alexa Activity of Ribavirin against Hantaan Virus Correlates with Production of Ribavirin-5-Triphosphate, Not with Inhibition of IMP Dehydrogenase
Microbiology

Microbiology

Journal of Antimicrobial Agents

Author(s): Yanjie Sun

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Hanta virus infections represent an important and growing source of disease in both developed and developing countries (11). Although no vaccines or antiviral agents are approved by the FDA to treat the disease, ribavirin (RBV) has been shown to have antiviral activity against hantaviral infections in in vitro assays and in the suckling-mouse model (9, 12). There is also evidence that it is effective in people infected with Hantaan virus (HTNV) (8). RBV is a broad-spectrum antiviral agent with activity against both DNA and RNA viruses (2, 21). Although much is known about the metabolism and biochemical effects of RBV in human cells (17), the mechanism of action of RBV against HTNV has not yet been determined. Once transported into human cells, RBV is rapidly converted to RBV 5-monophosphate (RBV-MP) by adenosine kinase (1, 25), and successive phosphorylation leads to the formation and accumulation of RBV-5-triphosphate (RBV-TP) (5). RBV-MP is a potent competitive inhibitor of IMP dehydrogenase with respect to its natural substrate, IMP (15, 23), and the inhibition of this enzyme by RBV-MP is believed to be responsible for the toxicity of RBV to human cells. Other activities of RBV that could result in antiviral activity include its ability to (i) interfere with capping of the 5 end of the mRNA (6), (ii) inhibit the viral polymerase by RBV-TP (3, 4, 18, 24, 26), and (iii) induce error catastrophe (7). These activities of RBV are all associated with the production of RBV-TP in virus-infected cells. Severson et al. (20) have shown that treatment with RBV results in an increase in the mutation frequency in the HTNV genome, which suggests that the direct incorporation of RBV in viral RNAs (vRNAs) by the viral polymerase is responsible for its antiviral activity against HTNV. T

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This article was published in ANTIMICROBIAL AGENTS AND CHEMOTHERAPY and referenced in Journal of Antimicrobial Agents

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