Identification of Small Molecule Activators of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway Using a Cell-Based Screen

Tai, Zheng Fu; Zhang, Guo Lin; Wang, Fei

doi:10.1248/bpb.35.65

Cited by 29 publications

(33 citation statements)

References 27 publications

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“…34 Similarly, our results 35,36 In this regard, it has been described that quercetin may increase the antiviral gene expression regulated by the IFN-activated JAK-STAT pathway. 37 Nevertheless, the molecular mechanisms involved in quercetin-mediated impairment of HCV replication seem to be more complex. Thereby, quercetin may also inhibit the NS5A-driven augmentation of internal ribosomal entry site (IRES)-mediated translation 21,38 and reduce viral production by inhibiting both NS3 and heat-shock proteins essential for HCV replication.…”

Section: Discussionmentioning

confidence: 99%

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Pisonero-Vaquero

García‐Mediavilla

Jorquera

et al. 2014

Laboratory Investigation

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There is experimental evidence that some antioxidant flavonoids show therapeutic potential in the treatment of hepatitis C through inhibition of hepatitis C virus (HCV) replication. We examined the effect of treatment with the flavonols quercetin and kaempferol, the flavanone taxifolin and the flavone apigenin on HCV replication efficiency in an in vitro model. While all flavonoids studied were able to reduce viral replication at very low concentrations (ranging from 0.1 to 5 mM), quercetin appeared to be the most effective inhibitor of HCV replication, showing a marked anti-HCV activity in replicon-containing cells when combined with interferon (IFN)a. The contribution of oxidative/nitrosative stress and lipogenesis modulation to inhibition of HCV replication by quercetin was also examined. As expected, quercetin decreased HCV-induced reactive oxygen and nitrogen species (ROS/RNS) generation and lipoperoxidation in replicating cells. Quercetin also inhibited liver X receptor (LXR)a-induced lipid accumulation in LXRa-overexpressing and replicon-containing Huh7 cells. The mechanism underlying the LXRa-dependent lipogenesis modulatory effect of quercetin in HCV-replicating cells seems to involve phosphatidylinositol 3-kinase (PI3K)/AKT pathway inactivation. Thus, inhibition of the PI3K pathway by LY294002 attenuated LXRa upregulation and HCV replication mediated by lipid accumulation, showing an additive effect when combined with quercetin. Inactivation of the PI3K pathway by quercetin may contribute to the repression of LXRa-dependent lipogenesis and to the inhibition of viral replication induced by the flavonol. Combined, our data suggest that oxidative/nitrosative stress blockage and subsequent modulation of PI3K-LXRa-mediated lipogenesis might contribute to the inhibitory effect of quercetin on HCV replication.

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Section: Discussionmentioning

confidence: 99%

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Pisonero-Vaquero

García‐Mediavilla

Jorquera

et al. 2014

Laboratory Investigation

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“…The quest for small compounds activating the type I interferon response is a field of intense researches in academic laboratories and pharmaceutical companies 9–18 , and some molecules are already marketed or in advanced clinical trials 19, 20 . Compounds from imidazoquinoline family, such as resiquimod (R848) and imiquimod (R837), are well-known inducers of the IFN response that bind TLR7, TLR8 or both 21 .…”

Section: Introductionmentioning

confidence: 99%

Identification of a small molecule that primes the type I interferon response to cytosolic DNA

Khiar

Lucas‐Hourani

Nisole³

et al. 2017

Sci Rep

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The type I interferon response plays a pivotal role in host defense against infectious agents and tumors, and promising therapeutic approaches rely on small molecules designed to boost this system. To identify such compounds, we developed a high-throughput screening assay based on HEK-293 cells expressing luciferase under the control of Interferon-Stimulated Response Elements (ISRE). An original library of 10,000 synthetic compounds was screened, and we identified a series of 1H-benzimidazole-4-carboxamide compounds inducing the ISRE promoter sequence, specific cellular Interferon-Stimulated Genes (ISGs), and the phosphorylation of Interferon Regulatory Factor (IRF) 3. ISRE induction by ChX710, a prototypical member of this chemical series, was dependent on the adaptor MAVS and IRF1, but was IRF3 independent. Although it was unable to trigger type I IFN secretion per se, ChX710 efficiently primed cellular response to transfected plasmid DNA as assessed by potent synergistic effects on IFN-β secretion and ISG expression levels. This cellular response was dependent on STING, a key adaptor involved in the sensing of cytosolic DNA and immune activation by various pathogens, stress signals and tumorigenesis. Our results demonstrate that cellular response to cytosolic DNA can be boosted with a small molecule, and potential applications in antimicrobial and cancer therapies are discussed.

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“…Molecules that engage TLRs or IFN-α/β receptors have been identified using various combinations of functional screens, in silico molecular docking and binding assays [18], [19]. Phenotypic screens have also been used to identify stimulators of the antiviral gene cluster [9], [20], [21], [22], [23], [24], [25]. Several groups have recently described similar assays based on cells transfected with a reporter gene under control of IFN-stimulated response elements (ISRE) [21], [22], [23].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Pyrimidine Biosynthesis Pathway Suppresses Viral Growth through Innate Immunity

et al. 2013

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Searching for stimulators of the innate antiviral response is an appealing approach to develop novel therapeutics against viral infections. Here, we established a cell-based reporter assay to identify compounds stimulating expression of interferon-inducible antiviral genes. DD264 was selected out of 41,353 compounds for both its immuno-stimulatory and antiviral properties. While searching for its mode of action, we identified DD264 as an inhibitor of pyrimidine biosynthesis pathway. This metabolic pathway was recently identified as a prime target of broad-spectrum antiviral molecules, but our data unraveled a yet unsuspected link with innate immunity. Indeed, we showed that DD264 or brequinar, a well-known inhibitor of pyrimidine biosynthesis pathway, both enhanced the expression of antiviral genes in human cells. Furthermore, antiviral activity of DD264 or brequinar was found strictly dependent on cellular gene transcription, nuclear export machinery, and required IRF1 transcription factor. In conclusion, the antiviral property of pyrimidine biosynthesis inhibitors is not a direct consequence of pyrimidine deprivation on the virus machinery, but rather involves the induction of cellular immune response.

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Identification of Small Molecule Activators of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway Using a Cell-Based Screen

Cited by 29 publications

References 27 publications

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Identification of a small molecule that primes the type I interferon response to cytosolic DNA

Inhibition of Pyrimidine Biosynthesis Pathway Suppresses Viral Growth through Innate Immunity

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