AAC Accepts, published online ahead of print on 23 October 2006

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00790-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Antiviral activity of ribavirin against Hantaan virus correlates with production of ribavirin-5'-triphosphate, not with inhibition of inosine monophosphate dehydrogenase

Yanjie Sun, Dong-Hoon Chung, Yong-Kyu Chu, Colleen B. Jonsson, and William B. Parker^*

Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama, 35205

^* To whom correspondence should be addressed. Email: PARKER{at}SRI.ORG.

Ribavirin (RBV) is a broad spectrum antiviral agent that inhibits the production of infectious Hantaan virus (HTNV). Although the mechanism of action of RBV against HTNV is not understood, RBV is metabolized in human cells to both RBV-5'-monophosphate, which inhibits IMP dehydrogenase resulting in the decrease in intracellular GTP levels, and RBV-5'-triphosphate (RBV-TP), which could selectively interact with the viral RNA polymerase. To elucidate which activity of RBV was most important to its anti-HTNV activity, the mechanism of action of RBV was studied in Vero E6 cells. Incubation with 10 to 40 µg/ml RBV resulted in a small decrease in GTP levels that was not dose dependent. Increasing RBV concentration from 10 to 40 µg/ml resulted in a decrease in vRNA levels and an increase in RBV-TP formation. Mycophenolic acid (MPA), an inhibitor of IMP dehydrogenase, also resulted in a decrease in vRNA levels, however, treatment with MPA resulted in a much greater decrease in GTP levels than that seen with RBV. Treatment with both MPA and RBV resulted in increase reduction of vRNA levels, but did not result in enhanced depression of GTP levels. Although guanosine prevented the depression in GTP levels caused by RBV, guanosine only partially prevented the effect of RBV on vRNA levels. These results suggest that the inhibition of IMP dehydrogenase by RBV is of secondary importance to the inhibition of vRNA replication by RBV, and that the interaction of RBV-TP with the viral polymerase is the primary action of RBV.

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