Novel beta-lactams as inhibitors of ebola virus infections

 描述(申请人提供)：埃博拉病毒(EBOV)是引起严重病毒性出血热(VHF)的丝状病毒家族的成员。EBOV疫情虽然不常见，但可导致高达90%的高死亡率；随后的医疗和社会动荡可能是广泛和严重的，正如最近在西非爆发的疫情所看到的那样，在一个医疗服务不足的区域，疫情已造成1万多人死亡。尽管已报道使用单抗和多克隆抗体取得了一些成功，但如果没有美国和欧洲的大量援助，这些昂贵的治疗方法并不能广泛应用于非洲较贫穷的地区；此外，如果有能力储存治疗药物，以防未来爆发或生物恐怖主义，将是有益的。这一选择不容易通过抗体疗法实现。因此，对小分子疗法的迫切需求是相当明显的。实验药物布林多福韦、法韦拉韦和BCX 4430在体外显示出良好的前景，但没有临床试验证明它们在体内的有效性。为了满足这一关键的未得到满足的医疗需求，有必要采用新的小分子疗法/预防药物来避免未来流行的风险。利用一种模拟EBOV病毒进入过程的伪型病毒，我们已经鉴定出一组新的小分子EBOV进入抑制剂，并已在体外感染性EBOV检测中得到验证。基于β-内酰胺中心核心，这些化合物易于修饰，类似药物，代表了药物化学优化的良好起点。通过合成HIT化合物MBX 2806的新类似物，我们将产生构效关系，以更好地了解导致强大的抗EBOV活性和低细胞毒性的化学特征，并最终生产出具有药物样特征的有效、选择性的感染性EBOV抑制剂。目前的建议将使用药物化学来优化MBX 2806，目标有三：1)我们将合成MBX 2806的新类似物，并在EBOV感染的假型试验中检测其抗病毒活性。2)我们将在BSL4条件下验证感染性EBOV的假型检测结果。3)我们将在体外测量ADME预测因子，以提高支架的整体药物相似性。利用化合物设计、合成和生物检测的迭代过程，我们将合成有效、选择性和具有类药物特性的优化化合物，适合进一步开发用于治疗和/或预防EBOV感染的药物。

 DESCRIPTION (provided by applicant): Ebola virus (EBOV) is a member of the filovirus family that causes severe viral hemorrhagic fever (VHF). Although infrequent, epidemics of EBOV can cause high mortality rates of up to 90%; the subsequent medical and social upheaval can be widespread and severe, as seen in the recent outbreak in Western Africa which has already caused more than 10,000 fatalities in a region with insubstantial medical services. Although some success using monoclonal and polyclonal antibodies has been reported, these expensive treatments are not widely available to poorer regions of Africa without substantial assistance from America and Europe; additionally, it would be beneficial to have the ability to stockpile treatments in case of future outbreaks or bioterrorism. This option is not easily achieved with antibody therapies. A pressing need for small-molecule therapeutics is thus quite evident. The experimental drugs brincidofovir, favipiravir, and BCX 4430 have shown promise in vitro, but no clinical trials have proven their effectiveness in vivo. To address this critical unmet medical need, new small-molecule therapeutics/prophylactics are necessary to avert the risk of future epidemics. Using a pseudotype virus that mimics the viral entry process of EBOV, we have identified a novel set of small molecule EBOV entry inhibitors that has been validated in assays of infectious EBOV in vitro. Based on a beta-lactam central core, these compounds are readily modified, are drug-like, and represent an excellent starting point for medicinal chemistry optimization. By synthesizing new analogs of the hit compound, MBX 2806, we will generate structure-activity relationships to better understand the chemical features that lead to potent anti-EBOV activity and low cytotoxicity, and ultimately produce potent, selective inhibitors of infectious EBOV that display drug-like characteristics. The current proposal will use medicinal chemistry to optimize MBX 2806 using three aims: 1) We will synthesize novel analogs of MBX 2806 and assay the antiviral activity in a pseudotype assay of EBOV infection. 2) We will validate the results of the pseudotype assay using infectious EBOV under BSL4 conditions. 3) We will measure in vitro ADME predictors to improve the overall drug-likeness of the scaffold. Using an iterative process of compound design, synthesis, and biological assay, we will synthesize optimized compounds that are potent, selective, and have drug-like properties suitable for further development as therapeutics and/or prophylactics for EBOV infection.