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Lethal mutagenesis of picornaviruses with N-6-modified purine nucleoside analogues. | LitMetric

AI Article Synopsis

  • * Novel N-6-substituted purine analogues were synthesized, showing the ability to significantly reduce poliovirus and coxsackievirus levels while increasing mutation rates, outperforming the known mutagenic drug ribavirin.
  • * These new nucleosides showed limited interaction with the host cell's ribonucleotide reductase, which may protect the host's genetic integrity, and a high-fidelity poliovirus variant was found to resist the effects of these analogues, highlighting both potential benefits and challenges for the

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258490PMC
http://dx.doi.org/10.1128/AAC.01056-07DOI Listing

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