Identification of Small Molecule Activators of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway Using a Cell-Based Screen
Type I interferons (IFN-α/β) have been widely used in the treatment of many viral and malignant diseases by activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, but the side effects of protein-based IFN therapy severely limit their clinical us...
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| Veröffentlicht in: | Biological & pharmaceutical bulletin 2012/01/01, Vol.35(1), pp.65-71 |
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| creator | Tai, Zheng Fu Zhang, Guo Lin Wang, Fei |
| description | Type I interferons (IFN-α/β) have been widely used in the treatment of many viral and malignant diseases by activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, but the side effects of protein-based IFN therapy severely limit their clinical use. Discovering small molecules to activate the JAK/STAT pathway will greatly facilitate the development of new drugs which have similar pharmacological function to IFNs but with fewer side effects. To screen a natural products-based library, we established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid where the luciferase reporter activity is driven by interferon α-stimulated response element (ISRE), the motif specifically recognized by type I IFN-induced activation of JAK/STAT pathway. Among 1,431 natural product compounds screened, four compounds (emodin, quercetin, apigenin and luteolin) were identified as activators of the JAK/STAT pathway. Further studies demonstrated that these four compounds could increase the endogenous antiviral gene expression regulated by the IFN-activated JAK/STAT pathway. The identified small molecule activators are valuable for structural modification and warrant further investigation for use in new antiviral drugs as IFN mimics or adjuvants. |
| doi_str_mv | 10.1248/bpb.35.65 |
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Discovering small molecules to activate the JAK/STAT pathway will greatly facilitate the development of new drugs which have similar pharmacological function to IFNs but with fewer side effects. To screen a natural products-based library, we established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid where the luciferase reporter activity is driven by interferon α-stimulated response element (ISRE), the motif specifically recognized by type I IFN-induced activation of JAK/STAT pathway. Among 1,431 natural product compounds screened, four compounds (emodin, quercetin, apigenin and luteolin) were identified as activators of the JAK/STAT pathway. Further studies demonstrated that these four compounds could increase the endogenous antiviral gene expression regulated by the IFN-activated JAK/STAT pathway. The identified small molecule activators are valuable for structural modification and warrant further investigation for use in new antiviral drugs as IFN mimics or adjuvants.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.35.65</identifier><identifier>PMID: 22223339</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; apigenin ; Apigenin - pharmacology ; Apigenin - therapeutic use ; Drug Evaluation, Preclinical - methods ; emodin ; Emodin - pharmacology ; Emodin - therapeutic use ; Flavonoids - pharmacology ; Flavonoids - therapeutic use ; Gene Expression - drug effects ; Genes, Reporter ; Hep G2 Cells ; Humans ; interferon ; Interferon Type I - pharmacology ; Interferon Type I - therapeutic use ; Janus kinase/signal transducer and activator of transcription ; Janus Kinases - metabolism ; luteolin ; Luteolin - pharmacology ; Luteolin - therapeutic use ; Plant Extracts - pharmacology ; quercetin ; Quercetin - pharmacology ; Quercetin - therapeutic use ; Response Elements ; Signal Transduction - drug effects ; STAT Transcription Factors - metabolism ; Virus Diseases - drug therapy</subject><ispartof>Biological and Pharmaceutical Bulletin, 2012/01/01, Vol.35(1), pp.65-71</ispartof><rights>2012 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c684t-f7773c3bb785348c6024bc188de748621c49163d75491af74832b4534e8b8eb3</citedby><cites>FETCH-LOGICAL-c684t-f7773c3bb785348c6024bc188de748621c49163d75491af74832b4534e8b8eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1877,4010,27900,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22223339$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tai, Zheng Fu</creatorcontrib><creatorcontrib>Zhang, Guo Lin</creatorcontrib><creatorcontrib>Wang, Fei</creatorcontrib><creatorcontrib>Chinese Academy of Sciences</creatorcontrib><creatorcontrib>Chengdu Institute of Biology</creatorcontrib><title>Identification of Small Molecule Activators of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway Using a Cell-Based Screen</title><title>Biological & pharmaceutical bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>Type I interferons (IFN-α/β) have been widely used in the treatment of many viral and malignant diseases by activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, but the side effects of protein-based IFN therapy severely limit their clinical use. Discovering small molecules to activate the JAK/STAT pathway will greatly facilitate the development of new drugs which have similar pharmacological function to IFNs but with fewer side effects. To screen a natural products-based library, we established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid where the luciferase reporter activity is driven by interferon α-stimulated response element (ISRE), the motif specifically recognized by type I IFN-induced activation of JAK/STAT pathway. Among 1,431 natural product compounds screened, four compounds (emodin, quercetin, apigenin and luteolin) were identified as activators of the JAK/STAT pathway. Further studies demonstrated that these four compounds could increase the endogenous antiviral gene expression regulated by the IFN-activated JAK/STAT pathway. The identified small molecule activators are valuable for structural modification and warrant further investigation for use in new antiviral drugs as IFN mimics or adjuvants.</description><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral Agents - therapeutic use</subject><subject>apigenin</subject><subject>Apigenin - pharmacology</subject><subject>Apigenin - therapeutic use</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>emodin</subject><subject>Emodin - pharmacology</subject><subject>Emodin - therapeutic use</subject><subject>Flavonoids - pharmacology</subject><subject>Flavonoids - therapeutic use</subject><subject>Gene Expression - drug effects</subject><subject>Genes, Reporter</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>interferon</subject><subject>Interferon Type I - pharmacology</subject><subject>Interferon Type I - therapeutic use</subject><subject>Janus kinase/signal transducer and activator of transcription</subject><subject>Janus Kinases - metabolism</subject><subject>luteolin</subject><subject>Luteolin - pharmacology</subject><subject>Luteolin - therapeutic use</subject><subject>Plant Extracts - pharmacology</subject><subject>quercetin</subject><subject>Quercetin - pharmacology</subject><subject>Quercetin - therapeutic use</subject><subject>Response Elements</subject><subject>Signal Transduction - drug effects</subject><subject>STAT Transcription Factors - metabolism</subject><subject>Virus Diseases - drug therapy</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUcFuEzEQtRCIhsCBH0CWOCAOm9pr79p7QSoRlEIRSAlny-udTRw5dmrvgvobfDFOt2klfJiR_N68N6OH0GtKFrTk8rw9tAtWLerqCZpRxkVRlbR6imakobKoaSXP0IuUdoQQQUr2HJ2V-THGmhn6e9WBH2xvjR5s8Dj0eLXXzuHvwYEZHeALM9jfeggxHcFhC_ir9mPC36zXCc5XduO1w-uofepGAxFr3z0OHWfuMBPt4c7hpx62f_Qt_pWs32CNl-Bc8TFLdXhlIoB_iZ712iV4dd_naP3503r5pbj-cXm1vLguTC35UPRCCGZY2wpZMS5NTUreGiplB4LLuqSGN7Rmnahy133-Y2XLMxVkK6Flc_Rukj3EcDNCGtTeJpOX0R7CmFRDeV03JIvP0dv_mLswxnx1UpTzhslG0Caz3k8sE0NKEXp1iHav462iRB1jUjkmxSpVHxXf3CuO7R66B-Ypl0y4nAgZzdG44J318OhrkmhtcEGVhJaKEFYRqkg2IqSuchE0n85LKbPSh0lplwa9gQcrHQdrHJyWolPJwyfAbHVU4Nk_h-q6dg</recordid><startdate>20120101</startdate><enddate>20120101</enddate><creator>Tai, Zheng Fu</creator><creator>Zhang, Guo Lin</creator><creator>Wang, Fei</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20120101</creationdate><title>Identification of Small Molecule Activators of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway Using a Cell-Based Screen</title><author>Tai, Zheng Fu ; Zhang, Guo Lin ; Wang, Fei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c684t-f7773c3bb785348c6024bc188de748621c49163d75491af74832b4534e8b8eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral Agents - therapeutic use</topic><topic>apigenin</topic><topic>Apigenin - pharmacology</topic><topic>Apigenin - therapeutic use</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>emodin</topic><topic>Emodin - pharmacology</topic><topic>Emodin - therapeutic use</topic><topic>Flavonoids - pharmacology</topic><topic>Flavonoids - therapeutic use</topic><topic>Gene Expression - drug effects</topic><topic>Genes, Reporter</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>interferon</topic><topic>Interferon Type I - pharmacology</topic><topic>Interferon Type I - therapeutic use</topic><topic>Janus kinase/signal transducer and activator of transcription</topic><topic>Janus Kinases - metabolism</topic><topic>luteolin</topic><topic>Luteolin - pharmacology</topic><topic>Luteolin - therapeutic use</topic><topic>Plant Extracts - pharmacology</topic><topic>quercetin</topic><topic>Quercetin - pharmacology</topic><topic>Quercetin - therapeutic use</topic><topic>Response Elements</topic><topic>Signal Transduction - drug effects</topic><topic>STAT Transcription Factors - metabolism</topic><topic>Virus Diseases - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tai, Zheng Fu</creatorcontrib><creatorcontrib>Zhang, Guo Lin</creatorcontrib><creatorcontrib>Wang, Fei</creatorcontrib><creatorcontrib>Chinese Academy of Sciences</creatorcontrib><creatorcontrib>Chengdu Institute of Biology</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biological & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tai, Zheng Fu</au><au>Zhang, Guo Lin</au><au>Wang, Fei</au><aucorp>Chinese Academy of Sciences</aucorp><aucorp>Chengdu Institute of Biology</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of Small Molecule Activators of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway Using a Cell-Based Screen</atitle><jtitle>Biological & pharmaceutical bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2012-01-01</date><risdate>2012</risdate><volume>35</volume><issue>1</issue><spage>65</spage><epage>71</epage><pages>65-71</pages><issn>0918-6158</issn><eissn>1347-5215</eissn><abstract>Type I interferons (IFN-α/β) have been widely used in the treatment of many viral and malignant diseases by activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, but the side effects of protein-based IFN therapy severely limit their clinical use. Discovering small molecules to activate the JAK/STAT pathway will greatly facilitate the development of new drugs which have similar pharmacological function to IFNs but with fewer side effects. To screen a natural products-based library, we established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid where the luciferase reporter activity is driven by interferon α-stimulated response element (ISRE), the motif specifically recognized by type I IFN-induced activation of JAK/STAT pathway. Among 1,431 natural product compounds screened, four compounds (emodin, quercetin, apigenin and luteolin) were identified as activators of the JAK/STAT pathway. Further studies demonstrated that these four compounds could increase the endogenous antiviral gene expression regulated by the IFN-activated JAK/STAT pathway. 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| subjects | Antiviral Agents - pharmacology Antiviral Agents - therapeutic use apigenin Apigenin - pharmacology Apigenin - therapeutic use Drug Evaluation, Preclinical - methods emodin Emodin - pharmacology Emodin - therapeutic use Flavonoids - pharmacology Flavonoids - therapeutic use Gene Expression - drug effects Genes, Reporter Hep G2 Cells Humans interferon Interferon Type I - pharmacology Interferon Type I - therapeutic use Janus kinase/signal transducer and activator of transcription Janus Kinases - metabolism luteolin Luteolin - pharmacology Luteolin - therapeutic use Plant Extracts - pharmacology quercetin Quercetin - pharmacology Quercetin - therapeutic use Response Elements Signal Transduction - drug effects STAT Transcription Factors - metabolism Virus Diseases - drug therapy |
| title | Identification of Small Molecule Activators of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway Using a Cell-Based Screen |
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