Cathepsin B Inhibitors as Therapeutics for Ebola Infection

 描述(申请人提供)：丝状病毒家族的埃博拉病毒(EBOV)是一种有包膜的单链RNA病毒，可在包括人类和非人类灵长类动物在内的多种哺乳动物中引起严重出血热。最近在西非爆发的2013-2014年EBOV疫情迄今已导致近40%的感染患者死亡，并通过旅行者在整个西非和国际上传播到美国和西班牙。因此，了解这种病毒如何入侵宿主并导致疾病，以促进治疗和预防方法是至关重要的。由于进入宿主细胞是病毒生命周期的第一步，这一领域提供了治疗和预防的主要目标。重要的是，已经证明EBOV需要人组织蛋白酶B(CatB)的活性来顺序处理其糖蛋白GP1。事实上，EBOV利用这一关键的人类蛋白酶CatB进入EBOV，这为开发抗EBOV抑制剂药物提供了机会。我们的目标是通过探索初级侧-螺旋结合口袋来产生有效的、特异的CatB抑制剂，该结合口袋在活细胞检测中能够抑制EBOV感染。

 DESCRIPTION (provided by applicant): Ebola virus (EBOV) of the filovirus family is an enveloped, single-stranded RNA virus that causes severe hemorrhagic fever in multiple mammals including humans and non-human primates. The recent 2013-2014 outbreak of EBOV in West Africa has resulted in the deaths of nearly 40% of infected patients to date, spreading throughout West Africa and internationally to the United States and Spain via travelers. Therefore, it is essential to understand how this virus invades its hosts and causes disease, to spur approaches to treatment and prevention. Because entry into host cells is the first step in the viral life cycle, this area offers a major target for treatment and prevention. Importantly, ithas been demonstrated that EBOV requires the activity of human Cathepsin B (CatB) for sequential processing of its glycoprotein GP1. The fact that EBOV utilizes this key human protease, CatB, for entry offers an opportunity to develop anti-EBOV inhibitor drugs. We aim to generate potent, specific inhibitors for CatB via exploration of the prime side -helical binding pocket that resuts in inhibition of EBOV infection in live cell assays.