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The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen

Nature Medicine volume 6, pages 1375–1379 (2000)Cite this article

An Erratum to this article was published on 01 February 2001

Abstract

The ribonucleoside analog ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) shows antiviral activity against a variety of RNA viruses and is used in combination with interferon-α 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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Figure 1: RMP incorporation by 3Dpol in vitro.
Figure 2: Molecular modeling of ribavirin.
Figure 3: Analysis of poliovirus translation and replication in the presence of ribavirin.

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Acknowledgements

We thank D. Gohara for preparation of RTP molecular models; S. Scaringe for synthesis of ribavirin phosphoramidite; J. Lecomte for structural analysis of RTP; S. Firestine and J. Herold for discussions; J. Frydman and A. Frankel for comments; and G. Reyes for support. This work was supported in part by a National Cancer Institute National Institutes of Health Howard Temin Award CA75118 (to C.E.C.) and National Institute of Allergy and Infectious Diseases National Institutes of Health grants AI45818 (to C.E.C.) and AI40085 (to R.A.). S.C. is a Howard Hughes Medical Institute doctoral fellow.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, 94143-0414, California, USA

    Shane Crotty & Raul Andino

  2. Department of Biochemistry & Molecular Biology, Pennsylvania State University, 201 Althouse Lab, University Park, 16802-4500, Pennsylvania, USA

    David Maag, Jamie J. Arnold & Craig E. Cameron

  3. Antiviral Therapy, Schering-Plough Research Institute, Kenilworth, 07033-1300, New Jersey, USA

    Weidong Zhong, Johnson Y. N. Lau & Zhi Hong

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Correspondence to Craig E. Cameron.

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Crotty, S., Maag, D., Arnold, J. et al. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med 6, 1375–1379 (2000). https://doi.org/10.1038/82191

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