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 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.
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, PR China.
Zheng Fu
ZF
Tai
Guo Lin
GL
Zhang
Fei
F
Wang
D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D047310:Apigenin / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004642:Emodin / Q000494:pharmacology* / Q000627:therapeutic use; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology* / Q000627:therapeutic use; D053612:Janus Kinases / Q000378:metabolism*; D047311:Luteolin / Q000494:pharmacology / Q000627:therapeutic use; D010936:Plant Extracts / Q000494:pharmacology*; D011794:Quercetin / Q000494:pharmacology / Q000627:therapeutic use; D020218:Response Elements; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014777:Virus Diseases / Q000188:drug therapy
D000998:Antiviral Agents; D005419:Flavonoids; D007370:Interferon Type I; D010936:Plant Extracts; D050791:STAT Transcription Factors; D047310:Apigenin; D011794:Quercetin; D053612:Janus Kinases; D004642:Emodin; D047311:Luteolin