Department of Virology, Bernhard-Nocht-Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany.
Antiviral Res. 2011 Aug;91(2):89-93. doi: 10.1016/j.antiviral.2011.05.006. Epub 2011 May 17.
Ribavirin (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) is the standard treatment for Lassa fever, though its mode of action is unknown. One possibility is depletion of the intracellular GTP pool via inhibition of the cellular enzyme inosine monophosphate dehydrogenase (IMPDH). This study compared the anti-arenaviral effect of ribavirin with that of two other IMPDH inhibitors, mycophenolic acid (MPA) and 5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (EICAR). All three compounds were able to inhibit Lassa virus replication by ≥2 log units in cell culture. Restoring the intracellular GTP pool by exogenous addition of guanosine reversed the inhibitory effects of MPA and EICAR, while ribavirin remained fully active. Analogous experiments performed with Zaire Ebola virus showed that IMPDH inhibitors are also active against this virus, although to a lesser extent than against Lassa virus. In conclusion, the experiments with MPA and EICAR indicate that replication of Lassa and Ebola virus is sensitive to depletion of the GTP pool mediated via inhibition of IMPDH. However, this is not the predominant mechanism by which ribavirin exerts its in-vitro antiviral effect on Lassa virus.
利巴韦林（1-β-d- 呋喃核糖基-1,2,4-三唑-3-羧酰胺）是治疗拉沙热的标准药物，但其作用机制尚不清楚。一种可能性是通过抑制细胞内酶肌苷单磷酸脱氢酶（IMPDH）来耗尽细胞内 GTP 池。本研究比较了利巴韦林与另外两种 IMPDH 抑制剂霉酚酸（MPA）和 5-乙炔基-1-β-d-呋喃核糖基咪唑-4-羧酰胺（EICAR）的抗沙波病毒作用。这三种化合物在细胞培养中均能抑制拉沙病毒复制≥2 个对数单位。通过外源性添加鸟苷恢复细胞内 GTP 池，可逆转 MPA 和 EICAR 的抑制作用，而利巴韦林仍保持完全活性。用扎伊尔埃博拉病毒进行的类似实验表明，IMPDH 抑制剂对该病毒也具有活性，尽管其活性低于拉沙病毒。总之，与 MPA 和 EICAR 的实验表明，拉沙病毒和埃博拉病毒的复制对通过抑制 IMPDH 导致的 GTP 池耗竭敏感。然而，这不是利巴韦林在体外对拉沙病毒发挥抗病毒作用的主要机制。
