Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses
Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses
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DOI：
10.1016/j.antiviral.2019.04.004
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发表时间：
2019-07-01
影响因子：
7.6
通讯作者：
Golden, Jennifer E.
中科院分区：
文献类型：
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作者：
Jonsson, Colleen B.;Cao, Xufeng;Golden, Jennifer E.
目前，还没有获得许可的人类疫苗或抗病毒药物可用于治疗或预防脑炎甲病毒感染。由于流行病具有散发性和不可预测性，地方病常见但诊断很少，因此很难确定所有需要接种疫苗的人群；因此，需要一种有效的暴露后治疗方法来中断正在发生的疫情。为了满足这一公共卫生需求，我们继续开发 ML336，以提供一种具有预防和治疗潜力的分子，可用于委内瑞拉马脑炎病毒 (VEEV) 的自然流行病或故意释放情况。我们报告了 ML336 四种类似物的体外评估结果，以及其中三种新衍生物 BDGR-4、BDGR-69 和 BDGR-70 的体内筛选结果。观察到最大保护的最佳剂量为 12.5 mg/kg/天，每天两次，持续 8 天。进一步测试了 BDGR-4 在接受 VEEV Trinidad Donkey (TrD) 攻击的小鼠中的预防和治疗功效。接受 VEEV TrD 攻击的小鼠在感染后 24 小时和 48 小时接受治疗时，分别显示出 100% 和 90% 的致命疾病保护。我们还测量了接受东方马脑炎病毒攻击的小鼠体内 BDGR-4 的保护率为 90%。在单独对小鼠进行的 BDGR-4 的额外评估中，我们观察到根据临床化学指标评估，在 4 天内剂量高达 25 mg/kg/天时没有明显的毒性。在这些相同的小鼠中，我们没有观察到干扰素的诱导。最后，通过下一代测序评估了 VEEV 对 BDGR-4 的抗性，该测序揭示了病毒聚合酶 nsP4 的特定突变。
Currently, there are no licensed human vaccines or antivirals for treatment of or prevention from infection with encephalitic alphaviruses. Because epidemics are sporadic and unpredictable, and endemic disease is common but rarely diagnosed, it is difficult to identify all populations requiring vaccination; thus, an effective post-exposure treatment method is needed to interrupt ongoing outbreaks. To address this public health need, we have continued development of ML336 to deliver a molecule with prophylactic and therapeutic potential that could be relevant for use in natural epidemics or deliberate release scenario for Venezuelan equine encephalitis virus (VEEV). We report findings from in vitro assessments of four analogs of ML336, and in vivo screening of three of these new derivatives, BDGR-4, BDGR-69 and BDGR-70. The optimal dosing for maximal protection was observed at 12.5 mg/kg/day, twice daily for 8 days. BDGR-4 was tested further for prophylactic and therapeutic efficacy in mice challenged with VEEV Trinidad Donkey (TrD). Mice challenged with VEEV TrD showed 100% and 90% protection from lethal disease when treated at 24 and 48 h post-infection, respectively. We also measured 90% protection for BDGR-4 in mice challenged with Eastern equine encephalitis virus. In additional assessments of BDGR-4 in mice alone, we observed no appreciable toxicity as evaluated by clinical chemistry indicators up to a dose of 25 mg/kg/day over 4 days. In these same mice, we observed no induction of interferon. Lastly, the resistance of VEEV to BDGR-4 was evaluated by next-generation sequencing which revealed specific mutations in nsP4, the viral polymerase.