RNA Binding Properties of Novel Gene Silencing Pyrrole-Imidazole Polyamides

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  • Iguchi Akifumi
    Division of Life Science, Advanced Research Institute of the Sciences and Humanities, Nihon University Graduate School
  • Fukuda Noboru
    Division of Life Science, Advanced Research Institute of the Sciences and Humanities, Nihon University Graduate School Department of Medicine, Nihon University School of Medicine
  • Takahashi Teruyuki
    Division of Life Science, Advanced Research Institute of the Sciences and Humanities, Nihon University Graduate School
  • Watanabe Takayoshi
    Chiba Cancer Center Research Institute
  • Matsuda Hiroyuki
    Department of Medicine, Nihon University School of Medicine
  • Nagase Hiroki
    Chiba Cancer Center Research Institute
  • Bando Toshikazu
    Department of Chemistry, Graduate School of Science, Kyoto University
  • Sugiyama Hiroshi
    Department of Chemistry, Graduate School of Science, Kyoto University
  • Shimizu Kazufumi
    Open Research Center for Genome and Infectious Disease Control, Nihon University School of Medicine

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Pyrrole-imidazole (PI) polyamides are a novel group of gene-silencing compounds, which bind to a minor groove of double stranded (ds)DNA in a sequence-specific manner. To explore the RNA binding properties of PI polyamides targeting rat transforming growth factor-β1 (TGF-β1 Polyamide) and influenza A virus (PA polyamide), we designed dsRNAs with an identical sequence to the target DNA and analyzed RNA binding properties of the polyamide. Biacore assay showed fast binding of TGF-β1 Polyamide to the dsRNA, whereas mismatch polyamide did not bind to the dsRNA. Dissociation equilibrium constant (KD) value was 6.7×10−7 of the target dsRNA. These results indicate that PI polyamide could bind to RNA with a 2 log lower binding affinity than its DNA-binding affinity. We designed a PI polyamide targeting the panhandle stem region of influenza A virus. KD value of the PI polyamide to dsRNA targeting influenza A virus was 4.6×10−7. Gel-shift assay showed that TGF-β1 and PA polyamides bound to the appropriate dsDNA, whereas these PI polyamides did not show obvious gel-shift with the appropriate dsRNA. Structural modeling suggests that PI polyamide binds to the appropriate B-form dsDNA in the minor groove, whereas it does not fit in the minor groove to dsRNA. Thus PI polyamides have a lower binding affinity with target dsRNA than they do with dsDNA. The distinct binding properties of PI polyamides to dsRNA and dsDNA may be associated with differences of secondary structure and chemical binding properties between target RNA and DNA.

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