The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection
The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection
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DOI：
10.1016/j.antiviral.2019.104597
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发表时间：
2019-11-01
影响因子：
7.6
通讯作者：
Kolykhalov, Alexander A.
中科院分区：
文献类型：
--
作者：
Painter, George R.;Bowen, Richard A.;Kolykhalov, Alexander A.
新世界甲病毒委内瑞拉、东方和西方马脑炎病毒（分别为VEEV、EEEV和WEEV）通常引起可进展为脑膜脑炎的发热性疾病，导致显著的发病率和死亡率。为了解决对用于治疗甲病毒感染的治疗剂的需求，我们鉴定并进行了核糖核苷类似物EIDD-1931（β-D-N-4-羟基胞苷，NHC）的临床前表征，其在体外显示出针对甲病毒的广泛活性，并且对于耐药性的发展具有非常高的遗传屏障。为了真正有效地作为VEEV感染的治疗剂，药物必须穿透血脑屏障并阻止病毒在脑中复制。经口给药后，小鼠中EIDD-1931的血浆水平迅速达到高水平。一旦进入血浆，EIDD-1931就有效地分布到器官中，包括大脑，在那里它迅速转化为其活性的5 '-三磷酸。EIDD-1931在小鼠中以高达1000 mg/kg/天的剂量重复给药7天后显示出良好的安全性特征。在小鼠模型研究中，当治疗性治疗迟至感染后24小时开始时，EIDD-1931在保护小鼠免受致死性鼻内感染方面具有90-100%的有效性，并且当治疗延迟至感染后48小时时实现部分保护。这些结果支持EIDD-1931作为潜在抗甲病毒药物的进一步临床前开发。
The New World alphaviruses Venezuelan, Eastern, and Western equine encephalitis viruses (VEEV, EEEV and WEEV, respectively) commonly cause a febrile disease that can progress to meningoencephalitis, resulting in significant morbidity and mortality. To address the need for a therapeutic agent for the treatment of Alphavirus infections, we identified and pursued preclinical characterization of a ribonucleoside analog EIDD-1931 (beta-D-N-4-hydroxycytidine, NHC), which has shown broad activity against alphaviruses in vitro and has a very high genetic barrier for development of resistance. To be truly effective as a therapeutic agent for VEEV infection a drug must penetrate the blood brain barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly achieved in mice after oral dosing. Once in the plasma EIDD-1931 is efficiently distributed into organs, including brain, where it is rapidly converted to its active 5'-triphosphate. EIDD-1931 showed a good safety profile in mice after 7-day repeated dosing with up to 1000 mg/kg/day doses. In mouse model studies, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal infection when therapeutic treatment was started as late as 24 h post-infection, and partial protection was achieved when treatment was delayed for 48 h post-infection. These results support further preclinical development of EIDD-1931 as a potential anti-alphavirus drug.