Journal
CELL REPORTS
Volume 21, Issue 4, Pages 1063-1076Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.10.005
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Funding
- Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg
- NIH/NIAID [AI045818]
- TU Delft startup grant
- Burroughs Wellcome Fund Collaborative Research Travel Grant
- Netherlands Organisation for Scientific Research (NWO) via its TOP-GO program
- European Union via an ERC consolidator grant (DynGenome) [312221]
- European Research Council (ERC) [312221] Funding Source: European Research Council (ERC)
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RNA viruses pose a threat to public health that is exacerbated by the dearth of antiviral therapeutics. The RNA-dependent RNA polymerase (RdRp) holds promise as a broad-spectrum, therapeutic target because of the conserved nature of the nucleotide-substrate-binding and catalytic sites. Conventional, quantitative, kinetic analysis of antiviral ribonucleotides monitors one or a few incorporation events. Here, we use a high-throughput magnetic tweezers platformto monitor the elongation dynamics of a prototypicalRdRpover thousands of nucleotide-addition cycles in the absence and presence of a suite of nucleotide analog inhibitors. We observe multiple RdRpRNA elongation complexes; only a subset of which are competent for analog utilization. Incorporation of a pyrazine-carboxamide nucleotide analog, T-1106, leads to RdRp backtracking. This analysis reveals a mechanism of action for this antiviral ribonucleotide that is corroborated by cellular studies. We propose that induced backtracking represents a distinct mechanistic class of antiviral ribonucleotides.
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