Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ribavirin 5'-triphosphate (RTP), derived from the broad-spectrum antiviral compound ribavirin (Virazole), can selectively inhibit influenza virus ribonucleic acid polymerase in a cell-free assay. Ribavirin and its 5'-monophosphate have no effect on the polymerase. The inhibition is competitive with respect to adenosine 5'-triphosphate and guanosine 5'-triphosphate. RTP also inhibits ApG- and GpC-stimulated influenza virus ribonucleic acid polymerase. Since ribavirin is phosphorylated in the cell, the inhibition of influenza multiplication in the cell may also be caused by RTP.
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PMID:Inhibition of influenza virus ribonucleic acid polymerase by ribavirin triphosphate. 87 60

Ribavirin was administered orally in escalating doses for 2 or 4 weeks to 15 symptom-free, human immunodeficiency virus seropositive homosexual men with generalized lymphadenopathy. Reverse transcriptase activity was inhibited during therapy when steady-state plasma concentrations were greater than 6 mumol/L. These concentrations were achieved with 1200 or 2400 mg/day for 2 weeks or a loading dose of 2400 mg/day for 3 days followed by 600 mg/day for 4 weeks. Drug accumulation occurred at all doses. The elimination half-life appeared to be approximately 2 weeks. Reversible adverse reactions, principally resulting in central nervous system symptoms and anemia, correlated with dose and duration of therapy. Immunologic enhancement of T-lymphocyte-mediated mitogen-induced responses was observed in the majority of patients who had reduction in reverse transcriptase activity. However, specific T4+ lymphocyte-mediated antigen-induced responses increased to within the normal range in only three patients. Significant enhancement appeared to correlate with the severity of baseline antigen-induced functional impairment. These data indicate that oral ribavirin can be given for at least 1 month with acceptable toxicity at doses that appear to inhibit human immunodeficiency virus replication.
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PMID:Ribavirin pharmacodynamics in high-risk patients for acquired immunodeficiency syndrome. 244 79

Inhibition of visna virus replication in vitro by several compounds previously reported to inhibit replication of human immunodeficiency virus (HIV) was examined. Ribavirin concentrations as high as 1 mM reduced virus production by less than 50% relative to controls. The concentration of phosphonoformate reducing virus replication by 50% was 80 microM. 2',3'-Dideoxynucleosides were potent inhibitors of visna virus replication. The 50% inhibitory concentrations for dideoxyguanosine, dideoxyadenosine, and dideoxycytidine were 0.1, 0.2, and 0.3 microM, respectively. In contrast, weak inhibition was produced by 100 microM dideoxythymidine. These results are consistent with the reported susceptibility of HIV replication to inhibition by these compounds in vitro. The interaction of visna virus reverse transcriptase with several inhibitors was also examined. Reverse transcriptase was inhibited by phosphonoformate, ribavirin 5'-triphosphate, ddATP, ddCTP, ddGTP, and ddTTP. The last four compounds inhibited incorporation of homologous 2'-deoxynucleoside 5'-triphosphates into polynucleotides by a competitive mechanism. In view of the biological similarities between visna virus and HIV and the similar in vitro susceptibility of visna virus replication to known inhibitors of HIV, visna virus may provide a good model for studying the inhibition of HIV replication in vitro. Because visna virus is not pathogenic to humans, this model may facilitate the identification of compounds for further investigation into the treatment of HIV-induced disease.
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PMID:Visna virus as an in vitro model for human immunodeficiency virus and inhibition by ribavirin, phosphonoformate, and 2',3'-dideoxynucleosides. 244 82

Ribavirin 5'-sulfamate, a nucleotide analog, inhibited Semliki Forest virus cytopathology by 50% at 10 microM, whereas ribavirin was inactive at less than or equal to 1 mM. Actinomycin D did not reverse (antagonize) the effect of ribavirin 5'-sulfamate against the virus. The compound inhibited amino acid incorporation into macromolecules of uninfected cells but had no appreciable effect on uridine incorporation. Infected cells treated with actinomycin D and nucleotide analog were inhibited in amino acid and uridine incorporation. The compound blocked the formation of the viral RNA polymerase protein in cells, which could account for the inhibited synthesis of new viral RNA. By electrophoresis, inhibition of the synthesis of viral proteins was more pronounced than the inhibition of cellular polypeptides. The analog inhibited the translation of mRNA to protein. Most animals treated intraperitoneally for 7 days with ribavirin 5'-sulfamate at 20 and 40 mg/kg/day starting 2 h before intraperitoneal Semliki Forest virus inoculation survived the otherwise lethal infection.
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PMID:Antiviral activity and mode of action of ribavirin 5'-sulfamate against Semliki Forest virus. 285 56

Administration of a single-stranded polynucleotide copolymer containing 9% cytidine residues and 91% 4-thiouridine residues [poly(C,S4U10)], a known potent inhibitor of the virion transcriptase of influenza viruses, suppressed the amount of virus recoverable from the nasal washes of influenza virus-infected hamsters and ferrets. The incidence of sneezing and nasal discharge in infected ferrets was also reduced. In hamsters, poly(C,S4U10) was more effective than amantadine-HCl or Virazole. Polyinosinic acid in combination with poly-5-hydroxy cytidylic acid also had anti-influenza effects. Poly(C,S4U10) annealed to polyadenylic acid was not effective, nor was the double-stranded polymer (polyinosinic acid) . (polycytidylic acid) even when complexed with carboxymethylcellulose and polylysine. No toxic effects of poly(C,S4U10) were apparent in the treated hamsters and ferrets, and high doses (greater than or equal to 2.86 g/kg) administered intraperitoneally to mice produced no adverse effects.
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PMID:Antiviral effects of single-stranded polynucleotide inhibitors of the influenza virion-associated transcriptase against influenza virus infection of hamsters and ferrets. 628 Jun 8

Several RNA virus inhibitors were evaluated against simian (SA11) rotavirus infections in vitro and murine rotavirus gastroenteritis in vivo. Test compounds included 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin), 3-deazaguanine (3-DG), 3-deazauridine, and 9-(S)-(2,3-dihydroxypropyl)adenine [(S)-DHPA]. All drugs inhibited total infectious SA11 virus yields in MA-104 cells. Ribavirin, 3-DG, and (S)-DHPA affected [3H]uridine uptake into uninfected MA-104 cells in both the acid-soluble and -insoluble fractions. All drugs reduced the levels of dense (precursor) and light (complete) SA11 particle yields compared with control but did not alter the relative amounts of dense compared with light particles, suggesting that the agents did not interfere with virus assembly. Ribavirin and 3-DG inhibited SA11 polypeptide synthesis, as determined by polyacrylamide gel electrophoresis studies. None of the agents or mono- and triphosphate derivatives of ribavirin inhibited SA11 RNA polymerase activity. In murine rotavirus studies, oral therapy with ribavirin-2',3',5'-triacetate and (S)-DHPA increased mean survival time, but no increase in survivor rate was observed. 3-DG- and (S)-DHPA-treated mice had a more rapid weight gain than controls, suggesting a probable lessening of the severity of the disease.
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PMID:Inhibition of rotaviruses by selected antiviral substances: mechanisms of viral inhibition and in vivo activity. 628 9

The balance of virus production and clearance for untreated patients with chronic hepatitis C changes into a decline of viraemia when initiating effective anti-viral treatment. During the first phase of interferon-alpha (IFN-a) therapy, the kinetics of the viral load is characterised by a rapid dose-dependent decline starting after a delay of about eight to nine hours. This early response can be observed for almost all patients treated with IFN-a. After about 24 to 48 hours, the viral decline slows down leading to a second phase with a relatively stable exponential decay. Some non-responding patients show a nearly constant viraemia and some even a rebound throughout this second phase. Kinetic models allow the estimation of rates of viral production and clearance and reveal high turnover rates of hepatitis C virus (HCV) and an in vivo half-life of hepatitis C virions of a few hours, only. Due to the continuous and high replication rate in vivo, the low fidelity of the ribonucleic acid (RNA)-dependent RNA polymerase, and the immune surveillance of the host, HCV exists in an individual patient as a heterogeneous population of related viruses (quasispecies). A high degree of quasispecies variability correlates with a lower response to IFN-a therapy. Changes of the quasispecies population are more pronounced after initiation of treatment with IFN-a or interleukin-12 than during the natural course of disease. Ribavirin, however, has not been found to affect the HCV quasispecies population. Identification of a specific region within an envelope-encoding gene as the most variable region of HCV and as a critical neutralisation domain suggests that viral escape mechanisms are a possible cause for chronification and poses a major challenge for the development of a broadly reactive vaccine against HCV.
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PMID:Hepatitis C virus: kinetics and quasispecies evolution during anti-viral therapy. 1071 56

The ribonucleoside analog ribavirin (1-beta-D-ribofuranosyl-1,2, 4-triazole-3-carboxamide) shows antiviral activity against a variety of RNA viruses and is used in combination with interferon-alpha to treat hepatitis C virus infection. Here we show in vitro use of ribavirin triphosphate by a model viral RNA polymerase, poliovirus 3Dpol. Ribavirin incorporation is mutagenic, as it templates incorporation of cytidine and uridine with equal efficiency. Ribavirin reduces infectious poliovirus production to as little as 0. 00001% in cell culture. The antiviral activity of ribavirin correlates directly with its mutagenic activity. These data indicate that ribavirin forces the virus into 'error catastrophe'. Thus, mutagenic ribonucleosides may represent an important class of anti-RNA virus agents.
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PMID:The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. 1110 Jan 23

Ribavirin is administered in combination with interferon-alpha for treatment of hepatitis C virus (HCV) infection. Recently, we demonstrated that the antiviral activity of ribavirin can result from the ability of a viral RNA polymerase to utilize ribavirin triphosphate and to incorporate this nucleotide with reduced specificity, thereby mutagenizing the genome and decreasing the yield of infectious virus (Crotty, S., Maag, D., Arnold, J. J., Zhong, W., Lau, J. Y., Hong, Z., Andino, R., and Cameron, C. E. (2000) Nat. Med. 6, 1375-1379). In this study, we performed a quantitative analysis of a novel HCV RNA polymerase derivative that is capable of utilizing stably annealed primer-template substrates and exploited this derivative to evaluate whether lethal mutagenesis of the HCV genome is a possible mechanism for the anti-HCV activity of ribavirin. These studies demonstrate HCV RNA polymerase-catalyzed incorporation of ribavirin opposite cytidine and uridine. In addition, we demonstrate that templates containing ribavirin support CMP and UMP incorporation with equivalent efficiency. Surprisingly, templates containing ribavirin can also cause a significant block to RNA elongation. Together, these data suggest that ribavirin can exert a direct effect on HCV replication, which is mediated by the HCV RNA polymerase. We discuss the implications of this work on the development of nucleoside analogs for treatment of HCV infection.
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PMID:Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. 1160 68

Ribavirin (RBV), a guanosine analogue, has been suggested to exert an antiviral action against hepatitis C virus (HCV) by causing lethal mutations and suppressing RNA polymerase in vitro, but the mechanism of its clinical therapeutic effects is currently unknown. To test the hypothesis that RBV could act both as an RNA mutagen and inhibit viral RNA synthesis in vivo, we studied the evolution of the nucleotide sequences of HCV RNA at the nonstructural (NS) 5B region in patients receiving RBV, placebo, or interferon alfa (IFN-alpha) monotherapy. The RBV group showed a slightly more accelerated evolution rate of HCV RNA quasispecies than either the IFN-alpha or placebo group. RBV caused preferentially A-to-G and U-to-A mutations. Interestingly, an NS5B amino acid 415 Phe-to-Tyr (F415Y) mutation emerged in all (5 of 5) patients infected with HCV genotype 1a during the RBV treatment. Subsequently, the parental 415F strain reemerged in some patients after the treatment was discontinued. The effect of the amino acid substitution at NS5B415 on HCV RNA replication was then investigated using an HCV subgenomic replicon in Huh7 cells. We showed that treatment of replicon cells with RBV reduced the HCV RNA level of NS5B415F replicon, but not NS5B415Y, in a dose-dependent manner. Thus, NS5B F415Y mutation represents an RBV-resistant variant. The 3-dimensional modeling and structure analysis of NS5B protein revealed that the 415th amino acid is located at the P helix region of the thumb subdomain, which may interact with the minor groove of the template-primer duplex in the putative RNA-binding cleft. In conclusion, RBV could work as a weak mutagen for HCV RNA in HCV-infected patients. Furthermore, the selection of an RBV-resistant variant with a single amino acid substitution in NS5B suggested that RBV may directly interact with HCV RNA polymerase, thus interfering with its enzymatic activity.
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PMID:Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy. 1451 67


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