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    Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues

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    PetersonB_AAC_52(3)971.pdf (772.4Kb)
    Issue Date
    2008-03
    Author
    Graci, Jason D.
    Too, Kathleen
    Smidansky, Eric D.
    Edathil, Jocelyn P.
    Barr, Eric W.
    Harki, Daniel A.
    Gakarraga, Jessica E.
    Bollinger, J. Martin Jr.
    Peterson, Blake R.
    Loakes, David
    Brown, Daniel M.
    Cameron, Craig E.
    Publisher
    The American Society for Microbiology
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
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    Abstract
    RNA viruses exhibit extraordinarily high mutation rates during genome replication. Nonnatural ribonucleosides that can increase the mutation rate of RNA viruses by acting as ambiguous substrates during replication have been explored as antiviral agents acting through lethal mutagenesis. We have synthesized novel N-6-substituted purine analogues with ambiguous incorporation characteristics due to tautomerization of the nucleobase. The most potent of these analogues reduced the titer of poliovirus (PV) and coxsackievirus (CVB3) over 1,000-fold during a single passage in HeLa cell culture, with an increase in transition mutation frequency up to 65-fold. Kinetic analysis of incorporation by the PV polymerase indicated that these analogues were templated ambiguously with increased efficiency compared to the known mutagenic nucleoside ribavirin. Notably, these nucleosides were not efficient substrates for cellular ribonucleotide reductase in vitro, suggesting that conversion to the deoxyriboucleoside may be hindered, potentially limiting genetic damage to the host cell. Furthermore, a high-fidelity PV variant (G64S) displayed resistance to the antiviral effect and mutagenic potential of these analogues. These purine nucleoside analogues represent promising lead compounds in the development of clinically useful antiviral therapies based on the strategy of lethal mutagenesis.
    URI
    http://hdl.handle.net/1808/17652
    DOI
    https://doi.org/10.1128/AAC.01056-07
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Graci et al. "Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues." Antimicrob. Agents Chemother. March 2008 vol. 52 no. 3 971-979. http://dx.doi.org/10.1128/AAC.01056-07

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    KU Libraries
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    Lawrence, KS 66045
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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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