title: Effects of introduction of hydrophobic group on ribavirin base on mutation induction and anti-RNA viral activity.
abstract: One of the possible mechanisms of antiviral action of ribavirin (1-beta- 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-beta- d-ribofuranosylpyrazole-3-carboxamide ( 7a), 4-propynyl-1-beta- d-ribofuranosylpyrazole-3-carboxamide ( 7b), and 4-phenylethynyl-1-beta-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 3D (pol) and a strategy for a rational design of more active ribavirin analogues are discussed.
authors: Shujitsu University, School of Pharmacy, Nishigawara, Okayama 703-8516, Japan. k_moriyama@research.otsuka.co.jp
authors: Kei
authors: K
authors: Moriyama
authors: Tetsuya
authors: T
authors: Suzuki
authors: Kazuo
authors: K
authors: Negishi
authors: Jason D
authors: JD
authors: Graci
authors: Corinne N
authors: CN
authors: Thompson
authors: Craig E
authors: CE
authors: Cameron
authors: Masahiko
authors: M
authors: Watanabe
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D009154:Mutation; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017955:Poliovirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000998:Antiviral Agents; D010755:Organophosphates; D012367:RNA, Viral; D012254:Ribavirin; D012324:RNA-Dependent RNA Polymerase