A5046701561- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Computational Drug Discovery Methods
- Cell Image Analysis Techniques
- Viral Infectious Diseases and Gene Expression in Insects
- CRISPR and Genetic Engineering
- Gene Regulatory Network Analysis
- SARS-CoV-2 detection and testing
- SARS-CoV-2 and COVID-19 Research
- Genetics, Bioinformatics, and Biomedical Research
- Protein Kinase Regulation and GTPase Signaling
- Innovative Microfluidic and Catalytic Techniques Innovation
- Single-cell and spatial transcriptomics
- Signaling Pathways in Disease
- Cancer, Hypoxia, and Metabolism
- Insect symbiosis and bacterial influences
- Advanced Fluorescence Microscopy Techniques
- Migraine and Headache Studies
- Olfactory and Sensory Function Studies
- RNA and protein synthesis mechanisms
- Phenothiazines and Benzothiazines Synthesis and Activities
- Bone health and treatments
- Pain Mechanisms and Treatments
- Animal testing and alternatives
- Molecular Biology Techniques and Applications
AstraZeneca (United Kingdom)
2015-2023
Medicines Discovery Catapult
2020-2021
AstraZeneca (Germany)
2021
GlaxoSmithKline (United Kingdom)
2007-2016
AstraZeneca (Brazil)
2014
Molecular Discovery (United Kingdom)
2008
University of Leeds
1999-2008
Research Triangle Park Foundation
2003
University of Nottingham
1999
GPR41 and GPR43 are related members of a homologous family orphan G protein-coupled receptors that tandemly encoded at single chromosomal locus in both humans mice. We identified the acetate anion as an agonist human during routine ligand bank screening yeast. This activity was confirmed after transient transfection into mammalian cells using Ca2+ mobilization [35S]guanosine 5′-O-(3-thiotriphosphate) binding assays by coexpression with GIRK protein-regulated potassium channels Xenopus laevis...
G protein-coupled receptor (GPCR) signaling is the primary method eukaryotes use to respond specific cues in their environment. However, relationship between stimulus and response for each GPCR difficult predict due diversity natural signal transduction architecture expression. Using genome engineering yeast, we constructed an insulated, modular system study how stimuli can be predictably tuned using synthetic tools. We delineated contributions of a minimal set key components via...
A variety of G-protein–coupled receptor (GPCR) screening technologies have successfully partnered a number GPCRs with their cognate ligands. GPCR-mediated β-arrestin recruitment is now recognized as distinct intracellular signaling pathway, and ligand-receptor interactions may show bias toward over classical GPCR pathways. We hypothesized that the failure to identify native ligands for remaining orphan be consequence biased signaling. To investigate this, we assembled 10 500 candidate...
Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival fecundity, making Wolbachia a promising therapeutic target. Here we perform high-throughput screen of AstraZeneca's 1.3 million in-house compound library identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the...
BackgroundWhole-genome sequencing (WGS) is the gold standard diagnostic tool to identify and genetically characterise emerging pathogen mutations (variants), but cost, capacity, timeliness limit its use when large populations need rapidly assessing. We assessed potential of genotyping assays provide accurate timely variant information at scale by retrospectively examining surveillance for SARS-CoV-2 variants in England between March September, 2021, were used widely detection.MethodsWe chose...
Asthma is a multifactorial disease, in which the intricate interplay between genetic and environmental factors underlies overall phenotype of disease. Using genome-wide scan for linkage population comprising Danish families, we identified novel linked locus on chromosome 1qter (LOD 3.6, asthma) supporting evidence this was both asthma atopic-asthma phenotypes GAIN (Genetics International Network) families. The putative susceptibility gene progressively localized to 4.5 Mb region 1q adjacent...
While mechanisms of cytotoxicity and cytostaticity have been studied extensively from the biological side, relatively little is currently understood regarding areas chemical space leading to cytostasis in large compound collections. Predicting rationalizing potential adverse mechanism-of-actions (MoAs) small molecules however crucial for screening library design, given link even low level events observed man. In this study, we analyzed results a cell-based cascade, comprising 296 970...
Abstract Agonist bias occurs when different ligands produce distinct signalling outputs acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate endogenous agonist with consequences for calcitonin receptor-like receptor, CLR. By switching receptor-activity modifying protein (RAMP) associated CLR can “re-route” pathways activated by agonists gene-related peptide (CGRP), adrenomedullin (AM) 2...
A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification a novel series inhibitors. Elucidation bound ligand crystal structure showed that inhibitors exhibited binding mode in previously identified allosteric site (R132H). This information guided optimization yielding submicromolar enzyme with promising cellular activity. Encouragingly, one compound from this was found induce myeloid differentiation...
The receptor for calcitonin gene-related peptide (CGRP) has been the target development of novel small molecule antagonists treatment migraine. Two such antagonists, BIBN4096BS and MK-0974, have shown great promise in clinical trials hence a deeper understanding mechanism their interaction with is now required. structure CGRP unusual since it comprised hetero-oligomeric complex between receptor-like (CRL) an accessory protein (RAMP1). Both CLR RAMP1 components extracellular domains which...
The global impact of synthetic biology has been accelerating, because the plummeting cost DNA synthesis, advances in genetic engineering, growing understanding genome organization, and explosion data science. However, much discipline's application pharmaceutical industry remains enigmatic. In this review, we highlight recent examples on target validation, assay development, hit finding, lead optimization, chemical through to development cellular therapeutics. We also availability tools...
The rise of new SARS-CoV-2 variants worldwide requires global molecular surveillance strategies to support public health control. Early detection and evaluation their associated risk spreading within the population are pivotal.
Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: antagonists are inducers, while maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, P450 profile, specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize developability profile series. Following this...
Flow cytometry is a powerful tool providing multiparametric analysis of single cells or particles. The introduction faster plate-based sampling technologies on flow cytometers has transformed the technology into one that become attractive for higher throughput drug discovery screening. This article describes AstraZeneca's perspectives deployment and application high-throughput (HTFC) platforms small-molecule screening (HTS), structure-activity relationship (SAR) phenotypic screening,...
Cell-based assays have long been important within hit discovery paradigms; however, improving the disease relevance of assay system can positively affect translation small-molecule drug discovery, especially if adopted in initial identification assay. Consequently, there is an increasing need for disease-relevant systems capable running at large scale, including use induced pluripotent stem cells and donor-derived primary cells. Major hurdles to adopting these high-throughput screening are...
Receptor component protein (RCP) is a 148 amino acid intracellular peripheral membrane protein, previously identified as promoting the coupling of CGRP to cAMP production at receptor, heterodimer calcitonin receptor like-receptor (CLR), family B G protein-coupled (GPCR) and activity modifying 1 (RAMP1). We extend these observations show that it selectively enhances Gs but not Gq or pERK activation. At other GPCRs, calcitonin, corticotrophin releasing factor type 1a glucagon-like peptide 2...
Signalling of the calcitonin-like receptor (CLR) is multifaceted, due to its interaction with activity modifying proteins (RAMPs), and three endogenous peptide agonists. Previous studies have focused on bias G protein signalling mediated by internalisation CLR-RAMP complex has been assumed follow same pattern as other Class B1 Protein-Coupled Receptors (GPCRs). Here we sought measure desensitisation complexes in response agonists, through measurement β-arrestin recruitment internalisation....
Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) bind activate the PTH/PTHrP receptor (PTH-1R). However, while related PTH-2R responds potently to PTH, it is not activated by PTHrP. Two sites are known be responsible for these different potencies. First, absence of efficacy PTHrP at due presence His-5 in (Ile-5 PTH), which interacts with receptor's juxtamembrane domain. Second, has lower affinity than PTH because Phe-23 (Trp-23 N-terminal extracellular We used...
Measurement of intracellular calcium release following agonist challenge within cells expressing the relevant membrane protein is a commonly used format to derive structure-activity relationship (SAR) data compound profiling assay. The Fluorometric Imaging Plate Reader (FLIPR) has become gold standard for this purpose. FLIPR traditionally uses that are maintained in continuous culture iterative chemistry campaigns. This supply dictates assays can only be run on 4 5 weekdays, or alternative...
The novel 7-transmembrane receptor MrgX1 is located predominantly in the dorsal root ganglion and has consequently been implicated perception of pain. Here we describe discovery optimization a small molecule agonist initial docking studies this ligand into order to provide suitable lead tool compound for elucidation physiological function receptor.
The Anti- Wolbachia (A·WOL) consortium at the Liverpool School of Tropical Medicine (LSTM) has partnered with Global High-Throughput Screening (HTS) Centre AstraZeneca to create first anthelmintic HTS for neglected tropical diseases (NTDs). A·WOL aims identify novel macrofilaricidal drugs targeting essential bacterial symbiont ( Wolbachia) filarial nematodes causing onchocerciasis and lymphatic filariasis. Working in collaboration, we have validated a robust high-throughput assay capable...
Abstract Lighthouse Labs network tests for the presence of RNA SARS-CoV-2, causative agent COVID-19. The Thermofisher TaqPath assay targets three regions SARS-CoV-2; ORF1ab, N and S-genes. identified a drop in S-gene target detection among positive samples due to circulation new SARS-CoV-2 Variant Concern (VOC) designated as 202012/01. By end December 2020, 60% daily test results at Alderley Park Labs, were linked Concern. This timeline view identifies rapid spread variant across country.