Effects of Introduction of Hydrophobic Group on Ribavirin Base on Mutation Induction and Anti-RNA Viral Activity

• Published in: Journal of medicinal chemistry 2008-01, Vol.51 (1), p.159-166
• Main Authors: Moriyama, Kei, Suzuki, Tetsuya, Negishi, Kazuo, Graci, Jason D, Thompson, Corinne N, Cameron, Craig E, Watanabe, Masahiko
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Medical sciences; Mutation; Organophosphates - chemical synthesis; Organophosphates - chemistry; Organophosphates - pharmacology; Pharmacology. Drug treatments; Poliovirus - drug effects; Poliovirus - enzymology; Poliovirus - genetics; Ribavirin - analogs & derivatives; Ribavirin - chemical synthesis; Ribavirin - chemistry; Ribavirin - pharmacology; RNA Replicase - chemistry; RNA, Viral - genetics; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm7009952

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, 3Dpol, 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.