Antiviral efficacy of the helicase-primase inhibitor amenamevir in murine models of severe herpesvirus infection
Antiviral efficacy of the helicase-primase inhibitor amenamevir in murine models of severe herpesvirus infection
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DOI：
10.1016/j.bcp.2018.10.024
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发表时间：
2018-12-01
影响因子：
5.8
通讯作者：
Suzuki, Hiroshi
中科院分区：
文献类型：
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作者：
Katsumata, Kiyomitsu;Chono, Koji;Suzuki, Hiroshi
现有的治疗方法对与单纯疱疹病毒(HSV)和带状疱疹病毒(VZV)相关的严重感染的疗效有限，特别是对免疫功能低下的患者和多皮瘤感染的患者。这一问题，以及有关耐药性的问题，支持了改进治疗方案的必要性。为探讨VZV和HSV解旋酶-引物酶抑制剂阿米诺韦在严重感染条件下的抗病毒作用，采用免疫抑制或多皮瘤感染的方法建立了严重HSV-1感染的小鼠模型。对环孢素诱导的免疫抑制和皮肤背侧接种HSV-1感染的小鼠，给予阿米诺韦(10-100 mg/kg/d)不同疗程(2-5天)的治疗。免疫抑制的小鼠在没有治疗的情况下保持了皮肤HSV-1的高滴度。Amenamevir在所有测试剂量下都成功地降低了免疫抑制小鼠的HSV-1滴度，但需要更长的治疗期才能避免免疫抑制导致的病毒滴度反弹。为了比较阿米诺韦和万乃洛韦的疗效，建立了一种小鼠多皮瘤HSV-1感染模型，方法是将皮肤背外侧划成一条线，并广泛接种HSV-1。这些小鼠在感染后第3、4或5天开始服用阿米诺韦或万乃洛韦，为期5天。虽然这两种药物在第3天开始治疗时都类似地降低了疾病评分，但阿米诺韦在第4天开始治疗时也降低了疾病严重程度，而万乃洛韦则没有。就有效口服剂量而言，Amenamevir不受宿主免疫状态的影响，即使在治疗开始延迟的情况下，Amenamevir在治疗严重皮肤感染方面也更有效。
Existing treatments have limited efficacy against severe infection associated with herpes simplex virus (HSV) and herpes zoster virus (VZV), particularly in immunocompromized patients and those with multidermatomal infection. This issue, along with issues regarding drug resistance, support the need for improved therapeutic options. To investigate the antiviral effect of amenamevir, a VZV and HSV helicase-primase inhibitor, in severe infection conditions, mouse models of severe HSV-1 infection were developed by immunosuppression or multidermatomal infection. Mice with cyclosporin-induced immunosuppression and HSV-1 infection via inoculation of a dorsolateral area of skin were orally treated with amenamevir (10-100 mg/kg/day) for different durations (2-5 days). Immunosuppressed mice maintained high skin HSV-1 titers in the absence of treatment. Amenamevir successfully reduced HSV-1 titers at all tested doses in immunosuppressed mice, but required a longer treatment period to avoid a rebound in viral titers due to immunosuppression. To compare the efficacy of amenamevir and valacyclovir, a murine model of multidermatomal HSV-1 infection was generated by scarifying the dorsolateral area of skin in a line and inoculating broadly with HSV-1. The mice were treated with amenamevir or valacyclovir starting on Day 3, 4, or 5 post-infection for 5 days. Although both drugs similarly reduced disease scores when treatment was started on Day 3, amenamevir also reduced disease severity when treatment was initiated on Day 4, whereas valacyclovir did not. Amenamevir was not affected by the host's immune status in terms of effective oral doses and was more efficacious in treating severe cutaneous infection even when treatment initiation was delayed.