24 results on '"Herschke F"'
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2. Liver monocytes and kupffer cells remain transcriptionally distinct during chronic viral infection
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Garde, M.D.B. (Martijn) van de, Movita, D. (Dowty), Van Der Heide, M. (Marieke), Herschke, F. (Florence), De Jonghe, S. (Sandra), Gama, L. (Lucio), Boonstra, P.A. (André), Vanwolleghem, T. (Thomas), Garde, M.D.B. (Martijn) van de, Movita, D. (Dowty), Van Der Heide, M. (Marieke), Herschke, F. (Florence), De Jonghe, S. (Sandra), Gama, L. (Lucio), Boonstra, P.A. (André), and Vanwolleghem, T. (Thomas)
- Abstract
Due to the scarcity of immunocompetent animal models for chronic viral hepatitis, little is known about the role of the innate intrahepatic immune system during viral replication in the liver. These insights are however fundamental for the understanding of the inappropriate adaptive immune responses during the chronic phase of the infection. We apply the Lymphocytic Choriomenigitis Virus (LCMV) clone 13 mouse model to examine chronic virus-host interactions of Kupffer cells (KC) and infiltrating monocytes (IM) in an infected liver. LCMV infection induced overt clin
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- 2016
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3. Liver Monocytes and Kupffer Cells Remain Transcriptionally Distinct during Chronic Viral Infection
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Garde, Martijn, Movita, Dowty, Mulder, Marieke, Herschke, F, De Jonghe, S, Gama, L, Boonstra, Andre, Vanwolleghem, Thomas, Garde, Martijn, Movita, Dowty, Mulder, Marieke, Herschke, F, De Jonghe, S, Gama, L, Boonstra, Andre, and Vanwolleghem, Thomas
- Published
- 2016
4. Inflammatory monocytes recruited to the liver within 24 hours after virus-induced inflammation resemble kupffer cells but are functionally distinct
- Author
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Movita, D. (Dowty), Garde, M.D.B. (Martijn) van de, Biesta, P.J. (Paula), Kreefft, K. (Kim), Haagmans, B.L. (Bart), Zuniga, E. (Elina), Herschke, F. (Florence), De Jonghe, S. (Sandra), Janssen, H.L.A. (Harry), Gama, L. (Lucio), Boonstra, P.A. (André), Vanwolleghem, T. (Thomas), Movita, D. (Dowty), Garde, M.D.B. (Martijn) van de, Biesta, P.J. (Paula), Kreefft, K. (Kim), Haagmans, B.L. (Bart), Zuniga, E. (Elina), Herschke, F. (Florence), De Jonghe, S. (Sandra), Janssen, H.L.A. (Harry), Gama, L. (Lucio), Boonstra, P.A. (André), and Vanwolleghem, T. (Thomas)
- Abstract
Due to a scarcity of immunocompetent animal models for viral hepatitis, little is known about the early innate immune responses in the liver. In various hepatotoxic models, both pro- and anti-inflammatory activities of recruited monocytes have been described. In this study, we compared the effect of liver inflammation induced by the Toll-like receptor 4 ligand lipopolysaccharide (LPS) with that of a persistent virus, lymphocytic choriomeningitis virus (LCMV) clone 13, on early innate intrahepatic immune responses in mice. LCMV infection induces a remarkable influx of inflammatory monocytes in the liver within 24 h, accompanied by increased transcript levels of several proinflammatory cytokines and chemokines in whole liver. Importantly, while a single LPS injection results in similar recruitment of inflammatory monocytes to the liver, the functional properties of the infiltrating cells are dramatically different in response to LPS versus LCMV infection. In fact, intrahepatic inflammatory monocytes are skewed toward a secretory phenotype with impaired phagocytosis in LCMV-induced liver inflammation but exhibit increased endocytic capacity after LPS challenge. In contrast, F4/80high-Kupffer cells retain their steady-state endocytic functions upon LCMV infection. Strikingly, the gene expression levels of inflammatory monocytes dramatically change upon LCMV exposure and resemble those of Kupffer cells. Since inflammatory monocytes outnumber Kupffer cells 24 h after LCMV infection, it is highly likely that inflammatory monocytes contribute to the intrahepatic inflammatory response during the early phase of infection. Our findings are instrumental in understanding the early immunological events during virus-induced liver disease and point toward inflammatory monocytes as potential target cells for future treatment options in viral hepatitis.
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- 2015
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5. Cell-Cell Fusion Induced by Measles Virus Amplifies the Type I Interferon Response
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Herschke, F., primary, Plumet, S., additional, Duhen, T., additional, Azocar, O., additional, Druelle, J., additional, Laine, D., additional, Wild, T. F., additional, Rabourdin-Combe, C., additional, Gerlier, D., additional, and Valentin, H., additional
- Published
- 2007
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6. The engagement of activating FcγRs inhibits primate lentivirus replication in human macrophages
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David, A., primary, Sáez-Cirión, A., additional, Versmisse, P., additional, Malbec, O., additional, Iannascoli, B., additional, Herschke, F., additional, Lucas, M., additional, Barré-Sinoussi, F., additional, Mouscadet, J.-F., additional, Daëron, M., additional, and Pancino, G., additional
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- 2007
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7. The engagement of activating FcγRs inhibits primate lentivirus replication in human macrophages
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David, A., Asier Sáez-Cirión, Versmisse, P., Malbec, O., Iannascoli, B., Herschke, F., Lucas, M., Barré-Sinoussi, F., Mouscadet, J. -F, Daëron, M., and Pancino, G.
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Immunology ,Immunology and Allergy
8. Direct-acting antivirals for RSV treatment, a review.
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Bonneux B, Jacoby E, Ceconi M, Stobbelaar K, Delputte P, and Herschke F
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- Humans, Drug Discovery, Virus Replication drug effects, Animals, Drug Resistance, Viral, Drug Development, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Virus Infections virology, Respiratory Syncytial Virus, Human drug effects, Respiratory Syncytial Virus, Human genetics
- Abstract
Respiratory syncytial virus (RSV) causes respiratory disease and complications in infants, the elderly and the immunocompromised. While three vaccines and two prophylactic monoclonal antibodies are now available, only one antiviral, ribavirin, is currently approved for treatment. This review aims to summarize the current state of treatments directly targeting RSV. Two major viral processes are attractive for RSV-specific antiviral drug discovery and development as they play essential roles in the viral cycle: the entry/fusion process carried out by the fusion protein and the replication/transcription process carried out by the polymerase complex constituted of the L, P, N and M2-1 proteins. For each viral target resistance mutations to small molecules of different chemotypes seem to delineate definite binding pockets in the fusion proteins and in the large proteins. Elucidating the mechanism of action of these inhibitors thus helps to understand how the fusion and polymerase complexes execute their functions. While many inhibitors have been studied, few are currently in clinical development for RSV treatment: one is in phase III, three in phase II and two in phase I. Progression was halted for many others because of strategic decisions, low enrollment, safety, but also lack of efficacy. Lessons can be learnt from the halted programs to increase the success rate of the treatments currently in development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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9. Discovery of gem -Dimethyl-hydroxymethylpyridine Derivatives as Potent Non-nucleoside RSV Polymerase Inhibitors.
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Grosse S, Cooymans L, Embrechts W, McGowan D, Jacoby E, Stoops B, Gupta K, Ackermann M, Alnajjar S, Guillemont J, Jin Z, Kesteleyn B, Matcha K, Sriboonyapirat P, Truong A, Van Den Berg J, Yu X, Herschke F, Roymans D, Raboisson P, Rigaux P, and Jonckers THM
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- Animals, Humans, Mice, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Virus Infections virology, Structure-Activity Relationship, Sheep, Drug Discovery, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis, Respiratory Syncytial Virus, Human drug effects, Respiratory Syncytial Viruses drug effects, Antiviral Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents chemical synthesis, Pyridines pharmacology, Pyridines chemistry, Pyridines chemical synthesis
- Abstract
Respiratory syncytial virus (RSV) is an RNA virus infecting the upper and lower respiratory tract and is recognized as a major respiratory health threat, particularly to older adults, immunocompromised individuals, and young children. Around 64 million children and adults are infected every year worldwide. Despite two vaccines and a new generation monoclonal antibody recently approved, no effective antiviral treatment is available. In this manuscript, we present the medicinal chemistry efforts resulting in the identification of compound 28 (JNJ-8003), a novel RSV non-nucleoside inhibitor displaying subnanomolar activity in vitro as well as prominent efficacy in mice and a neonatal lamb models.
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- 2024
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10. Spiro-Azetidine Oxindoles as Long-Acting Injectables for Pre-Exposure Prophylaxis against Respiratory Syncytial Virus Infections.
- Author
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Kesteleyn B, Herschke F, Darville N, Stoops B, Jacobs T, Jacoby E, Shaffer P, Lammens L, Van Rompaey D, Matcha K, Martinez Lamenca C, Coesemans E, Hache G, Pieters S, Lecomte M, Hu L, Demin S, Milligan C, Abeywickrema P, De Bruyn S, Van Den Berg J, Ysebaert N, De Zwart L, Nájera I, Rigaux P, Roymans D, and Jonckers THM
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- Humans, Animals, Pre-Exposure Prophylaxis methods, Injections, Intramuscular, Indoles chemistry, Indoles administration & dosage, Indoles pharmacology, Injections, Subcutaneous, Respiratory Syncytial Virus, Human drug effects, Virus Internalization drug effects, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Infections drug therapy, Oxindoles chemistry, Oxindoles pharmacology, Spiro Compounds chemistry, Spiro Compounds pharmacology, Spiro Compounds pharmacokinetics, Spiro Compounds administration & dosage, Antiviral Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents administration & dosage, Azetidines chemistry, Azetidines pharmacology, Azetidines administration & dosage, Azetidines pharmacokinetics
- Abstract
Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.
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- 2024
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11. JNJ-7184, a respiratory syncytial virus inhibitor targeting the connector domain of the viral polymerase.
- Author
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Bonneux B, Shareef A, Tcherniuk S, Anson B, de Bruyn S, Verheyen N, Thys K, Conceição-Neto N, Van Ginderen M, Kwanten L, Ysebaert N, Vranckx L, Peeters E, Lanckacker E, Gallup JM, Sitthicharoenchai P, Alnajjar S, Ackermann MR, Adhikary S, Bhaumik A, Patrick A, Fung A, Sutto-Ortiz P, Decroly E, Mason SW, Lançois D, Deval J, Jin Z, Eléouët JF, Fearns R, Koul A, Roymans D, Rigaux P, and Herschke F
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- Animals, Humans, Sheep, Drug Resistance, Viral, Viral Proteins antagonists & inhibitors, Viral Proteins metabolism, Viral Proteins genetics, Lung virology, Antiviral Agents pharmacology, Antiviral Agents chemistry, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Virus Infections virology, Virus Replication drug effects, Respiratory Syncytial Virus, Human drug effects
- Abstract
Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology., Competing Interests: Declaration of competing interest The following authors were employees of Johnson & Johnson (the sponsor of the work) at the time when the described work was performed, and may hold Johnson & Johnson shares: BA, SdB, NV, KT, NCN, MVG, LK, NY, LV, EP, EL, AB, AP, AF, SWM, DL, JD, ZJ, AK, DR, PR, FH. The work of the other authors on this project was funded by Johnson & Johnson. BB is an employee of Antwerpen University and received funding from Johnson & Johnson and from Flanders Innovation & Entrepreneurship organization (VLAIO, HBC.2019.2157) for this work.RF has a sponsored research agreement with Merck & Co unrelated to the work presented here., (Copyright © 2024 Janssen Pharmaceutica NV. Published by Elsevier B.V. All rights reserved.)
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- 2024
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12. Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor.
- Author
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Yu X, Abeywickrema P, Bonneux B, Behera I, Anson B, Jacoby E, Fung A, Adhikary S, Bhaumik A, Carbajo RJ, De Bruyn S, Miller R, Patrick A, Pham Q, Piassek M, Verheyen N, Shareef A, Sutto-Ortiz P, Ysebaert N, Van Vlijmen H, Jonckers THM, Herschke F, McLellan JS, Decroly E, Fearns R, Grosse S, Roymans D, Sharma S, Rigaux P, and Jin Z
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- RNA-Dependent RNA Polymerase chemistry, Protein Binding, RNA metabolism, Nucleotides metabolism, Respiratory Syncytial Virus, Human
- Abstract
The respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA dependent RNA polymerase, capping, and Methyltransferase domains on L. Several nucleoside and non-nucleoside inhibitors have been reported to inhibit this polymerase complex, but the structural details of the exact inhibitor-polymerase interactions have been lacking. Here, we report a non-nucleoside inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral and polymerase assays. Our 2.9 Å resolution cryo-EM structure revealed that JNJ-8003 binds to an induced-fit pocket on the capping domain, with multiple interactions consistent with its tight binding and resistance mutation profile. The minigenome and gel-based de novo RNA synthesis and primer extension assays demonstrated that JNJ-8003 inhibited nucleotide polymerization at the early stages of RNA transcription and replication. Our results support that JNJ-8003 binding modulates a functional interplay between the capping and RdRp domains, and this molecular insight could accelerate the design of broad-spectrum antiviral drugs., (© 2023. Springer Nature Limited.)
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- 2023
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13. A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults.
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Pierson W, Tuefferd M, Herschke F, Slaets L, Crabbe M, Verstappen D, De Pelsmaeker S, Strickland I, Gane EJ, Schwabe C, Zhang Y, Meerts P, Vandenbossche J, Van Remoortere P, Verbrugge I, and De Creus A
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- Adult, Humans, Cytokines metabolism, Interferon-alpha therapeutic use, Phenotype, Transcriptome, Hepatitis B, Chronic drug therapy, Toll-Like Receptor 7 agonists
- Abstract
Background: Chronic hepatitis B (CHB) is responsible for major disease burden worldwide. However, the number of available therapies is limited; cure remains an elusive goal. JNJ-64794964 (JNJ-4964) is an oral toll-like receptor-7 (TLR7) agonist being evaluated for the treatment of CHB. Here, we investigated the capacity of JNJ-4964 to induce transcriptomic and immune cell changes in peripheral blood in healthy volunteers., Methods: Peripheral blood was collected in the JNJ-4964 first-in-human phase 1 trial at multiple time points to assess transcriptomics and changes in frequency and phenotype of peripheral-blood mononuclear cells. Correlation of changes to JNJ-4964 exposure (C
max ) and changes in cytokine levels (C-X-C motif chemokine ligand 10 [CXCL10] and interferon alpha [IFN-α]) were evaluated., Results: Fifty-nine genes, mainly interferon-stimulated genes, were up-regulated between 6 hours and 5 days after JNJ-4964 administration. JNJ-4964 increased frequencies of CD69, CD134, CD137, and/or CD253-expressing natural killer (NK) cells, indicative of NK cell activation. These changes correlated with Cmax , increase of CXCL10, and induction of IFN-α and were observed at IFN-α levels that are associated with no/acceptable flu-like adverse events. JNJ-4964 administration resulted in increased frequencies of CD86-expressing B cells, indicative of B-cell activation. These changes were predominantly observed at high IFN-α levels, which are associated with flu-like adverse events., Conclusions: JNJ-4964 administration led to changes in transcriptional profiles and immune cell activation phenotype, particularly for NK cells and B cells. Together, these changes could represent a set of biomarkers for the characterization of the immune response in CHB patients receiving TLR7 agonists.- Published
- 2023
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14. JNJ-64794964 (AL-034/TQ-A3334), a TLR7 agonist, induces sustained anti-HBV activity in AAV/HBV mice via non-cytolytic mechanisms.
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Herschke F, Li C, Zhu R, Han Q, Wu Q, Lu Q, Barale-Thomas E, De Jonghe S, Lin TI, and De Creus A
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- Animals, Antiviral Agents pharmacology, Cytokines immunology, Drug Evaluation, Preclinical, Hepatitis B immunology, Hepatitis B virus immunology, Male, Mice, Mice, Inbred C57BL, Antiviral Agents therapeutic use, Cytokines blood, Drugs, Investigational therapeutic use, Hepatitis B drug therapy, Hepatitis B Antibodies blood, Hepatitis B virus drug effects, Toll-Like Receptor 7 agonists
- Abstract
JNJ-64794964 (JNJ-4964/AL-034/TQ-A3334), an oral toll-like receptor 7 agonist, is being investigated for the treatment of chronic hepatitis B (CHB), a condition with a high unmet medical need. The anti-hepatitis B (HBV) activity of JNJ-4964 was assessed preclinically in an adeno-associated virus vector expressing HBV (AAV/HBV) mouse model. Mice were treated orally with 2, 6 or 20 mg/kg of JNJ-4964 once-per-week for 12 weeks and then followed up for 4 weeks. At 6 mg/kg, a partial decrease in plasma HBV-DNA and plasma hepatitis B surface antigen (HBsAg) was observed, and anti-HBs antibodies and HBsAg-specific T cells were observed in 1/8 animals. At 20 mg/kg, plasma HBV-DNA and HBsAg levels were undetectable for all animals 3 weeks after start of treatment, with no rebound observed 4 weeks after JNJ-4964 treatment was stopped. High anti-HBs antibody levels were observed until 4 weeks after JNJ-4964 treatment was stopped. In parallel, HBsAg-specific immunoglobulin G-producing B cells and interferon-γ-producing CD4
+ T cells were detected in the spleen. In 2/4 animals, liver HBV-DNA and HBV-RNA levels and liver hepatitis B core antigen expression dropped 4 weeks after JNJ-4964 treatment-stop. In these animals, HBsAg-specific CD8+ T cells were detectable. Throughout the study, normal levels of alanine aminotransferase were observed, with no hepatocyte cell death (end of treatment and 4 weeks later) and minimal infiltrations of B and T cells into the liver, suggesting induction of cytokine-mediated, non-cytolytic mechanisms., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
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15. Design and synthesis of tetrahydropyridopyrimidine based Toll-Like Receptor (TLR) 7/8 dual agonists.
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McGowan DC, Herschke F, Khamlichi MD, Rosauro ML, Benedicto SMP, Pauwels F, Stoops B, Pande V, Scholliers A, Van Schoubroeck B, Mostmans W, Van Dijck K, Thoné T, Horton H, Fanning G, Jonckers THM, and Raboisson P
- Subjects
- Administration, Oral, Animals, Drug Design, Mice, Structure-Activity Relationship, Pyrimidines pharmacology, Toll-Like Receptor 7 agonists, Toll-Like Receptor 8 agonists
- Abstract
In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure-activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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16. 2,4-Diaminoquinazolines as Dual Toll-like Receptor (TLR) 7/8 Modulators for the Treatment of Hepatitis B Virus.
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Embrechts W, Herschke F, Pauwels F, Stoops B, Last S, Pieters S, Pande V, Pille G, Amssoms K, Smyej I, Dhuyvetter D, Scholliers A, Mostmans W, Van Dijck K, Van Schoubroeck B, Thone T, De Pooter D, Fanning G, Jonckers THM, Horton H, Raboisson P, and McGowan D
- Subjects
- Animals, Antiviral Agents chemistry, Antiviral Agents metabolism, HEK293 Cells, Humans, Male, Mice, Molecular Docking Simulation, Protein Conformation, Quinazolines chemistry, Quinazolines metabolism, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Toll-Like Receptor 7 chemistry, Toll-Like Receptor 8 chemistry, Antiviral Agents pharmacology, Hepatitis B virus drug effects, Quinazolines pharmacology, Toll-Like Receptor 7 metabolism, Toll-Like Receptor 8 metabolism
- Abstract
A novel series of 2,4-diaminoquinazolines was identified as potent dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target activity. The stereochemistry of the amino alcohol was found to influence the TLR7/8 selectivity with the ( R) isomer resulting in selective TLR8 agonism. Lead optimization toward a dual agonist afforded ( S)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol 31 as a potent analog, being structurally different from previously described dual agonists ( McGowan J. Med. Chem. 2016 , 59 , 7936 ). Pharmacokinetic and pharmacodynamic (PK/PD) studies revealed the desired high first pass profile aimed at limiting systemic cytokine activation. In vivo pharmacodynamic studies with lead compound 31 demonstrated production of cytokines consistent with TLR7/8 activation in mice and cynomolgus monkeys and ex vivo inhibition of hepatitis B virus (HBV).
- Published
- 2018
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17. Discovery of selective 2,4-diaminoquinazoline toll-like receptor 7 (TLR 7) agonists.
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Pieters S, McGowan D, Herschke F, Pauwels F, Stoops B, Last S, Embrechts W, Scholliers A, Mostmans W, Van Dijck K, Van Schoubroeck B, Thoné T, De Pooter D, Fanning G, Rosauro ML, Khamlichi MD, Houpis I, Arnoult E, Jonckers THM, and Raboisson P
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- Animals, Cytochrome P-450 Enzyme Inhibitors chemical synthesis, Cytochrome P-450 Enzyme Inhibitors chemistry, Cytochrome P-450 Enzyme Inhibitors pharmacokinetics, Cytochrome P-450 Enzyme Inhibitors pharmacology, HEK293 Cells, Half-Life, Humans, Interferon-alpha metabolism, Male, Mice, Inbred C57BL, Microsomes, Liver metabolism, Molecular Docking Simulation, Molecular Structure, Quinazolines chemical synthesis, Quinazolines chemistry, Quinazolines pharmacokinetics, Rats, Sprague-Dawley, Structure-Activity Relationship, Toll-Like Receptor 8 agonists, Membrane Glycoproteins agonists, Quinazolines pharmacology, Toll-Like Receptor 7 agonists
- Abstract
The discovery of a novel series of highly potent quinazoline TLR 7/8 agonists is described. The synthesis and structure-activity relationship is presented. Structural requirements and optimization of this series toward TLR 7 selectivity afforded the potent agonist 48. Pharmacokinetic and pharmacodynamic studies highlighted 48 as an orally available endogenous interferon (IFN-α) inducer in mice., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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18. Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B.
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McGowan DC, Herschke F, Pauwels F, Stoops B, Smyej I, Last S, Pieters S, Embrechts W, Khamlichi MD, Thoné T, Van Schoubroeck B, Mostmans W, Wuyts D, Verstappen D, Scholliers A, De Pooter D, Dhuyvetter D, Borghys H, Tuefferd M, Arnoult E, Hong J, Fanning G, Bollekens J, Urmaliya V, Teisman A, Horton H, Jonckers THM, and Raboisson P
- Subjects
- Administration, Oral, Animals, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Dendritic Cells drug effects, Dendritic Cells metabolism, Dogs, Female, Genes, Reporter, HEK293 Cells, Hepatitis B immunology, Humans, Immunotherapy, Interferons biosynthesis, Macaca fascicularis, Madin Darby Canine Kidney Cells, Mice, Inbred C57BL, Molecular Docking Simulation, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Pyrroles pharmacokinetics, Pyrroles pharmacology, Rats, Structure-Activity Relationship, Toll-Like Receptor 7 genetics, Toll-Like Receptor 8 agonists, Toll-Like Receptor 8 genetics, Antiviral Agents chemical synthesis, Hepatitis B drug therapy, Pyrimidines chemical synthesis, Pyrroles chemical synthesis, Toll-Like Receptor 7 agonists
- Abstract
Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis.
- Published
- 2017
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19. Liver Monocytes and Kupffer Cells Remain Transcriptionally Distinct during Chronic Viral Infection.
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van de Garde MD, Movita D, van der Heide M, Herschke F, De Jonghe S, Gama L, Boonstra A, and Vanwolleghem T
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- Animals, Antigens, Viral immunology, Female, Kupffer Cells immunology, Mice, Mice, Inbred C57BL, Monocytes immunology, Phenotype, Hepatitis B, Chronic genetics, Hepatitis B, Chronic immunology, Kupffer Cells metabolism, Liver immunology, Monocytes metabolism, Transcription, Genetic
- Abstract
Due to the scarcity of immunocompetent animal models for chronic viral hepatitis, little is known about the role of the innate intrahepatic immune system during viral replication in the liver. These insights are however fundamental for the understanding of the inappropriate adaptive immune responses during the chronic phase of the infection. We apply the Lymphocytic Choriomenigitis Virus (LCMV) clone 13 mouse model to examine chronic virus-host interactions of Kupffer cells (KC) and infiltrating monocytes (IM) in an infected liver. LCMV infection induced overt clinical hepatitis, with rise in ALT and serum cytokines, and increased intrahepatic F4/80 expression. Despite ongoing viral replication, whole liver transcriptome showed baseline expression levels of inflammatory cytokines, interferons, and interferon induced genes during the chronic infection phase. Transcriptome analyses of sorted KC and IMs using NanoString technology revealed two unique phenotypes with only minimal overlap. At the chronic viral infection phase, KC showed no increased transcription of activation markers Cd80 and Cd86, but an increased expression of genes related to antigen presentation, whereas monocytes were more activated and expressed higher levels of Tnf transcripts. Although both KCs and intrahepatic IM share the surface markers F4/80 and CD11b, their transcriptomes point towards distinctive roles during virus-induced chronic hepatitis., Competing Interests: FH and SdJ are employees of Janssen-Pharmaceutica NV. Other authors declare no commercial relationships that might pose a conflict of interest in connection with the submitted manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2016
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20. Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus.
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McGowan D, Herschke F, Pauwels F, Stoops B, Last S, Pieters S, Scholliers A, Thoné T, Van Schoubroeck B, De Pooter D, Mostmans W, Khamlichi MD, Embrechts W, Dhuyvetter D, Smyej I, Arnoult E, Demin S, Borghys H, Fanning G, Vlach J, and Raboisson P
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- Animals, Antiviral Agents chemical synthesis, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Computer Simulation, Cytokines biosynthesis, Dogs, Hepatitis B drug therapy, Hepatitis B virology, Hepatitis B virus physiology, High-Throughput Screening Assays, Humans, Macaca fascicularis, Mice, Mice, Inbred C57BL, Molecular Docking Simulation, Pyrimidines chemical synthesis, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Sprague-Dawley, Stereoisomerism, Structure-Activity Relationship, Virus Replication drug effects, Antiviral Agents chemistry, Hepatitis B virus drug effects, Pyrimidines chemistry, Toll-Like Receptor 7 agonists, Toll-Like Receptor 8 agonists
- Abstract
Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.
- Published
- 2016
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21. Inflammatory monocytes recruited to the liver within 24 hours after virus-induced inflammation resemble Kupffer cells but are functionally distinct.
- Author
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Movita D, van de Garde MD, Biesta P, Kreefft K, Haagmans B, Zuniga E, Herschke F, De Jonghe S, Janssen HL, Gama L, Boonstra A, and Vanwolleghem T
- Subjects
- Animals, Cytokines metabolism, Gene Expression Profiling, Mice, Inbred C57BL, Hepatitis, Viral, Animal pathology, Kupffer Cells immunology, Liver pathology, Lymphocytic choriomeningitis virus immunology, Monocytes immunology
- Abstract
Unlabelled: Due to a scarcity of immunocompetent animal models for viral hepatitis, little is known about the early innate immune responses in the liver. In various hepatotoxic models, both pro- and anti-inflammatory activities of recruited monocytes have been described. In this study, we compared the effect of liver inflammation induced by the Toll-like receptor 4 ligand lipopolysaccharide (LPS) with that of a persistent virus, lymphocytic choriomeningitis virus (LCMV) clone 13, on early innate intrahepatic immune responses in mice. LCMV infection induces a remarkable influx of inflammatory monocytes in the liver within 24 h, accompanied by increased transcript levels of several proinflammatory cytokines and chemokines in whole liver. Importantly, while a single LPS injection results in similar recruitment of inflammatory monocytes to the liver, the functional properties of the infiltrating cells are dramatically different in response to LPS versus LCMV infection. In fact, intrahepatic inflammatory monocytes are skewed toward a secretory phenotype with impaired phagocytosis in LCMV-induced liver inflammation but exhibit increased endocytic capacity after LPS challenge. In contrast, F4/80(high)-Kupffer cells retain their steady-state endocytic functions upon LCMV infection. Strikingly, the gene expression levels of inflammatory monocytes dramatically change upon LCMV exposure and resemble those of Kupffer cells. Since inflammatory monocytes outnumber Kupffer cells 24 h after LCMV infection, it is highly likely that inflammatory monocytes contribute to the intrahepatic inflammatory response during the early phase of infection. Our findings are instrumental in understanding the early immunological events during virus-induced liver disease and point toward inflammatory monocytes as potential target cells for future treatment options in viral hepatitis., Importance: Insights into how the immune system deals with hepatitis B virus (HBV) and HCV are scarce due to the lack of adequate animal model systems. This knowledge is, however, crucial to developing new antiviral strategies aimed at eradicating these chronic infections. We model virus-host interactions during the initial phase of liver inflammation 24 h after inoculating mice with LCMV. We show that infected Kupffer cells are rapidly outnumbered by infiltrating inflammatory monocytes, which secrete proinflammatory cytokines but are less phagocytic. Nevertheless, these recruited inflammatory monocytes start to resemble Kupffer cells on a transcript level. The specificity of these cellular changes for virus-induced liver inflammation is corroborated by demonstrating opposite functions of monocytes after LPS challenge. Overall, this demonstrates the enormous functional and genetic plasticity of infiltrating monocytes and identifies them as an important target cell for future treatment regimens., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
- View/download PDF
22. Cellular receptors, differentiation and endocytosis requirements are key factors for type I IFN response by human epithelial, conventional and plasmacytoid dendritic infected cells by measles virus.
- Author
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Duhen T, Herschke F, Azocar O, Druelle J, Plumet S, Delprat C, Schicklin S, Wild TF, Rabourdin-Combe C, Gerlier D, and Valentin H
- Subjects
- Antigens, CD immunology, Cells, Cultured, Dendritic Cells cytology, Dendritic Cells virology, Epithelial Cells cytology, Epithelial Cells virology, Humans, Measles physiopathology, Measles virology, Measles virus genetics, Measles virus immunology, Membrane Cofactor Protein immunology, Receptors, Cell Surface immunology, Signaling Lymphocytic Activation Molecule Family Member 1, Viral Tropism, Cell Differentiation, Dendritic Cells immunology, Endocytosis, Epithelial Cells immunology, Interferon Type I immunology, Measles immunology, Measles virus physiology, Receptors, Virus immunology
- Abstract
While the antiviral response during measles virus (MeV) infection is documented, the contribution of the hosting cell type to the type I interferon (IFN-alpha/beta) response is still not clearly established. Here, we report that a signature heterogeneity of the IFN-alpha/beta response according to the cell type. The MeV tropism dictated by the expression of appropriate cellular receptor appeared to be crucial for epithelial cells. For conventional DCs (cDCs), the maturation state played a prominent role. In response to both wild type MeV isolates and laboratory/vaccine strains, immature cDCs produced higher levels of IFN-alpha than mature cDCs, despite the reduced expression levels of both CD46 and CD150 receptors by the former ones. While in epithelial cells and cDCs the MeV transcription was required to activate the IFN-alpha/beta response, plasmacytoid DCs (pDCs) rapidly produced large amounts of IFN-alpha mostly independently of the viral infection cycle. This argues for a significant contribution of pDCs in response to MeV infection and/or vaccination., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
23. Cytosolic 5'-triphosphate ended viral leader transcript of measles virus as activator of the RIG I-mediated interferon response.
- Author
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Plumet S, Herschke F, Bourhis JM, Valentin H, Longhi S, and Gerlier D
- Subjects
- Genome, Viral, Humans, Immunity, Innate, Measles genetics, Measles immunology, Measles virus immunology, Mononegavirales genetics, RNA, Messenger genetics, RNA, Viral chemistry, Reverse Transcriptase Polymerase Chain Reaction, Transcription, Genetic, Interferon-beta genetics, Measles virus genetics, RNA, Double-Stranded genetics, RNA, Viral genetics
- Abstract
Background: Double stranded RNA (dsRNA) is widely accepted as an RNA motif recognized as a danger signal by the cellular sentries. However, the biology of non-segmented negative strand RNA viruses, or Mononegavirales, is hardly compatible with the production of such dsRNA., Methodology and Principal Findings: During measles virus infection, the IFN-beta gene transcription was found to be paralleled by the virus transcription, but not by the virus replication. Since the expression of every individual viral mRNA failed to activate the IFN-beta gene, we postulated the involvement of the leader RNA, which is a small not capped and not polyadenylated RNA firstly transcribed by Mononegavirales. The measles virus leader RNA, synthesized both in vitro and in vivo, was efficient in inducing the IFN-beta expression, provided that it was delivered into the cytosol as a 5'-trisphosphate ended RNA. The use of a human cell line expressing a debilitated RIG-I molecule, together with overexpression studies of wild type RIG-I, showed that the IFN-beta induction by virus infection or by leader RNA required RIG-I to be functional. RIG-I binds to leader RNA independently from being 5-trisphosphate ended; while a point mutant, Q299A, predicted to establish contacts with the RNA, fails to bind to leader RNA. Since the 5'-triphosphate is required for optimal RIG-I activation but not for leader RNA binding, our data support that RIG-I is activated upon recognition of the 5'-triphosphate RNA end., Conclusions/significance: RIG-I is proposed to recognize Mononegavirales transcription, which occurs in the cytosol, while scanning cytosolic RNAs, and to trigger an IFN response when encountering a free 5'-triphosphate RNA resulting from a mislocated transcription activity, which is therefore considered as the hallmark of a foreign invader.
- Published
- 2007
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24. The engagement of activating FcgammaRs inhibits primate lentivirus replication in human macrophages.
- Author
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David A, Sáez-Cirión A, Versmisse P, Malbec O, Iannascoli B, Herschke F, Lucas M, Barré-Sinoussi F, Mouscadet JF, Daëron M, and Pancino G
- Subjects
- Animals, Cells, Cultured, DNA, Complementary analysis, DNA, Viral analysis, Humans, Lentivirus physiology, Macrophage Activation, Macrophages drug effects, Primates virology, Proviruses isolation & purification, Receptors, IgG genetics, HIV-1 physiology, Macrophages immunology, Macrophages virology, Receptors, IgG agonists, Virus Replication
- Abstract
We previously reported that the stimulation of monocyte-derived macrophages (MDM) by plate-bound i.v. Igs inhibits HIV-1 replication. In this study, we show that IgG immune complexes also suppress HIV-1 replication in MDMs and that activating receptors for the Fc portion of IgG-FcgammaRI, FcgammaRIIA, and FcgammaRIII-are responsible for the inhibition. MDM stimulation through FcgammaRs induces activation signals and the secretion of HIV-1 modulatory cytokines, such as M-CSF, TNF-alpha, and macrophage-derived chemokine. However, none of these cytokines contribute to HIV-1 suppression. HIV-1 entry and postintegration steps of viral replication are not affected, whereas reduced levels of reverse transcription products and of integrated proviruses, as determined by real-time PCR analysis, account for the suppression of HIV-1 gene expression in FcgammaR-activated MDMs. We found that FcgammaR-dependent activation of MDMs also inhibits the replication of HIV-2, SIVmac, and SIVagm, suggesting a common control mechanism for primate immunodeficiency lentiviruses in activated macrophages.
- Published
- 2006
- Full Text
- View/download PDF
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