Synergistic antiviral effects of ribavirin and the C-nucleoside analogs tiazofurin and selenazofurin against togaviruses, bunyaviruses, and arenaviruses

Huggins, John W.; Robins, Roland K.; Canonico, Peter G.

doi:10.1128/aac.26.4.476

Cited by 104 publications

(50 citation statements)

References 19 publications

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“…Selenazofurin was previously shown to have antiviral activity against a number of different viruses in vitro (5,8,9). We demonstrated that selenazofurin also inhibits replication of influenza A and B viruses in vitro (ID50 = 25 and 19 ,uM, respectively).…”

Section: Discussionmentioning

confidence: 75%

Effects of selenazofurin and ribavirin and their 5'-triphosphates on replicative functions of influenza A and B viruses

Wray¹,

Smith²,

Gilbert³

et al. 1986

Antimicrob Agents Chemother

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We studied the effects of selenazofurin alone and in combination with ribavirin on replication of influenza A and B viruses. These drugs showed little cytotoxicity as measured by leucine incorporation into protein in MDCK cells, although they were potent inhibitors of viral replication in the same cells. Selenazofurin inhibited growth of influenza A and B viruses at concentrations (50% inhibitory dose = 25 and 19 ,uM, respectively) which were similar to those at which growth was inhibited by ribavirin (50% inhibitory dose = 50 and 30 ,uM, respectively). The inhibition of replication of either influenza A or B virus was additive for any combination of ribavirin and selenazofurin. The effects of the 5'-triphosphate of selenazofurin on two replicative functions associated with the influenza virus RNA-dependent RNA polymerases, primer generation (initiation of transcription) and its subsequent elongation, were measured. Elongation was more sensitive to selenazofurin 5'-triphosphate than was primer generation, and the effects of this drug on these functions were approximately the same as those of ribavirin 5'-triphosphate. The activities of ribavirin triphosphate and selenazofurin triphosphate were additive, and combinations did not potentiate the individual inhibitory effects of these drugs on elongation.Selenazofurin (2-p-D-ribofuranosylselenazole-4-carboxamide)is a new synthetic nucleoside analog which is structurally related to ribavirin, a potent broad-spectrum antiviral agent (15). Selenazofurin is a potent antiviral agent in vitro, inhibiting the replication of such diverse viruses as

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Section: Discussionmentioning

confidence: 75%

Effects of selenazofurin and ribavirin and their 5'-triphosphates on replicative functions of influenza A and B viruses

Wray¹,

Smith²,

Gilbert³

et al. 1986

Antimicrob Agents Chemother

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“…We determined that RBV had a narrow TI of 4.7 Ϯ 2.5 in the BVDV assay, with only a slight margin between the concentration required for antiviral effects and that causing cytotoxicity. RBV was (20) and 28 g/ml (29) also determined with inhibition-of-CPE assays, yet it was higher than the 8-g/ml IC 50 determined with a plaque reduction assay endpoint (18) or the IC 50 of Ͼ500 M found in another study utilizing inhibition of CPE as an endpoint (28). RBV also failed to reach a TC 50 in most published YFV antiviral evaluation studies (20,28,29), while one study found a TC 50 for RBV of 63 g/ml (18).…”

mentioning

confidence: 99%

Synergistic In Vitro Interactions between Alpha Interferon and Ribavirin against Bovine Viral Diarrhea Virus and Yellow Fever Virus as Surrogate Models of Hepatitis C Virus Replication

Buckwold

Wei

Wenzel-Mathers

et al. 2003

Antimicrob Agents Chemother

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Monotherapy of hepatitis C virus infection with either alpha interferon or ribavirin alone is rather ineffective, while the use of the two antivirals together is much more efficacious. In vitro drug-drug combination analysis utilizing related members of the family Flaviviridae, bovine viral diarrhea virus and yellow fever virus, revealed significant direct synergistic interactions between these drugs' antiviral activities that might explain this clinical observation.Hepatitis C virus (HCV) is the most common cause of chronic hepatitis in the United States and represents a major risk factor for the development of liver cirrhosis and hepatocellular carcinoma (3,19). Currently, HCV infections are treated with a combination therapy of alpha interferon (IFN-␣) and the purine nucleoside analogue ribavirin (RBV; 1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide). Monotherapy of HCVinfected patients with RBV does not reduce viral loads or lead to sustained virologic responses (SVR) (4, 10, 11), while monotherapy utilizing IFN-␣ leads to SVR in approximately 20% of chronically infected HCV patients (16). The combination of IFN-␣ and RBV is much more effective clinically than either drug alone, leading to rates of SVR of approximately 40% (16).The mechanism of action of IFN-␣ as an effective agent against HCV is uncertain, but both direct and immune-mediated mechanisms may be involved (5,17,24). It has been hypothesized that RBV may act indirectly as an antiviral agent against HCV through an enhancement of the immune response and/or act directly against HCV through its action as an IMP dehydrogenase inhibitor (40), as an inhibitor of the HCV RNA-dependent RNA polymerase NS5B (27), or as an RNA mutagen (8, 9, 21, 22, 35; reviewed in reference 14). Recently it was demonstrated that RBV has activity against HCV RNA replicons (22) and against HCV that was produced in a fulllength binary expression system (7). Both of these studies found evidence that the antiviral effects of RBV could be ascribed to its mutagenic role, inducing error-prone replication. The mechanism of action of RBV is controversial (reviewed in references 14, 24, and 37). But since RBV has little if any direct activity against HCV in vivo (4, 10, 11), none of the hypotheses concerning the mechanism of action of the drug adequately explains the known clinical synergy of action between the two drugs observed in HCV-infected patients (16). In order to ascertain the potential for direct synergy of antiviral effects between IFN-␣ and RBV, we performed a drug-drug combination analysis using related members of the family Flaviviridae.The family Flaviviridae comprises three genera: Hepacivirus, Pestivirus, and Flavivirus (25). The structural organization of the genomes of representative members of the Flaviviridae is shown in Fig. 1. The genus Hepacivirus includes only HCV. Since there are no robust methods by which cultured cells can be infected with and replicate HCV virions, other methods are often employed in the study of anti-HCV agents. HCV RNA replicons (26; r...

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“…A limited number of antivirals have been tested, and few have been effective against viruses within the family Bunyaviridae. Ribavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboamide) (RBV), a broad-spectrum antiviral agent, and related C-nucleoside analogues ribamidine, selenazofurin (SEL), and tiazofurin (TIA) show potent antiviral activity in vitro against HTNV (17,19). RBV was proven effective in the treatment of lethal encephalitic suckling mice infected with HTNV (16).…”

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confidence: 99%

Ribavirin Reveals a Lethal Threshold of Allowable Mutation Frequency for Hantaan Virus

Chung

Sun

Parker

et al. 2007

J Virol

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The broad spectrum of antiviral activity of ribavirin (RBV) lies in its ability to inhibit IMP dehydrogenase, which lowers cellular GTP. However, RBV can act as a potent mutagen for some RNA viruses. Previously we have shown a lack of correlation between antiviral activity and GTP repression for Hantaan virus (HTNV) and evidence for RBV's ability to promote error-prone replication. To further explore the mechanism of RBV, GTP levels, specific infectivity, and/or mutation frequency was measured in the presence of RBV, mycophenolic acid (MPA), selenazofurin, or tiazofurin. While all four drugs resulted in a decrease in the GTP levels and infectious virus, only RBV increased the mutation frequency of viral RNA (vRNA). MPA, however, could enhance RBV's mutagenic effect, which suggests distinct mechanisms of action for each. Therefore, a simple drop in GTP levels does not drive the observed error-prone replication. To further explore RBV's mechanism of action, we made a comprehensive analysis of the mutation frequency over several RBV concentrations. Of importance, we observed that the viral population reached a threshold after which mutation frequency did not correlate with a dose-dependent decrease in the level of vRNA, PFU, or [RTP]/[GTP] (where RTP is ribavirin-5-triphosphate) over these same concentrations of RBV. Modeling of the relationship of mutation frequency and drug concentration showed an asymptotic relationship at this point. After this threshold, approximately 57% of the viral cDNA population was identical to the wild type. These studies revealed a lethal threshold, after which we did not observe a complete loss of the quasispecies structure of the wild-type genome, although we observed extinction of HTNV.

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Synergistic antiviral effects of ribavirin and the C-nucleoside analogs tiazofurin and selenazofurin against togaviruses, bunyaviruses, and arenaviruses

Cited by 104 publications

References 19 publications

Effects of selenazofurin and ribavirin and their 5'-triphosphates on replicative functions of influenza A and B viruses

Effects of selenazofurin and ribavirin and their 5'-triphosphates on replicative functions of influenza A and B viruses

Synergistic In Vitro Interactions between Alpha Interferon and Ribavirin against Bovine Viral Diarrhea Virus and Yellow Fever Virus as Surrogate Models of Hepatitis C Virus Replication

Ribavirin Reveals a Lethal Threshold of Allowable Mutation Frequency for Hantaan Virus

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