...
Synthetic oligonucleotides, their complexes and conjugates with other biomolecules represent valuable research tools therapeutic agents. In spite of growing applications in basic clinical science, only few studies have addressed the issue such compounds' stability biological media. Herein, we studied two therapeutically relevant oligonucleotide probes simulated biofluids; 21 nucleotide-long DNA/locked nucleic acid ON targeted toward cancer-associated BRAF V600E mutation, a longer DNA analog...