Metabolism and antiviral activity of ribavirin.

Thirty years after its synthesis, the mechanism of action of ribavirin is still not completely understood. Although much is known about the metabolism and biochemical effects of ribavirin in human cells, there is still much to be learned about the precise mechanism of action of ribavirin with the various viruses. New information about its ability to induce mutations in viral genomes has led to new questions about its mechanism of action. There is considerable evidence that indicates that ribavirin triphosphate (RTP) can interact with the various viral RNA polymerases, and it seems likely that this interaction is important to the mechanism of action of ribavirin. It seems likely that ribavirin will not have one universal mechanism of action, but will inhibit different viruses in different ways. In some cases, inhibition of IMP dehydrogenase may be sufficient for antiviral activity. Whereas, in other cases, inhibition of viral RNA polymerases by RTP may be more important. It is also likely that RTP will interact with the different viral RNA polymerases in different ways leading to different mechanisms of actions. More comprehensive studies are needed that address all aspects of ribavirin metabolism and biochemical actions to gain a thorough understanding of the activity of this agent. Finally, the differences in the metabolism and biochemical actions of ribavirin, selenazofurin, and tiazofurin indicate that small structural changes can have profound effects on biological activity. This observation is well known by investigators familiar with nucleoside analogs, but indicate that one should not assume that agents of similar structure have identical activities.

[1]  B. K. Murray,et al.  Broad-spectrum synergistic antiviral activity of selenazofurin and ribavirin , 1984, Antimicrobial Agents and Chemotherapy.

[2]  Y. Yamada,et al.  Adenosine kinase from human liver. , 1981, Biochimica et biophysica acta.

[3]  C. Cameron,et al.  Hepatitis C Virus RNA-dependent RNA Polymerase (NS5B) as a Mediator of the Antiviral Activity of Ribavirin* , 2001, The Journal of Biological Chemistry.

[4]  L. Philipson,et al.  Inhibition of Influenza Virus Ribonucleic Acid Polymerase by Ribavirin Triphosphate , 1977, Antimicrobial Agents and Chemotherapy.

[5]  C. Cameron,et al.  RNA virus error catastrophe: Direct molecular test by using ribavirin , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. Glazer,et al.  Mechanism of resistance to the oncolytic C-nucleoside 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC-286193). , 1982, Biochemical pharmacology.

[7]  T. Zimmerman,et al.  Metabolism of 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide and related five-membered heterocycles to 5'-triphosphates in human blood and L5178Y cells. , 1978, Biochemical pharmacology.

[8]  J. K. Lowe,et al.  Consequences of inhibition of guanine nucleotide synthesis by mycophenolic acid and virazole. , 1977, Cancer research.

[9]  V. Knight,et al.  Biochemistry and clinical applications of ribavirin , 1986, Antimicrobial Agents and Chemotherapy.

[10]  R. K. Robins,et al.  Conversion of 2-beta-D-ribofuranosylselenazole-4-carboxamide to an analogue of NAD with potent IMP dehydrogenase-inhibitory properties. , 1982, Biochemical pharmacology.

[11]  W. Müller,et al.  Virazole (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide; A cytostatic agent , 1977 .

[12]  K. Paull,et al.  Comparison of biochemical parameters of benzamide riboside, a new inhibitor of IMP dehydrogenase, with tiazofurin and selenazofurin. , 1994, Biochemical pharmacology.

[13]  E. Schmidt,et al.  Viral RNA Mutations Are Region Specific and Increased by Ribavirin in a Full-Length Hepatitis C Virus Replication System , 2002, Journal of Virology.

[14]  J. Janin,et al.  Structural analysis of the activation of ribavirin analogs by NDP kinase: comparison with other ribavirin targets. , 2003, Molecular pharmacology.

[15]  B. K. Murray,et al.  Broad-spectrum antiviral activity of 2-beta-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agent , 1983, Antimicrobial Agents and Chemotherapy.

[16]  R. J. Bauer,et al.  Mechanism of action of 1- -D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[17]  E. De Clercq,et al.  Mechanism of the potentiating effect of ribavirin on the activity of 2',3'-dideoxyinosine against human immunodeficiency virus. , 1991, The Journal of biological chemistry.

[18]  Isabelle Bougie,et al.  Initial Binding of the Broad Spectrum Antiviral Nucleoside Ribavirin to the Hepatitis C Virus RNA Polymerase* , 2003, Journal of Biological Chemistry.

[19]  J. Connor,et al.  The metabolism of ribavirin in erythrocytes and nucleated cells. , 1990, The International journal of biochemistry.

[20]  V. Marquez,et al.  Ribavirin, tiazofurin, and selenazofurin: mononucleotides and nicotinamide adenine dinucleotide analogues. Synthesis, structure, and interactions with IMP dehydrogenase. , 1985, Journal of medicinal chemistry.

[21]  R. K. Robins,et al.  The phosphorylation of ribavirin by deoxyadenosine kinase from rat liver. Differentiation between adenosine and deoxyadenosine kinase. , 1974, Biochemistry.

[22]  R. K. Robins,et al.  Tiazofurin is phosphorylated by three enzymes from Chinese hamster ovary cells. , 1990, Cancer research.

[23]  J. Arnold,et al.  The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen , 2000, Nature Medicine.

[24]  L. D. Powell,et al.  The Quest for an Efficacious Antiviral for Respiratory Syncytial Virus , 2002, Antiviral chemistry & chemotherapy.

[25]  Y. Yamada,et al.  IMP dehydrogenase and action of antimetabolites in human cultured blast cells. , 1990, Biochimica et biophysica acta.

[26]  D. Smee,et al.  Metabolism of ribavirin in respiratory syncytial virus-infected and uninfected cells , 1986, Antimicrobial Agents and Chemotherapy.

[27]  E. Domingo,et al.  Viruses at the edge of adaptation. , 2000, Virology.

[28]  R. Miller,et al.  Adenosine kinase from rabbit liver. II. Substrate and inhibitor specificity. , 1979, The Journal of biological chemistry.

[29]  P. Franchetti,et al.  Nucleoside and non-nucleoside IMP dehydrogenase inhibitors as antitumor and antiviral agents. , 1999, Current medicinal chemistry.

[30]  E. De Clercq,et al.  Eicar (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide). A novel potent inhibitor of inosinate dehydrogenase activity and guanylate biosynthesis. , 1993, The Journal of biological chemistry.

[31]  J. B. Antczak,et al.  Studies on the mechanism of the antiviral activity of ribavirin against reovirus. , 1989, Virology.

[32]  V. Knight,et al.  Effect of ribavirin triphosphate on primer generation and elongation during influenza virus transcription in vitro. , 1985, Antiviral research.

[33]  R. K. Robins,et al.  Ribavirin: an antiviral agent. , 1979, Pharmacology & therapeutics.

[34]  W. Plunkett,et al.  Metabolism and action of purine nucleoside analogs. , 1991, Pharmacology & therapeutics.

[35]  J. Patterson,et al.  Molecular mechanisms of action of ribavirin. , 1990, Reviews of infectious diseases.

[36]  D. Carson,et al.  Adenosine kinase initiates the major route of ribavirin activation in a cultured human cell line. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[37]  B. K. Murray,et al.  The importance of IMP dehydrogenase inhibition in the broad spectrum antiviral activity of ribavirin and selenazofurin. , 1985, Advances in Enzyme Regulation.

[38]  C. Cameron,et al.  Pleiotropic mechanisms of ribavirin antiviral activities. , 2002, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[39]  M. E. Jones,et al.  Pyrimidine nucleotide biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis. , 1980, Annual review of biochemistry.

[40]  V. Stollar,et al.  Inhibitors of IMP dehydrogenase prevent sindbis virus replication and reduce GTP levels in Aedes albopictus cells. , 1981, Virology.

[41]  J. Arnold,et al.  Incorporation fidelity of the viral RNA-dependent RNA polymerase: a kinetic, thermodynamic and structural perspective☆ , 2004, Virus Research.

[42]  D. Smee,et al.  Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro , 2001, Antiviral chemistry & chemotherapy.

[43]  R. K. Robins,et al.  Modulation of nicotinamide adenine dinucleotide and poly(adenosine diphosphoribose) metabolism by the synthetic "C" nucleoside analogs, tiazofurin and selenazofurin. A new strategy for cancer chemotherapy. , 1985, The Journal of clinical investigation.

[44]  R. K. Robins,et al.  Broad-Spectrum Antiviral Activity of Virazole: 1-f8- D-Ribofuranosyl- 1,2,4-triazole- 3-carboxamide , 1972, Science.

[45]  Z. Hong,et al.  Mechanisms of Action of Ribavirin in Antiviral Therapies , 2001, Antiviral chemistry & chemotherapy.

[46]  W. Sadee,et al.  Biochemical differences among four inosinate dehydrogenase inhibitors, mycophenolic acid, ribavirin, tiazofurin, and selenazofurin, studied in mouse lymphoma cell culture. , 1985, Cancer research.

[47]  C. Cameron,et al.  Quasispecies, error catastrophe, and the antiviral activity of ribavirin. , 2002, Virology.

[48]  Rong Liu,et al.  The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA. , 2003, Virology.

[49]  William E. Severson,et al.  Ribavirin Causes Error Catastrophe during Hantaan Virus Replication , 2003, Journal of Virology.

[50]  K. O'connell,et al.  Effect of phosphorylated ribavirin on vesicular stomatitis virus transcription , 1988, Antimicrobial Agents and Chemotherapy.

[51]  V. Knight,et al.  Mode of action of ribavirin: effect of nucleotide pool alterations on influenza virus ribonucleoprotein synthesis. , 1985, Antiviral research.

[52]  G. Weber,et al.  Action of the active metabolites of tiazofurin and ribavirin on purified IMP dehydrogenase. , 1988, Biochemistry.

[53]  R. Lanford,et al.  Ribavirin Induces Error-Prone Replication of GB Virus B in Primary Tamarin Hepatocytes , 2001, Journal of Virology.

[54]  M. Lai,et al.  Mutagenic and inhibitory effects of ribavirin on hepatitis C virus RNA polymerase. , 2003, Biochemistry.

[55]  R. K. Robins,et al.  THE RELATIONSHIP BETWEEN THE METABOLISM OF RIBAVIRIN AND ITS PROPOSED MECHANISM OF ACTION , 1977, Annals of the New York Academy of Sciences.

[56]  Manfred Eigen,et al.  Error catastrophe and antiviral strategy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[57]  K. O'connell,et al.  Molecular analysis of the inhibitory effect of phosphorylated ribavirin on the vesicular stomatitis virus in vitro polymerase reaction , 1989, Antimicrobial Agents and Chemotherapy.