Ebola Virus Entry Inhibitors

 描述（由申请人提供）：几种埃博拉病毒与人类严重病毒性出血热（VHF）相关。人类感染通常通过接触蝙蝠和其他受感染动物或人类的血液或体液发生。迄今为止，非洲中部和西部的所有重大埃博拉病毒爆发都来自扎伊尔埃博拉病毒（EBOV）、苏丹埃博拉病毒（SUDV）和本迪布焦埃博拉病毒（BDBV），病死率为40- 90%。最重要的记录爆发目前正在今年进行，迄今为止可能累计有1323例埃博拉出血热（EHF）病例，估计有729人死亡，这凸显了对有效埃博拉抗病毒药物的需求，而目前没有。鉴于缺乏有效的治疗和抗病毒药物，与感染相关的高死亡率以及地理移植的可能性，开发用于治疗和预防VHF的广谱埃博拉病毒抗病毒药物是NIAID的优先事项。在这里，我们建议优化两个不同的化学系列，抑制VSV假型病毒表达EBOV或BDBV糖蛋白，但不是VSV糖蛋白。两种进入抑制剂化学系列中的一些命中化合物表现出亚微摩尔IC 50、低细胞毒性和>10或更高的治疗指数。这些化学系列代表了开发新型埃博拉病毒抗病毒治疗剂的有吸引力的起点。

 DESCRIPTION (provided by applicant): Several Ebola virus species have been associated with severe viral hemorrhagic fevers (VHF) in humans. Human infection typically occurs through contact with blood or bodily fluids from bats and other infected animals or humans. To date all of the significant Ebola virus outbreaks in central and western Africa have been from the Ebola- Zaire (EBOV), Sudan (SUDV) and Bundibugyo (BDBV) species with case-fatality rates ranging from 40-90%. The most significant recorded outbreak is currently underway this year and has a probable cumulative total of 1323 cases of Ebola hemorrhagic fever (EHF) and an estimated 729 fatalities to date highlighting the need for effective Ebola antivirals, for which there are currently none. Given the lack of effective treatments and prophylactics, the high mortality rate associated with infection, and the potential for geographical transplantation the development of broad spectrum Ebola virus antivirals for the treatment and prophylaxis of VHF is an NIAID priority. Here we propose to optimize two distinct chemical series that inhibit VSV pseudotype viruses expressing either the EBOV or BDBV glycoprotein but not that of the VSV glycoprotein. Some of the hit compounds from within both entry inhibitor chemical series exhibit submicromolar IC50s, low cytotoxicity and therapeutics indices of >10 or more. These chemical series represent attractive starting points for the development of novel Ebola virus antiviral therapeutics.