107 results found
Marcellini A, Swieboda D, Guedan A, et al., 2021, Glucocorticoids impair type I IFN signalling and enhance rhinovirus replication, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 893, ISSN: 0014-2999
McErlean P, Kelly A, Dhariwal J, et al., 2020, Profiling of H3K27Ac Reveals the Influence of Asthma on the Epigenome of the Airway Epithelium, FRONTIERS IN GENETICS, Vol: 11
Anderson C, Patel P, Viney J, et al., 2020, A degradatory fate for CCR4 suggests a primary role in Th2 inflammation, Journal of Leukocyte Biology, Vol: 107, Pages: 455-466, ISSN: 0741-5400
CCR4 is the sole receptor for the chemokines CCL22 and CCL17. Clinical studies of asthmatic airways have shown levels of both ligands and CCR4+ Th2 cells to be elevated, suggestive of a role in disease. Consequently, CCR4 has aroused much interest as a potential therapeutic target and an understanding of how its cell surface expression is regulated is highly desirable. To this end, receptor expression, receptor endocytosis, and chemotaxis were assessed using transfectants expressing CCR4, CCR4+ human T cell lines, and human Th2 cells polarized in vitro. CCL17 and CCL22 drove rapid endocytosis of CCR4 in a dose‐dependent manner. Replenishment at the cell surface was slow and sensitive to cycloheximide, suggestive of de novo synthesis of CCR4. Constitutive CCR4 endocytosis was also observed, with the internalized CCR4 found to be significantly degraded over a 6‐h incubation. Truncation of the CCR4 C‐terminus by 40 amino acids had no effect on cell surface expression, but resulted in significant impairment of ligand‐induced endocytosis. Consequently, migration to both CCL17 and CCL22 was significantly enhanced. In contrast, truncation of CCR4 did not impair constitutive endocytosis or degradation, suggesting the use of alternative receptor motifs in these processes. We conclude that CCR4 cell surface levels are tightly regulated, with a degradative fate for endocytosed receptor. We postulate that this strict control is desirable, given that Th2 cells recruited by CCR4 can induce the further expression of CCR4 ligands in a positive feedback loop, thereby enhancing allergic inflammation.
Marcellini A, Contoli M, Casolari P, et al., 2019, ICS/LABA effects on antiviral innate immune response. An in vitro analysis, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bryans JS, Kettleborough CA, Solari R, 2019, Are academic drug discovery efforts receiving more recognition with declining industry efficiency?, Expert Opin Drug Discov, Vol: 14, Pages: 605-607
McLean G, Girkin J, Solari R, 2019, Emerging therapeutic approaches, Rhinovirus Infections: Rethinking the Impact on Human Health and Disease, Pages: 239-263, ISBN: 9780128164174
There are currently no approved drugs for the treatment of rhinovirus (RV) or indeed of any picornavirus infection, despite decades of drug discovery efforts. Likewise there are no licensed vaccines for RV even though trials began in the late 1960s. However, a large number of experimental approaches that target RV itself, the RV-induced inflammatory response, or promote broad RV-specific immunity have been through preclinical development and clinical trials with mixed success. This chapter will amalgamate these studies and highlight the most promising and applicable therapeutic approaches.
McCrae C, Dzgoev A, Stahlman M, et al., 2018, Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 59, Pages: 713-722, ISSN: 1044-1549
An N, Guedan A, Mousnier A, et al., 2018, Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets, JOURNAL OF LIPID RESEARCH, Vol: 59, Pages: 1671-1684, ISSN: 0022-2275
Singanayagam A, Glanville N, Girkin J, et al., 2018, Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations, Nature Communications, Vol: 9, Pages: 1-16, ISSN: 2041-1723
Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor (IFNAR1−/−) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect.
Custovic A, Belgrave D, Lin L, et al., 2018, Cytokine responses to rhinovirus and development of asthma, allergic sensitization and respiratory infections during childhood, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1265-1274, ISSN: 1073-449X
BACKGROUND: Immunophenotypes of anti-viral responses, and their relationship with asthma, allergy and lower respiratory tract infections (LRTIs) are poorly understood. We characterized multiple cytokine responses of peripheral-blood mononuclear cells to rhinovirus stimulation, and their relationship with clinical outcomes. METHODS: In a population-based birth cohort, we measured 28 cytokines post-stimulation with rhinovirus-16 in 307 children aged 11 years. We used machine learning to identify patterns of cytokine responses, and related these patterns to clinical outcomes using longitudinal models. We also ascertained phytohaemagglutinin-induced TH2-cytokine responses [PHA-TH2]. RESULTS: We identified six clusters of children based on their rhinovirus-16 responses, which were differentiated by the expression of four cytokine/chemokine groups: interferon-related-(IFN); pro-inflammatory-(Inflam); TH2-chemokine-(TH2-chem); regulatory-(Reg). Clusters differed in their clinical characteristics. Children with IFNmodInflamhighestTH2-chemhighestReghighestrhinovirus-16-induced pattern had PHA-TH2lowresponse, and a very low asthma risk (OR:0.08 [95%CI 0.01-0.81], P=0.03). Two clusters had high risk of asthma and allergic sensitization, but with different trajectories from infancy to adolescence. The IFNlowestInflamhighTH2-chemlowRegmodcluster exhibited PHA-TH2lowestresponse, and was associated with early-onset asthma and sensitization, and the highest risk of asthma exacerbations (1.37 [1.07-1.76], P=0.014) and LRTI hospitalizations (2.40 [1.26-4.58], P=0.008) throughout childhood. In contrast, cluster with IFNhighestInflammodTH2-chemmodReghighrhinovirus-16-cytokine pattern was characterized by PHA-TH2highestresponse, and a low prevalence of asthma/sensitization in infancy which increased sharply to become the highest among all clusters by adolescence (but with low risk of asthma exacerbations). CONCLUSIONS: Early-onset troublesome asthma with early-life sensitization, later-
Mousnier A, Bell AS, Swieboda DP, et al., 2018, Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus, Nature Chemistry, Vol: 10, Pages: 599-606, ISSN: 1755-4330
Rhinoviruses are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. Identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking, and conformational control over linker geometry. We show that inhibition of co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, delivering low nanomolar antiviral activity against multiple rhinovirus strains, poliovirus and foot-and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.
Dhariwal J, Cameron A, Wong E, et al., 2018, Pulmonary Innate Lymphoid Cell Responses During Rhinovirus-Induced Asthma Exacerbations, American-Academy-of-Allergy-Asthma-and-Immunology / World-Allergy-Organization Joint Congress, Publisher: MOSBY-ELSEVIER, Pages: AB195-AB195, ISSN: 0091-6749
Toussaint M, Jackson DJ, Swieboda D, et al., 2017, Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation., Nat Med, Vol: 23, Pages: 1384-1384
This corrects the article DOI: 10.1038/nm.4332.
Marcellini A, Swieboda D, Guedan A, et al., 2017, Modulation of pro-inflammatory and anti-viral responses in BEAS2B cells by glucocorticoid agonists, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Toussaint M, Jackson DJ, Swieboda D, et al., 2017, Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation, Nature Medicine, Vol: 23, Pages: 681-691, ISSN: 1078-8956
Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.
Toussaint M, Swieboda D, Guedan A, et al., 2017, NETosis and associated host DNA orchestrate rhinovirus-induced type 2 allergic asthma exacerbation, Nature Medicine, ISSN: 1546-170X
Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of type 2 immunity is strongly implicated in asthma exacerbation, but how virus infection boosts type 2 responses during exacerbation is poorly understood. We report a significant correlation between release of host double stranded DNA (dsDNA) following rhinovirus infection and exacerbation of type 2 allergic inflammation and disease severity in patients. In a mouse model, we show that rhinovirus infection triggers neutrophil extracellular traps (NETs) formation and host dsDNA release. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or degrading NETs with DNase protects mice from type 2 allergic asthma exacerbations. Furthermore, injection of host dsDNA alone is sufficient to recapitulate many features of rhinovirus-induced type 2 immune responses and asthma pathology. Thus, NETosis and host dsDNA contribute to exacerbation pathogenesis and may represent potential targets for novel treatments of rhinovirus-induced asthma exacerbations.
Guedan A, Swieboda D, Charles M, et al., 2017, Investigation of the Role of Protein Kinase D in Human Rhinovirus Replication, Journal of Virology, Vol: 91, ISSN: 0022-538X
Picornavirus replication is known to cause extensive remodeling of Golgi and endoplasmic reticulum membranes, and a number of the host proteins involved in the viral replication complex have been identified, including oxysterol binding protein (OSBP) and phosphatidylinositol 4-kinase III beta (PI4KB). Since both OSBP and PI4KB are substrates for protein kinase D (PKD) and PKD is known to be involved in the control of Golgi membrane vesicular and lipid transport, we hypothesized that PKD played a role in viral replication. We present multiple lines of evidence in support of this hypothesis. First, infection of HeLa cells with human rhinovirus (HRV) induced the phosphorylation of PKD. Second, PKD inhibitors reduced HRV genome replication, protein expression, and titers in a concentration-dependent fashion and also blocked the replication of poliovirus (PV) and foot-and-mouth disease virus (FMDV) in a variety of cells. Third, HRV replication was significantly reduced in HeLa cells overexpressing wild-type and mutant forms of PKD1. Fourth, HRV genome replication was reduced in HAP1 cells in which the PKD1 gene was knocked out by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. Although we have not identified the molecular mechanism through which PKD regulates viral replication, our data suggest that this is not due to enhanced interferon signaling or an inhibition of clathrin-mediated endocytosis, and PKD inhibitors do not need to be present during viral uptake. Our data show for the first time that targeting PKD with small molecules can inhibit the replication of HRV, PV, and FMDV, and therefore, PKD may represent a novel antiviral target for drug discovery.
McErlean P, Kelly A, Dhariwal J, et al., 2016, EPIGENETIC LANDSCAPE OF THE ASTHMATIC AIRWAYS, British Thoracic Society Winter Meeting 2016, Publisher: BMJ PUBLISHING GROUP, Pages: A214-A214, ISSN: 0040-6376
Carlile GW, Robert R, Matthes E, et al., 2016, Latonduine Analogs Restore F508del–Cystic Fibrosis Transmembrane Conductance Regulator Trafficking through the Modulation of Poly-ADP Ribose Polymerase 3 and Poly-ADP Ribose Polymerase 16 Activity, Molecular Pharmacology, Vol: 90, Pages: 65-79, ISSN: 1521-0111
Cystic fibrosis (CF) is a major lethal genetic disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR). This encodes a chloride ion channel on the apical surface of epithelial cells. The most common mutation in CFTR (F508del-CFTR) generates a protein that is misfolded and retained in the endoplasmic reticulum. Identifying small molecules that correct this CFTR trafficking defect is a promising approach in CF therapy. However, to date only modest efficacy has been reported for correctors in clinical trials. We identified the marine sponge metabolite latonduine as a corrector. We have now developed a series of latonduine derivatives that are more potent F508del-CFTR correctors with one (MCG315 [2,3-dihydro-1H-2-benzazepin-1-one]) having 10-fold increased corrector activity and an EC50 of 72.25 nM. We show that the latonduine analogs inhibit poly-ADP ribose polymerase (PARP) isozymes 1, 3, and 16. Further our molecular modeling studies point to the latonduine analogs binding to the PARP nicotinamide-binding domain. We established the relationship between the ability of the latonduine analogs to inhibit PARP-16 and their ability to correct F508del-CFTR trafficking. We show that latonduine can inhibit both PARP-3 and -16 and that this is necessary for CFTR correction. We demonstrate that latonduine triggers correction by regulating the activity of the unfolded protein response activator inositol-requiring enzyme (IRE-1) via modulation of the level of its ribosylation by PARP-16. These results establish latonduines novel site of action as well as its proteostatic mechanism of action.
Robertson AL, Ogryzko NV, Henry KM, et al., 2016, Identification of benzopyrone as a common structural feature in compounds with anti-inflammatory activity in a zebrafish phenotypic screen., Disease Models & Mechanisms, Vol: 9, Pages: 621-632, ISSN: 1754-8411
Neutrophils are essential for host defence and are recruited to sites of inflammation in response to tissue injury or infection. For inflammation to resolve, these cells must be cleared efficiently and in a controlled manner, either by apoptosis or reverse migration. If the inflammatory response is not well regulated, persistent neutrophils may cause damage to host tissues and contribute to the pathogenesis of chronic inflammatory diseases, which respond poorly to current treatments. It is therefore important to develop drug discovery strategies that can identify new therapeutics specifically targeting neutrophils, either by promoting their clearance or by preventing their recruitment. Our recent in vivo chemical genetic screen for accelerators of inflammation resolution identified a subset of compounds sharing a common chemical signature, the bicyclic benzopyrone rings. Here, we further investigate the mechanisms of action of the most active of this chemical series, isopimpinellin, in our zebrafish model of neutrophilic inflammation. We found that this compound targets both the recruitment and resolution phases of the inflammatory response. Neutrophil migration towards a site of injury is reduced by isopimpinellin and this occurs as a result of PI3K inhibition. We also show that isopimpinellin induces neutrophil apoptosis to drive inflammation resolution in vivo using a new zebrafish reporter line detecting in vivo neutrophil caspase-3 activity and allowing quantification of flux through the apoptotic pathway in real-time. Finally, our studies reveal that clinically available ‘cromones’ are structurally related to isopimpinellin and have previously undescribed pro-resolution activity in vivo. These findings may have implications for the therapeutic use of benzopyrones in inflammatory disease.
Anderson CA, Solari R, Pease JE, 2015, Biased agonism at chemokine receptors: obstacles or opportunities for drug discovery?, Journal of Leukocyte Biology, Vol: 99, Pages: 901-909, ISSN: 0741-5400
Solari R, Pease JE, 2015, Targeting chemokine receptors in disease - a case study of CCR4., European Journal of Pharmacology, Vol: 763, Pages: 167-177, ISSN: 0014-2999
Since their early 1990s, the chemokine receptor family of G protein-coupled receptors (GPCRs) has been the source of much pharmacological endeavour. Best known for their key roles in recruiting leukocytes to sites of infection and inflammation, the receptors present themselves as plausible drug targets for therapeutic intervention. In this article, we will focus our attention upon CC Chemokine Receptor Four (CCR4) which has been implicated in diseases as diverse as allergic asthma and lymphoma. We will review the discovery of the receptors and their ligands, their perceived roles in disease and the successful targeting of CCR4 by both small molecule antagonists and monoclonal antibodies. We will also discuss future directions and strategies for drug discovery in this field.
Xie W, Pariollaud M, Wixted WE, et al., 2015, Identification and Characterization of PERK Activators by Phenotypic Screening and Their Effects on NRF2 Activation, PLOS ONE, Vol: 10, ISSN: 1932-6203
Solari R, Pease JE, Begg M, 2015, "Chemokine receptors as therapeutic targets: Why aren't there more drugs?", EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 746, Pages: 363-367, ISSN: 0014-2999
Mousnier A, Swieboda D, Pinto A, et al., 2014, Human Rhinovirus 16 Causes Golgi Apparatus Fragmentation without Blocking Protein Secretion, JOURNAL OF VIROLOGY, Vol: 88, Pages: 11671-11685, ISSN: 0022-538X
Deakin A, Duddy G, Wilson S, et al., 2014, Characterisation of a K390R ITK Kinase Dead Transgenic Mouse - Implications for ITK as a Therapeutic Target, PLOS ONE, Vol: 9, ISSN: 1932-6203
Carlile GW, Robert R, Matthes E, et al., 2014, BIOLOGICAL EVALUATION OF LATONDUINE ANALOGUES AS CORRECTORS OF MUTANT CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR CHANNELS BY INHIBITION OF PARP-3 AND PARP-16, PEDIATRIC PULMONOLOGY, Vol: 49, Pages: 294-294, ISSN: 8755-6863
Ajram L, Begg M, Slack R, et al., 2014, Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 729, Pages: 75-85, ISSN: 0014-2999
Privolizzi R, Solari R, Johnston SL, et al., 2014, The application of prophylactic antibodies for rhinovirus infections., Antivir Chem Chemother, Vol: 23, Pages: 173-177
Rhinoviruses are extremely common pathogens of the upper respiratory tract with adults experiencing on average 2-5 infections per year and children up to 12 infections. Although infections are not life threatening, except in cases of chronic lung disease where rhinoviruses are the major precipitant of acute exacerbations of disease, there is a high associated economic cost resulting from lost productivity due to absence from work or school. Treatment of infections focuses on symptom relief with anti-pyretics/analgesics as there are no antiviral therapies available and vaccine strategies face difficulties because of the large number of viral serotypes. Here, we assess the potential for prophylactic antibody intervention for these ubiquitous human pathogens.
Robertson AL, Holmes GR, Bojarczuk AN, et al., 2014, A Zebrafish Compound Screen Reveals Modulation of Neutrophil Reverse Migration as an Anti-Inflammatory Mechanism, SCIENCE TRANSLATIONAL MEDICINE, Vol: 6, ISSN: 1946-6234
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.