A novel p38 mitogen activated protein kinase (MAPK) specific inhibitor suppresses respiratory syncytial virus and influenza A virus replication by inhibiting virus-induced p38 MAPK activation

24Autophagy has been implicated in innate immune responses against various intracellular 25 pathogens. Recent studies have reported that autophagy can be triggered by pathogen 26 recognizing sensors, including Toll-like receptors and cyclic guanosine monophosphate-27 adenosine monophosphate synthase, to participate in innate immunity. In the present study, 28 we examined whether the RIG-I signaling pathway, which detects viral infections by 29 recognizing viral RNA, triggers the autophagic process. The introduction of polyI:C into the 30 cytoplasm, or Sendai virus infection, significantly induced autophagy in normal cells but not 31 in RIG-I-deficient cells. PolyI:C transfection or Sendai virus infection induced autophagy in 32 the cells lacking type-I interferon signaling. This demonstrated that the effect was not due to 33 interferon signaling. RIG-I-mediated autophagy diminished by the deficiency of 34 mitochondrial antiviral signaling protein (MAVS) or tumor necrosis factor receptor-35 associated factor (TRAF)6, showing that the RIG-I-MAVS-TRAF6 signaling axis was 36critical for RIG-I-mediated autophagy. We also found that Beclin-1 was translocated to the 37 mitochondria, and it interacted with TRAF6 upon RIG-I activation. Furthermore, Beclin-1 38 underwent K63-polyubiquitination upon RIG-I activation, and the ubiquitination decreased 39 in TRAF6-deficient cells. This suggests that the RIG-I-MAVS-TRAF6 axis induced K63-40 linked polyubiquitination of Beclin-1, which has been implicated in triggering autophagy. 41Collectively, the results of this study show that the recognition of viral infection by RIG-I is 42 capable of inducing autophagy to control viral replication. As deficient autophagy increases 43 3 the type-I interferon response, the induction of autophagy by the RIG-I pathway might also 44 contribute to preventing an excessive interferon response as a negative-feedback mechanism. 45 46 Importance 47 Mammalian cells utilize various innate immune sensors to detect pathogens. Among those 48 sensors, RIG-I recognizes viral RNA to detect intracellular viral replication. Although cells 49 experience diverse physiological changes upon viral infection, studies to understand the role 50 of RIG-I signaling have focused on the induction of type-I interferon. Autophagy is a process 51that sequesters cytosolic regions and degrades the contents to maintain cellular homeostasis. 52Autophagy participates in the immune system, and has been known to be triggered by some 53 innate immune sensors, such as TLR4 and cGAS. We demonstrated that autophagy can be 54 triggered by the activation of RIG-I. In addition, we also proved that MAVS-TRAF6 55 downstream signaling is crucial for the process. Beclin-1, a key molecule in autophagy, is 56 translocated to mitochondria, where it undergoes K63-ubiquitination in a TRAF6-dependent 57 manner upon RIG-I activation. As autophagy negatively regulates RIG-I-mediated signaling, 58 the RIG-I-mediated activation of autophagy may function as a negative-feedback mechanism. 59 60 Intro...

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“…SeV (Cantell strain) was purchased from Charles River Laboratories. Influenza A virus was prepared and infected as described previously (35).…”

Section: Methodsmentioning

confidence: 99%

Activation of RIG-I-mediated antiviral signaling triggers autophagy through the MAVS-TRAF6-Beclin-1 signaling axis

Inn

Lee

Ban

et al. 2018

Preprint

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“…Within the past decade, several biphenyl amides have been developed as novel p38 MAPK inhibitors (19). In particular, we recently reported a class of novel biphenyl amide p38 MAPK inhibitors containing a benzophenone moiety and demonstrated that some of these inhibitors have potent p38 MAPK-inhibitory activities and kinase selectivities (14,20). In the current study, we explored the antiviral activities of these p38 MAPK inhibitors against HBV.…”

mentioning

confidence: 98%

“…Interestingly, several viruses, including Ebola virus, Epstein-Barr virus, influenza virus, and HBV, have been known to utilize p38 MAPK for their life cycles, and suppression of p38 MAPK results in suppression of viral replication (14)(15)(16)(17). p38 MAPK plays a crucial role in HBV surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) secretion, virus production, and the maintenance of HBV cccDNA in HBV-infected cells (18).…”

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confidence: 99%

An Effective Antiviral Approach Targeting Hepatitis B Virus with NJK14047, a Novel and Selective Biphenyl Amide p38 Mitogen-Activated Protein Kinase Inhibitor

Kim

et al. 2017

Antimicrob Agents Chemother

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Despite recent advances in therapeutic strategies against hepatitis B virus (HBV) infection, chronic hepatitis B remains a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified p38 mitogen-activated protein kinase (MAPK) as a possible target for antiviral strategies against various viruses, including HBV. Here, a series of biphenyl amides were synthesized as novel p38 MAPK selective inhibitors and assessed for their anti-HBV activities. The suppression of HBV surface antigen (HBsAg) production by these compounds was positively correlated with p38 MAPK-inhibitory activity. The selected compound NJK14047 displayed significant anti-HBV activity, as determined by HBsAg production, HBeAg secretion, and HBV production. NJK14047 efficiently suppressed the secretion of HBV antigens and HBV particles from HBV genome-transfected cells and HBV-infected sodium taurocholate cotransporting polypeptide-expressing human hepatoma cells. Furthermore, NJK14047 treatment resulted in a significant decrease of pregenomic RNA and covalently closed circular DNA (cccDNA) of HBV in HBV-harboring cells, indicating its ability to inhibit HBV replication. Considering that suppression of HBsAg secretion and elimination of cccDNA of HBV are the major aims of anti-HBV therapeutic strategies, the results suggested the potential use of these compounds as a novel class of anti-HBV agents targeting host factors critical for viral infection.

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“…Host kinases regulate not only IAV entry and replication but also initiate antiviral signaling cascades that regulate expression of pro-inflammatory chemokines and cytokines during infections and present viable targets for intervention (24,(49)(50)(51)(52)(53)(54)(55)(56)(57)(58).…”

Section: Therapeutic Small Moleculesmentioning

confidence: 99%

“…The mitogen activated protein kinase (MAPK), p38, regulates viral entry and replication (55,59). Furthermore, p38 regulates IFN stimulated gene (ISG) gene expression and ultimately cytokine production via STAT1 phosphorylation (25).…”

Section: Therapeutic Small Moleculesmentioning

confidence: 99%

Response Modifiers: Tweaking the Immune Response Against Influenza A Virus

et al. 2019

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Despite causing pandemics and yearly epidemics that result in significant morbidity and mortality, our arsenal of options to treat influenza A virus (IAV) infections remains limited and is challenged by the virus itself. While vaccination is the preferred intervention strategy against influenza, its efficacy is reduced in the elderly and infants who are most susceptible to severe and/or fatal infections. In addition, antigenic variation of IAV complicates the production of efficacious vaccines. Similarly, effectiveness of currently used antiviral drugs is jeopardized by the development of resistance to these drugs. Like many viruses, IAV is reliant on host factors and signaling-pathways for its replication, which could potentially offer alternative options to treat infections. While host-factors have long been recognized as attractive therapeutic candidates against other viruses, only recently they have been targeted for development as IAV antivirals. Future strategies to combat IAV infections will most likely include approaches that alter host-virus interactions on the one hand or dampen harmful host immune responses on the other, with the use of biological response modifiers (BRMs). In principle, BRMs are biologically active agents including antibodies, small peptides, and/or other (small) molecules that can influence the immune response. BRMs are already being used in the clinic to treat malignancies and autoimmune diseases. Repurposing such agents would allow for accelerated use against severe and potentially fatal IAV infections. In this review, we will address the potential therapeutic use of different BRM classes to modulate the immune response induced after IAV infections.

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A novel p38 mitogen activated protein kinase (MAPK) specific inhibitor suppresses respiratory syncytial virus and influenza A virus replication by inhibiting virus-induced p38 MAPK activation

Cited by 38 publications

References 21 publications

Activation of RIG-I-mediated antiviral signaling triggers autophagy through the MAVS-TRAF6-Beclin-1 signaling axis

Activation of RIG-I-mediated antiviral signaling triggers autophagy through the MAVS-TRAF6-Beclin-1 signaling axis

An Effective Antiviral Approach Targeting Hepatitis B Virus with NJK14047, a Novel and Selective Biphenyl Amide p38 Mitogen-Activated Protein Kinase Inhibitor

Response Modifiers: Tweaking the Immune Response Against Influenza A Virus

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