Embryotoxic, teratogenic, and metabolic effects of ribavirin in mice

Kochhar, D. M.; Penner, John D.; Knudsen, Thomas B.

doi:10.1016/0041-008x(80)90252-5

Cited by 124 publications

(77 citation statements)

References 9 publications

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“…Analysis of the interaction between ribavirin analogs and the HCV polymerase by fluorescence spectroscopy is particularly appealing. Side effects resulting from the use of ribavirin have been noted and include defects in sperm development and hemolytic anemia (43)(44)(45). Improved versions of ribavirin are thus needed to improve the safety and efficacy of the therapies against HCV.…”

Section: Binding Of Rtp In the Presence Of A Template-primer-thementioning

confidence: 99%

Initial Binding of the Broad Spectrum Antiviral Nucleoside Ribavirin to the Hepatitis C Virus RNA Polymerase

Bougie

Bisaillon

2003

Journal of Biological Chemistry

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Ribavirin is a broad spectrum antiviral nucleoside that displays activity against a variety of RNA and DNA viruses. Ribavirin is currently used in combination with interferon-␣ for the treatment of hepatitis C virus (HCV) infection and was recently shown to be directly incorporated by the HCV RNA polymerase into RNA products. This capacity ultimately leads to increased mutation rates and drastically reduces the viral fitness. As a first step toward elucidating the nature of the specific interaction between ribavirin and the HCV polymerase, we have utilized fluorescence spectroscopy to monitor precisely the binding of ribavirin triphosphate (RTP) to the viral polymerase. This spectroscopic approach allowed us to clearly separate the RTP binding activity from the concomitant catalytic steps. We report here the first detailed study of the binding kinetics and thermodynamic parameters involved in the interaction between RTP and an RNA polymerase. We demonstrate that RTP binds to the same active site as nucleotides. Furthermore, we provide evidence that the HCV polymerase cannot only bind to RTP but also to nonphosphorylated ribavirin, albeit with less affinity. By using various combinations of template-primers, we also demonstrate that base pairing is not involved in the initial binding of RTP to the HCV polymerase. Based on the results of circular dichroism and denaturation studies, we show that the RNA polymerase undergoes subtle conformational changes upon the binding of RTP, although the interaction does not significantly modify the stability of the protein. Finally, although metal ions are required for catalytic activity, they are not required for the initial binding of RTP to the polymerase. Such quantitative analyses are of primary importance for the rational design of new ribavirin analogues of potential therapeutic value and provide crucial insights on the interaction between RTP and the HCV RNA polymerase.Ribavirin is a broad spectrum antiviral nucleoside that displays activity against a variety of RNA and DNA viruses (1, 2). Once inside the cells, ribavirin is phosphorylated by cellular kinases, with ribavirin triphosphate as the major intracellular metabolite (3, 4). A number of possible mechanisms have been proposed over the years to account for the antiviral activity of ribavirin. Ribavirin has been shown to inhibit the host cell inosine monophosphate dehydrogenase, an enzyme involved in the de novo synthesis of GTP (5, 6). Because GTP is required for the transcription of viral genomes, and replication of RNA viruses, it has been assumed that the decrease in cytosolic concentration of GTP could affect the multiplication of viruses. Ribavirin has also been shown to modulate the host immune system by engendering a bias toward helper T-cells type 1 cytokine response (7,8). This would ultimately lead to an enhanced immune response against viral infections.Ribavirin has also been shown to have an inhibitory effect on viral polymerases (9, 10). It has been suggested that ribavirin triphosphate could bind to ...

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Section: Binding Of Rtp In the Presence Of A Template-primer-thementioning

confidence: 99%

Initial Binding of the Broad Spectrum Antiviral Nucleoside Ribavirin to the Hepatitis C Virus RNA Polymerase

Bougie

Bisaillon

2003

Journal of Biological Chemistry

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“…9,10,11,12 One study of a small number of baboons did not show teratogenic effects. 13 However, a NIOSH review of this study concluded that the study did not provide adequate evidence to evaluate reproductive outcome due to a small number of test animals.…”

Section: Evaluation Criteria a Toxicology Of Ribavirinmentioning

confidence: 99%

Health hazard evaluation report: HETA-91-178-2220, Geisinger Wyoming Valley Medical Center, Wilkes Barre, Pennsylvania.

1992

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“…2,3,4,5 One study which evaluated teratogenic effects in baboons did not show teratogenic effects. 20 Page 6 -Health Hazard Evaluation Report No.…”

Section: A Toxicology Of Ribavirinmentioning

confidence: 99%

“…Such a respirator would reduce the highest exposure concentration to an inmask concentration equal to, or less than, the contaminant's exposure limit for the majority of respiratory wearers. Any air-purifying full facepiece respirator equipped with any type of particulate filter 5 Any supplied-air respirator equipped with a half-mask and operated in a demand (negative pressure) mode 2 …”

Section: Distribution and Availability Of Reportmentioning

confidence: 99%

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Health hazard evaluation report: HETA-91-104-2229, Florida Hospital, Orlando, Florida.

1992

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Embryotoxic, teratogenic, and metabolic effects of ribavirin in mice

Cited by 124 publications

References 9 publications

Initial Binding of the Broad Spectrum Antiviral Nucleoside Ribavirin to the Hepatitis C Virus RNA Polymerase

Initial Binding of the Broad Spectrum Antiviral Nucleoside Ribavirin to the Hepatitis C Virus RNA Polymerase

Health hazard evaluation report: HETA-91-178-2220, Geisinger Wyoming Valley Medical Center, Wilkes Barre, Pennsylvania.

Health hazard evaluation report: HETA-91-104-2229, Florida Hospital, Orlando, Florida.

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