Optimizing Ridaifen-B analogs as potential therapeutics for Ebola viruses

总结 埃博拉病毒病（EVD）是由一组病毒感染引起的， 埃博拉病毒属。埃博拉病毒至少有五种，埃博拉病毒（扎伊尔， 埃博拉病毒（EBOV）、苏丹埃博拉病毒（SUDV）、本迪布焦病毒（BDBV）、莱斯顿病毒和泰森林病毒 病毒（TAFV）。感染这些病毒会导致严重的出血热， 人类和非人类灵长类动物，并与高达90%的死亡率相关， EBOV。出于安全考虑，这些病毒被指定为生物安全病毒。 四级特工目前还没有针对埃博拉病毒的有效治疗方法 感染和发病机制。因此，该应用程序的目标是开发 作为药物的GP特异性小分子抑制剂可用于治疗， 治疗EBOV和其他埃博拉病毒感染。因此我们 筛选了一个内部的小分子库，并确定了许多有效的条目， EBOV的抑制剂。我们已经发现了一系列有效的化合物， 它们将作为先导药物，经过化学优化， 治疗候选人在本申请中，提出了两个具体目标：（1）结构- 基于先导化合物的优化，和（2）先导化合物的体内评价 使用动物模型对抗EBOV感染的化合物。

Summary Ebola virus disease (EVD) is caused by an infection with a group of viruses within the genus Ebolavirus. There are at least five species of Ebolavirus, Ebola virus (Zaire, EBOV), Ebola Sudan (SUDV), Bundibugyo virus (BDBV), Reston virus and Tai Forest virus (TAFV). Infections with these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates, and are associated with up to 90% mortality rates with EBOV. Because of the safety concerns, these viruses are designated as the biosafety level 4 agents. Currently there is no effective therapeutic treatments against Ebola virus infection and pathogenesis in humans. Thus the goal of this application is to develop GP-specific small molecule inhibitors as drugs which can be used prophylactically and therapeutically against EBOV and other Ebola virus infections. To achieve this, we screened an in-house library of small molecules, and identified numerous potent entry inhibitors against EBOV. We have identified a series of potent compounds and will use them as leads which will be chemically optimized and developed as an anti-Ebola virus therapy candidate. In this application, two specific aims are proposed: (1) structure- based optimization of the lead compounds, and (2) In vivo evaluation of the lead compounds against EBOV infection using animal models.