Broad-spectrum antiviral activity of 2-beta-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agent

Kirsi, Jorma J.; North, James A.; McKernan, Patricia A.; Murray, Byron K.; Canonico, Peter G.; Huggins, John W.; Srivastava, Prem C.; Robins, Roland K.

doi:10.1128/aac.24.3.353

Cited by 156 publications

(102 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous studies examined the effect of ribavirin on the yield of infectious HTNV and determined an ED 50 of 15 g/ml; however, its mechanism of action is still unknown (12). We show here that ribavirin can cause a reduction in infectious HTNV, as measured by plaque assay.…”

Section: Discussionmentioning

confidence: 55%

“…Several members of the Bunyaviridae family are sensitive to the drug ribavirin; of these, HTNV is one of the most sensitive (10,12). Previous studies examined the effect of ribavirin on the yield of infectious HTNV and determined an ED 50 of 15 g/ml; however, its mechanism of action is still unknown (12).…”

Section: Discussionmentioning

confidence: 99%

“…In Vero E6 cells infected with HTNV, ribavirin acts as an inhibitor of the life cycle with an 50% effective dose (ED 50 ) of 14.8 g/ml (12). The mechanism of action for the observed sensitivity of HTNV to ribavirin at the molecular level is not known.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Ribavirin Causes Error Catastrophe during Hantaan Virus Replication

Severson

Schmaljohn

Javadian

et al. 2003

J Virol

168

124

View full text Add to dashboard Cite

Except for ribavirin, no other antiviral drugs for treating hantaviral diseases have been identified. It is well established that ribavirin will inhibit the production of infectious Hantaan virus (HTNV); however, its mechanism of action is unknown. To characterize the inhibitory effect of ribavirin on HTNV, the levels of viral RNAs, proteins, and infectious particles were measured for 3 days posttreatment of HTNV-infected Vero E6 cells. HTNV-infected cells treated with ribavirin showed a slight reduction in the levels of cRNA, viral RNA, and mRNA populations on the first day postinfection. The amount of cRNA and viral RNA increased to that observed for untreated HTNV-infected cells on day 2, whereas mRNA levels were more greatly reduced on days 2 and 3. Despite the finding of S-segment mRNA, albeit low, three of the viral proteins-nucleocapsid (N) protein and glycoproteins G1 and G2-could not be detected by immunohistochemistry in ribavirin-treated cells. To test the hypothesis that these effects were caused by incorporation of ribavirin into nascent RNA and a resultant "error catastrophe" was occurring, we cloned and sequenced the S-segment cRNA/mRNA from ribavirin-treated or untreated cells from day 3. We found a high mutation frequency (9.5/1,000 nucleotides) in viral RNA synthesized in the presence of ribavirin. Hence, the transcripts produced in the presence of the drug were not functional. These results suggest that ribavirin's mechanism of action lies in challenging the fidelity of the hantavirus polymerase, which causes error catastrophe.Hantaviruses, which are endemic in most regions of the world, persistently infect murid rodents and are shed through rodent excreta (20). Transmission of hantaviruses from rodent hosts to humans causes two illnesses, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome. Hantaan virus (HTNV), carried by Apodemus agrarius, produces one of the more severe HFRS illnesses caused by the Old World hantaviruses, causing death in 5 to 15% of the cases (14, 15). HTNV infections cause a renal dysfunction with fever, hemorrhaging, cardiovascular instability, and shock. Ribavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is the only antiviral drug shown to have efficacy against HFRS in clinical trials (11). Ribavirin has been tested for its effectiveness in clinical trials with patients suspected to have hantavirus pulmonary syndrome; however, its therapeutic benefits are still not known (2).Ribavirin has a broad spectrum of antiviral activity against both RNA and DNA viruses. Its mechanism of action, however, has been difficult to elucidate, primarily because of its pleiotropic effects (10, 17). Ribavirin 5Ј-monophosphate resembles GMP and can decrease cellular GTP pools due to the inhibition of the enzyme inosine monophosphate dehydrogenase dehydrogenase; however, this decrease does not completely account for the observed antiviral activity. Inhibitory effects have also been noted on the capping (9) and translation efficiency (23) of viral mRNA, a...

show abstract

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ribavirin Causes Error Catastrophe during Hantaan Virus Replication

Severson

Schmaljohn

Javadian

et al. 2003

J Virol

168

124

View full text Add to dashboard Cite

show abstract

“…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).…”

mentioning

confidence: 99%

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

Chung

Sun

Parker

et al. 2007

J Virol

View full text Add to dashboard Cite

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.

show abstract

“…The 2-(1,3-selenazolidin-2-ylidene)malononitriles 10a-d show two different CN absorptions in the IR spectra (KBr; ca. 2203 and 2190 cm -1 ) and 13 C NMR spectra (DMSO; ca. 112 and 118 ppm).…”

Section: Resultsmentioning

confidence: 99%

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 2‐Methylidene‐1,3‐selenazolidine Derivatives.

Sommen¹,

Linden²,

Heimgartner³

2006

ChemInform

View full text Add to dashboard Cite

A convenient and unequivocal synthesis of the title compounds from isoselenocyanates, malononitrile or 2-cyanoacetate, and 1,2-dibromoethane or a-halogenated carboxylic acid derivatives is reported. The proposed reaction mechanism involves in situ cyclization of different halogenated compounds with an intermediate keten-N,Se-acetal, generated by the base promoted nucleophilic addition of the acidic cyanomethylenes to aliphatic and aromatic isoselenocyanates. Chemical and spectroscopic evidence for the structures of the new compounds is presented.

show abstract

Broad-spectrum antiviral activity of 2-beta-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agent

Cited by 156 publications

References 33 publications

Ribavirin Causes Error Catastrophe during Hantaan Virus Replication

Ribavirin Causes Error Catastrophe during Hantaan Virus Replication

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

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 2‐Methylidene‐1,3‐selenazolidine Derivatives.

Contact Info

Product

Resources

About