Effects of introduction of hydrophobic group on ribavirin base on mutation induction and anti-RNA viral activity.
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.
Moriyama
Kei
K
Shujitsu University, School of Pharmacy, Nishigawara, Okayama 703-8516, Japan. k_moriyama@research.otsuka.co.jp
Suzuki
Tetsuya
T
Negishi
Kazuo
K
Graci
Jason D
JD
Thompson
Corinne N
CN
Cameron
Craig E
CE
Watanabe
Masahiko
M
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
D000577:Amides; D000998:Antiviral Agents; D010755:Organophosphates; D012367:RNA, Viral; D012254:Ribavirin; D012324:RNA-Dependent RNA Polymerase