Sun Yanjie, Chung Dong-Hoon, Chu Yong-Kyu, Jonsson Colleen B, Parker William B
Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA.
Antimicrob Agents Chemother. 2007 Jan;51(1):84-8. doi: 10.1128/AAC.00790-06. Epub 2006 Oct 23.
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 a 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 mug/ml RBV resulted in a small decrease in GTP levels that was not dose dependent. Increasing the RBV concentration from 10 to 40 mug/ml resulted in a decrease in viral RNA (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 increased 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.
利巴韦林（RBV）是一种广谱抗病毒药物，可抑制汉坦病毒（HTNV）的感染性产生。尽管RBV对HTNV的作用机制尚不清楚，但RBV在人体细胞中代谢为RBV-5'-单磷酸，其可抑制肌苷酸脱氢酶，导致细胞内GTP水平降低，以及RBV-5'-三磷酸（RBV-TP），其可选择性地与病毒RNA聚合酶相互作用。为了阐明RBV的哪种活性对其抗HTNV活性最为重要，在Vero E6细胞中研究了RBV的作用机制。用10至40μg/ml的RBV孵育导致GTP水平略有下降，且不依赖剂量。将RBV浓度从10μg/ml增加到40μg/ml导致病毒RNA（vRNA）水平下降以及RBV-TP形成增加。肌苷酸脱氢酶抑制剂霉酚酸（MPA）也导致vRNA水平下降；然而，用MPA处理导致GTP水平下降幅度比RBV处理时大得多。用MPA和RBV联合处理导致vRNA水平进一步下降，但并未导致GTP水平进一步降低。尽管鸟苷可防止RBV引起的GTP水平降低，但鸟苷只能部分防止RBV对vRNA水平的影响。这些结果表明，RBV对肌苷酸脱氢酶的抑制对RBV抑制vRNA复制来说是次要的，且RBV-TP与病毒聚合酶的相互作用是RBV的主要作用。
