Novel beta-lactams as inhibitors of ebola virus infections

 描述（由申请人提供）：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。虽然不常见，但EBOV的流行可导致高达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，如最近在西非爆发的疫情所示，该疫情已经在医疗服务薄弱的地区造成10，000多人死亡。虽然已经报道了使用单克隆和多克隆抗体的一些成功，但如果没有美国和欧洲的大量援助，这些昂贵的治疗方法在非洲较贫穷地区并不普遍;此外，如果有能力储存治疗方法，以备未来爆发或生物恐怖主义，将是有益的。这种选择不容易用抗体疗法实现。因此，对小分子治疗剂的迫切需求是相当明显的。实验性药物布林西多福韦、法匹拉韦和BCX 4430在体外显示出前景，但没有临床试验证明它们在体内的有效性。为了解决这一关键的未满足的医疗需求，有必要开发新的小分子疗法/药物，以避免未来流行病的风险。使用模拟EBOV的病毒进入过程的假型病毒，我们已经鉴定了一组新的小分子EBOV进入抑制剂，其已经在体外感染性EBOV的测定中得到验证。基于β-内酰胺中心核，这些化合物易于修饰，具有药物样性质，代表了药物化学优化的良好起点。通过合成命中化合物MBX 2806的新类似物，我们将产生结构-活性关系，以更好地理解导致有效抗EBOV活性和低细胞毒性的化学特征，并最终产生显示药物样特征的感染性EBOV的有效选择性抑制剂。目前的建议将使用药物化学来优化MBX 2806，使用三个目标：1）我们将合成MBX 2806的新类似物，并在EBOV感染的假型测定中测定抗病毒活性。2)我们将在BSL 4条件下使用感染性EBOV验证假型测定的结果。3)我们将测量体外ADME预测因子以改善支架的总体药物相似性。使用化合物设计、合成和生物测定的迭代过程，我们将合成优化的化合物，其是有效的、选择性的，并且具有适合于进一步开发作为EBOV感染的治疗剂和/或药物的药物样性质。

 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.