Induced intra- and intermolecular template switching as a therapeutic mechanism against RNA viruses

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  • Janissen, Richard
    • Other Affiliation: Kavli Institute of Nanoscience
  • Woodman, Andrew
    • Other Affiliation: Pennsylvania State University
  • Shengjuler, Djoshkun
    • Other Affiliation: Institut Pasteur
  • Vallet, Thomas
    • Other Affiliation: University of Minnesota
  • Lee, Kuo-Ming
    • Other Affiliation: Chang Gung University
  • Kuijpers, Louis
    • Other Affiliation: Kavli Institute of Nanoscience
  • Moustafa, Ibrahim M.
    • Other Affiliation: Pennsylvania State University
  • Fitzgerald, Fiona
    • Other Affiliation: Pennsylvania State University
  • Huang, Peng-Nien
    • Other Affiliation: Chang Gung University
  • Perkins, Angela L.
    • Other Affiliation: University of Minnesota
  • Harki, Daniel A.
    • Other Affiliation: University of Minnesota
  • Arnold, Jamie J.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Solano, Belen
    • Other Affiliation: Kavli Institute of Nanoscience
  • Shih, Shin-Ru
    • Other Affiliation: Chang Gung University
  • Vignuzzi, Marco
    • Other Affiliation: Institut Pasteur
  • Cameron, Craig E.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Dekker, Nynke H.
    • Other Affiliation: Kavli Institute of Nanoscience
Abstract
  • Viral RNA-dependent RNA polymerases (RdRps) are a target for broad-spectrum antiviral therapeutic agents. Recently, we demonstrated that incorporation of the T-1106 triphosphate, a pyrazine-carboxamide ribonucleotide, into nascent RNA increases pausing and backtracking by the poliovirus RdRp. Here, by monitoring enterovirus A-71 RdRp dynamics during RNA synthesis using magnetic tweezers, we identify the ‘‘backtracked’’ state as an intermediate used by the RdRp for copy-back RNA synthesis and homologous recombination. Cell-based assays and RNA sequencing (RNA-seq) experiments further demonstrate that the pyrazine-carboxamide ribonucleotide stimulates these processes during infection. These results suggest that pyrazine-carboxamide ribonucleotides do not induce lethal mutagenesis or chain termination but function by promoting template switching and formation of defective viral genomes. We conclude that RdRp-catalyzed intra- and intermolecular template switching can be induced by pyrazine-carboxamide ribonucleotides, defining an additional mechanistic class of antiviral ribonucleotides with potential for broad-spectrum activity.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Molecular Cell
Journal volume
  • 81
Page start
  • 22
Language
  • English
Version
  • Postprint

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