Optimizing Ridaifen-B analogs as potential therapeutics for Ebola viruses

摘要 埃博拉病毒病(EVD)是由感染一组病毒引起的 埃博拉病毒属。至少有五种埃博拉病毒，埃博拉病毒(扎伊尔， 埃博拉病毒)、苏丹埃博拉病毒(SUDV)、本迪布乔病毒(BDBV)、莱斯顿病毒和泰林 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，与高达90%的死亡率有关，与 EBOV。出于安全考虑，这些病毒被指定为生物安全 4级代理。目前还没有有效的治疗埃博拉病毒的方法 人类的感染和发病机制。因此，该应用程序的目标是开发 糖蛋白特异性小分子抑制剂作为药物，可预防性和 在治疗方面对抗埃博拉病毒和其他埃博拉病毒感染。为了实现这一目标，我们 筛选了一个内部的小分子文库，并确定了许多有效的条目 抗EBOV的抑制剂。我们已经确定了一系列有效的化合物，并将使用 它们作为先导，将在化学上进行优化，并开发为抗埃博拉病毒 接受治疗的候选人。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，以及(2)铅的体内评价 用动物模型研究化合物抗EBOV感染。

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.