Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus
Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus
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DOI：
10.1016/j.antiviral.2012.12.006
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发表时间：
2013-02-01
影响因子：
7.6
通讯作者：
Shiraki, Kimiyasu
中科院分区：
文献类型：
--
作者：
Chono, Koji;Katsumata, Kiyomitsu;Shiraki, Kimiyasu
ASP 2151（amenamevir）是一种解旋酶-引发酶复合物抑制剂，具有抗单纯疱疹病毒HSV-1、HSV-2和水痘带状疱疹病毒（VZV）的抗病毒活性。为了评估ASP 2151与现有抗HSV-1、HSV-2和VZV抗疱疹药物的联合治疗，我们进行了两种药物联合的体外和体内研究。通过空斑减少试验和MTS试验检测了ASP 2151与核苷类似物阿昔洛韦（ACV）、阿昔洛韦（PCV）或阿糖腺苷（VDB）的联合活性效应，并使用等效线图和响应面建模分析数据。在HSV-1感染带状疱疹样传播小鼠模型中研究了ASP 2151与伐昔洛韦（VACV）的体内联合治疗。ASP 2151与ACV和PCV联用对ACV敏感的HSV-1、HSV-2和VZV的抗病毒活性表现出统计学显著的协同作用（P < 0.05）。观察到ASP 2151与VDB对ACV敏感的HSV-2具有相加作用，对VZV具有协同作用。在带状疱疹样播散小鼠模型中，联合用药对疾病进展的抑制作用优于单药治疗（P < 0.05）。这些结果表明，ASP 2151与ACV和PCV联合治疗对HSV和VZV感染具有协同抗疱疹作用，在重度疾病（如疱疹性脑炎）或免疫抑制患者中可能是可行的。(c)2012爱思唯尔有限公司版权所有。
ASP2151 (amenamevir) is a helicase-primase complex inhibitor with antiviral activity against herpes simplex virus HSV-1, HSV-2, and varicella-zoster virus (VZV). To assess combination therapy of ASP2151 with existing antiherpes agents against HSV-1, HSV-2, and VZV, we conducted in vitro and in vivo studies of two-drug combinations. The combination activity effect of ASP2151 with nucleoside analogs acyclovir (ACV), penciclovir (PCV), or vidarabine (VDB) was tested via plaque-reduction assay and MTS assay, and the data were analyzed using isobolograms and response surface modeling. In vivo combination therapy of ASP2151 with valaciclovir (VACV) was studied in an HSV-1-infected zosteriform spread mouse model. The antiviral activity of ASP2151 combined with ACV and PCV against ACV-susceptible HSV-1, HSV-2, and VZV showed a statistically significant synergistic effect (P < 0.05). ASP2151 with VDB was observed to have additive effects against ACV-susceptible HSV-2 and synergistic effects against VZV. In the mouse model of zosteriform spread, the inhibition of disease progression via combination therapy was more potent than that of either drugs as monotherapy (P < 0.05). These results indicate that the combination therapies of ASP2151 with ACV and PCV have synergistic antiherpes effects against HSV and VZV infections and may be feasible in case of severe disease, such as herpes encephalitis or in patients with immunosuppression. (c) 2012 Elsevier B.V. All rights reserved.