Research Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Antiviral Res. 2013 Mar;97(3):264-9. doi: 10.1016/j.antiviral.2012.12.029. Epub 2013 Jan 5.
Enterovirus-71 (EV71) infections can cause life-threatening diseases with neurological symptoms. Currently, no direct targeting antivirals are available to combat severe EV71 infection. Rupintrivir (AG7088) is a compound originally designed for Rhinovirus 3C protease. Previous computational analyses by us and crystallography studies by others suggested that rupintrivir is also a high affinity inhibitor to EV71 3C. Thus, we aimed to further evaluate its anti-EV71 activity in vivo at clinically acceptable doses. It was observed that administration of rupintrivir in suckling mice largely protected them from limb paralysis and dramatically improved survival (38.5% DMSO vs. 90.9% at 0.1mg/kg, p=0.006). Histological, immunohistochemical and quantitative RT-PCR analyses confirmed that rupintrivir profoundly alleviated virus induced necrotizing myositis, suppressed viral RNA and blocked EV71 VP1 expression in various tissues. In conclusion, we established that rupintrivir can strongly contain the spread of EV71 infection in vivo at a clinically acceptable dose (as low as 0.1mg/kg). As its safety has been fully tested in previous clinical trials, rupintrivir is suitable for immediate evaluation of potential benefits in EV71-infected individuals with life-threatening neurological symptoms.
肠道病毒 71 型（EV71）感染可引起伴有神经症状的危及生命的疾病。目前，尚无针对严重 EV71 感染的直接靶向抗病毒药物。鲁匹那韦（AG7088）是一种最初为鼻病毒 3C 蛋白酶设计的化合物。我们之前的计算分析和其他人的晶体学研究表明，鲁匹那韦也是 EV71 3C 的高亲和力抑制剂。因此，我们旨在以临床可接受的剂量进一步评估其在体内抗 EV71 活性。结果观察到，鲁匹那韦在乳鼠中的给药在很大程度上保护它们免受肢体瘫痪，并显著提高存活率（0.1mg/kg 时 38.5% DMSO 与 90.9%，p=0.006）。组织学、免疫组织化学和定量 RT-PCR 分析证实，鲁匹那韦可显著减轻病毒诱导的坏死性肌炎，抑制病毒 RNA 并阻断各种组织中的 EV71 VP1 表达。总之，我们证实鲁匹那韦在临床可接受剂量（低至 0.1mg/kg）下可强烈抑制 EV71 感染在体内的传播。由于其安全性已在前临床试验中得到充分测试，鲁匹那韦适合立即评估对有危及生命的神经症状的 EV71 感染个体的潜在益处。
