A5081877677- Receptor Mechanisms and Signaling
- Diabetes Treatment and Management
- Pancreatic function and diabetes
- Neuropeptides and Animal Physiology
- Metabolism, Diabetes, and Cancer
- Enzyme Production and Characterization
- Infectious Encephalopathies and Encephalitis
- Drug-Induced Hepatotoxicity and Protection
- Neuroscience and Neuropharmacology Research
- Malaria Research and Control
- Peptidase Inhibition and Analysis
- Cardiac electrophysiology and arrhythmias
- Hemoglobin structure and function
- Ion channel regulation and function
- Protein Interaction Studies and Fluorescence Analysis
- Microfluidic and Capillary Electrophoresis Applications
- Protein Structure and Dynamics
- Carbohydrate Chemistry and Synthesis
- Adenosine and Purinergic Signaling
Covance (United Kingdom)
2023-2024
Imperial College London
2019-2021
GlaxoSmithKline (United Kingdom)
2009
ABSTRACT This study represents the first phase III trial of safety, tolerability, and effectiveness tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly prophylaxis with 200 mg (492 subjects) or 250 mefloquine (162 6 months on peacekeeping deployment to East Timor. After returning Australia, tafenoquine-receiving subjects placebo mefloquine-receiving 30 primaquine daily 14 days. There were no clinically significant differences...
Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) are important regulators of insulin secretion energy metabolism. GLP-1R agonists have been successfully deployed treatment type 2 diabetes, but it has suggested that their efficacy is limited by target receptor desensitization downregulation due to recruitment β-arrestins. Indeed, recently described with reduced β-arrestin-2 delivered promising results...
Background and Purpose Amino acid substitutions at the N‐termini of glucagon‐like peptide‐1 (GLP‐1) receptor agonist peptides result in distinct patterns intracellular signalling, sub‐cellular trafficking efficacy vivo. Here, we to determine whether sequence differences ligand C‐termini clinically approved GLP‐1 agonists exendin‐4 lixisenatide lead similar phenomena. Experimental Approach Exendin‐4, N‐terminally substituted analogues with biased signalling characteristics were compared...
The objective of this study was to determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy, and appetite suppression. In vitro signalling responses were measured using biochemical biosensor assays. GLP-1R trafficking determined by confocal microscopy diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects, suppression in acute, sub-chronic, chronic...
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking the GLP-1R influence its signalling properties and therapeutic potential type 2 diabetes. Here, we have evaluated how different factors combine to control post-endocytic recycling versus degradative pathways. Experiments were performed primary islet cells, INS-1 832/3 clonal beta cells HEK293 using biorthogonal labelling determine...
Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of glucagon-like peptide-1 receptor (GLP-1R) type 2 diabetes obesity. In present study, we evaluated a peptide series with varying sequence homology between native GLP-1 exendin-4, archetypal ligands on which approved GLP-1R agonists are based. We find notable differences agonist-mediated cyclic AMP signaling, recruitment β-arrestins, endocytosis, recycling, dependent both...
Receptor Activity-Modifying Protein 2 (RAMP2) is a chaperone protein which allosterically binds to and interacts with the glucagon receptor (GCGR). The aims of this study were investigate effects RAMP2 on GCGR trafficking signalling in liver, where (GCG) important for carbohydrate lipid metabolism.Subcellular localisation presence absence was investigated using confocal microscopy, radioligand binding assays human embryonic kidney (HEK293T) hepatoma (Huh7) cells. Mouse fibroblasts (MEFs)...
Glucagon receptor agonists show promise as components of next generation metabolic syndrome pharmacotherapies. However, the biology glucagon action is complex, controversial, and likely context dependent. As such, a better understanding chronic (GCGR) agonism essential to identify mitigate potential clinical side-effects. Herein we present novel, long-acting analogue (GCG104) with high receptor-specificity potent in vivo action. It has allowed us make two important observations about...
Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss improve glycaemic control in type 2 diabetes obesity. In this study, we investigated the cellular metabolic effects of modulating balance between G protein β-arrestin-2 recruitment at GLP-1R GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to duration action mono-agonists by reducing target desensitisation downregulation. Dipeptidyl dipeptidase-4...
Fluorescence-based potassium channel assays are typically run on expensive, hard to obtain, fluorescence imaging kinetic plate readers that uncommon in most laboratories. Here we describe the use of Brilliant Thallium Snapshot assay conduct an endpoint assay, so it can be used across multiple reader platforms more common many labs. These methods will allow users identify modulators channels. For this work, have taken a mode Molecular Devices FLIPR based protocol and adapted utilized readers,...
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions vivo. However, two prototypical protein-favouring agonists, P5 exendin-F1, are reported to divergent effects on insulin secretion. In this study we aimed resolve discrepancy by performing a...
From our NETSseq-derived human brain transcriptomics data, we identified GPR55 as a potential molecular target for the treatment of motor symptoms in patients with Parkinson's disease. high-throughput screen, and optimized agonists nanomolar potency against both rat GPR55. We discovered compounds either strong or limited β-arrestin signaling receptor desensitization, indicating biased signaling. A compound that showed minimal desensitization demonstrated reduction firing frequency medium...
Abstract Background and purpose Amino acid substitutions at the N-termini of glucagon-like peptide-1 receptor agonist (GLP-1RA) peptides result in distinct patterns intracellular signalling, sub-cellular trafficking efficacy vivo . Here we aimed to determine whether sequence differences ligand C-termini clinically approved GLP-1RAs exendin-4 lixisenatide lead similar phenomena. We also sought establish impact C-terminus on signal bias resulting from modifications elsewhere molecule....
Abstract Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) are important regulators of insulin secretion energy metabolism. Recently described GLP-1 receptor agonists showing signal bias in favour cyclic AMP over β-arrestin-2 recruitment have delivered promising results preclinical studies. Here we first sought to establish role β-arrestins control intracellular signalling trafficking responses at closely...
Abstract Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of glucagon-like peptide-1 receptor (GLP-1R) type 2 diabetes obesity. In present study, we evaluated a peptide series with varying sequence homology between native GLP-1 exendin-4, archetypal ligands on which approved GLP-1R agonists are based. We find notable differences agonist-mediated signalling, endocytosis recycling, dependent both introduction His → Phe switch...
Abstract Objectives Receptor Activity-Modifying Protein 2 (RAMP2) is a chaperone protein which allosterically binds to and interacts with the glucagon receptor (GCGR). The aims of this study were investigate effects RAMP2 on GCGR trafficking signalling in liver, where important for carbohydrate lipid metabolism. Methods Subcellular localisation presence absence was investigated using confocal microscopy, assays radioligand binding human embryonic kidney (HEK293T) hepatoma (Huh7) cells. Mouse...
Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | 1479-6848 (online)
Abstract Objective To determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy and appetite suppression. Methods In vitro signalling responses were measured using biochemical biosensor assays. GLP-1 trafficking was determined by confocal microscopy diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects suppression in acute, sub-chronic chronic settings...
Abstract The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions vivo . However, two prototypical protein-favouring agonists, P5 exendin-F1, are reported to divergent effects on insulin secretion. In this study we aimed resolve discrepancy by...
Abstract Objective Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss improve glycaemic control in type 2 diabetes obesity. In this study we investigated the cellular metabolic effects of modulating balance between G protein activation β-arrestin-2 recruitment at GLP-1R GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to duration action mono-agonists by reducing target desensitisation downregulation....
Conference Article| December 01 1987 A low buoyant density factor which inhibits proteoglycan aggregation PHILIP D. PICKFORD; PICKFORD 1Department of Physiological Sciences, The University Medical School, Framlington Place, Newcastle Upon Tyne, NE2 4HH, U.K. Search for other works by this author on: This Site PubMed Google Scholar JEFFREY P. PEARSON Biochem Soc Trans (1987) 15 (6): 1089–1090. https://doi.org/10.1042/bst0151089a Article history Received: June 18 Views Icon contents Figures &...