Research output per year
Research output per year
Richard Janissen, Andrew Woodman, Djoshkun Shengjuler, Thomas Vallet, Kuo Ming Lee, Louis Kuijpers, Ibrahim M. Moustafa, Fiona Fitzgerald, Nynke H. Dekker, More Authors
Research output: Contribution to journal › Article › Scientific › peer-review
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.
Original language | English |
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Pages (from-to) | 4467-4480.e7 |
Journal | Molecular Cell |
Volume | 81 |
Issue number | 21 |
DOIs | |
Publication status | Published - 2021 |
Research output: Thesis › Dissertation (TU Delft)