Effects of introduction of hydrophobic group on ribavirin base on mutation induction and anti-RNA viral activity

Kei Moriyama, Tetsuya Suzuki, Kazuo Negishi, Jason D. Graci, Corinne N. Thompson, Craig E. Cameron, Masahiko Watanabe

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21 Scopus citations

Abstract

One of the possible mechanisms of antiviral action of ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, 1) is the accumulation of mutations in viral genomic RNA. The ambiguous incorporation of 5′-triphosphate of ribavirin (RTP, 8) by a viral RNA-dependent RNA polymerase (RdRp) is a key step of the mutation induction. We synthesized three ribavirin analogues that possess hydrophobic groups, 4-iodo-1-β-D- ribofuranosylpyrazole-3-carboxamide (7a), 4-propynyl-1-β-D- ribofuranosylpyrazole-3-carboxamide (7b), and 4-phenylethynyl-1-β-D- ribofuranosylpyrazole-3-carboxamide (7c), and the corresponding triphosphates (9a, 9b, and 9c, respectively). Steady-state kinetics analysis of the incorporation of these triphosphate analogues by a poliovirus RdRp, 3D pol, revealed that while the incorporation efficiency of 9a was comparable to RTP, 9b and 9c showed lower efficiency than RTP. Antipolioviral activity of 7a and 7b was much more moderate than ribavirin, and 7c showed no antipolioviral activity. Effects of substituting groups on the incorporation efficiency by 3Dpol and a strategy for a rational design of more active ribavirin analogues are discussed.

Original languageEnglish (US)
Pages (from-to)159-166
Number of pages8
JournalJournal of Medicinal Chemistry
Volume51
Issue number1
DOIs
StatePublished - Jan 10 2008

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Moriyama, K., Suzuki, T., Negishi, K., Graci, J. D., Thompson, C. N., Cameron, C. E., & Watanabe, M. (2008). Effects of introduction of hydrophobic group on ribavirin base on mutation induction and anti-RNA viral activity. Journal of Medicinal Chemistry, 51(1), 159-166. https://doi.org/10.1021/jm7009952