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    Lethal Mutagenesis of Poliovirus Mediated by a Mutagenic Pyrimidine Analogue

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    PetersonBlake_et_al_2007.pdf (797.3Kb)
    Issue Date
    2007-10
    Author
    Graci, Jason D.
    Harki, Daniel A.
    Korneeva, Victoria S.
    Edathil, Jocelyn P.
    Too, Kathleen
    Franco, David
    Smidansky, Eric D.
    Paul, Aniko V.
    Peterson, Blake R.
    Brown, Daniel M.
    Loakes, David
    Cameron, Craig E.
    Publisher
    American Society for Microbiology
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Metadata
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    Abstract
    Lethal mutagenesis is the mechanism of action of ribavirin against poliovirus (PV) and numerous other RNA viruses. However, there is still considerable debate regarding the mechanism of action of ribavirin against a variety of RNA viruses. Here we show by using T7 RNA polymerase-mediated production of PV genomic RNA, PV polymerase-catalyzed primer extension, and cell-free PV synthesis that a pyrimidine ribonucleoside triphosphate analogue (rPTP) with ambiguous base-pairing capacity is an efficient mutagen of the PV genome. The in vitro incorporation properties of rPTP are superior to ribavirin triphosphate. We observed a log-linear relationship between virus titer reduction and the number of rPMP molecules incorporated. A PV genome encoding a high-fidelity polymerase was more sensitive to rPMP incorporation, consistent with diminished mutational robustness of high-fidelity PV. The nucleoside (rP) did not exhibit antiviral activity in cell culture, owing to the inability of rP to be converted to rPMP by cellular nucleotide kinases. rP was also a poor substrate for herpes simplex virus thymidine kinase. The block to nucleoside phosphorylation could be bypassed by treatment with the P nucleobase, which exhibited both antiviral activity and mutagenesis, presumably a reflection of rP nucleotide formation by a nucleotide salvage pathway. These studies provide additional support for lethal mutagenesis as an antiviral strategy, suggest that rPMP prodrugs may be highly efficacious antiviral agents, and provide a new tool to determine the sensitivity of RNA virus genomes to mutagenesis as well as interrogation of the impact of mutational load on the population dynamics of these viruses.
    Description
    This is the publisher's version, also available electronically from http://jvi.asm.org/content/81/20/11256
    URI
    http://hdl.handle.net/1808/14803
    DOI
    https://doi.org/10.1128/JVI.01028-07
    ISSN
    0022-538X
    Collections
    • Distinguished Professors Scholarly Works [918]
    • Medicinal Chemistry Scholarly Works [255]
    Citation
    Graci, Jason D. et al. (2007). Lethal Mutagenesis of Poliovirus Mediated by a Mutagenic Pyrimidine Analogue. Journal of Virology 81(20):11256-11266. http://www.dx.doi.org/10.1128/JVI.01028-07

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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