Novel beta-lactams as inhibitors of ebola virus infections

新型β-内酰胺作为埃博拉病毒感染的抑制剂

• 批准号: 9303299
• 负责人: Zachary David Aron
• 金额: $ 29.74万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-24 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303299
• 关键词: Address; Affinity; Africa; African; Americas; Animal Model; Antibody Therapy; Antiviral Agents; Biological; Biological Assay; Bioterrorism; Categories; Cell Culture Techniques; Characteristics; Chemicals; Clinical Trials; Development; Disease Outbreaks; Drug Kinetics; Ebola virus; Effectiveness; Engineering; Enzyme Inhibitor Drugs; Epidemic; Europe; Evaluation; Event; Exhibits; Family; Filoviridae; Filovirus; Fright; Future; Goals; Health system; In Vitro; Infection; Investigation; Isomerism; Lead; Libraries; Liver Microsomes; Measures; Medical; Membrane Glycoproteins; Military Personnel; Modification; Monitor; Monoclonal Antibodies; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Probability; Process; Property; Protein Isoforms; Reporting; Resources; Risk; Route; Series; Serum; Services; Site; Spain; Stereoisomer; Structure; Structure-Activity Relationship; Survivors; Testing; Therapeutic; TimeLine; Toxic effect; Treatment Efficacy; United Kingdom; United States; Vesicular stomatitis Indiana virus; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; Western Africa; analog; animal efficacy; base; beta-Lactams; chemical property; cytotoxicity; design; diphenyl; efficacy testing; enantiomer; improved; in vivo; inhibitor/antagonist; member; mortality; novel; novel therapeutics; pathogen; phase 2 study; polyclonal antibody; pre-clinical; preclinical development; prophylactic; public health relevance; scaffold; small molecule; small molecule therapeutics; social; success; transmission process

 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.

 描述（由适用提供）：埃博拉病毒（EBOV）是导致严重病毒出血热（VHF）的FILOVIRUS家族的成员。尽管很少见，但EBOV发作可能会导致高死亡率高达90％。随后的医疗和社会动荡可能是宽度和严重的，正如最近在西非的爆发中可以看出的那样，该地区已经造成了一个拥有不可思议的医疗服务的地区造成了10,000多人死亡。尽管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并未广泛用于非洲贫困地区；此外，在未来的爆发或生物恐怖主义中，有能力有能力储存治疗是有益的。使用抗体疗法不容易实现此选项。因此，对小分子疗法的紧迫需求是相当大的证据。实验药物Brincidofovir，Favipiravir和BCX 4430在体外表现出了希望，但没有临床试验证明它们在体内有效性。为了满足这种关键的未满足医疗需求，需要新的小分子疗法/预防学对于避免未来流行病的风险。使用模仿EBOV病毒进入过程的假型病毒，我们已经确定了一组新型的小分子EBOV进入抑制剂，该抑制剂已在体外具有传染性EBOV的屁股中得到验证。基于β-内酰胺中心核心，这些化合物很容易修饰，类似药物，并且是医学化学优化的绝佳起点。通过综合热门化合物的新类似物MBX 2806，我们将产生结构活性关系，以更好地理解导致潜在的抗EBOV活性和低细胞毒性的化学特征，并最终产生潜在的，具有表现出类似药物的特征的感染性EBOV的潜在选择性抑制剂。当前的建议将使用医学化学使用三个目的来优化MBX 2806：1）我们将合成MBX 2806的新型类似物，并在EBOV感染的假型测定中测定抗病毒活性。 2）我们将在BSL4条件下使用传染性EBOV验证假型测定的结果。 3）我们将使用复合设计，合成和生物学测定的迭代过程测量体外ADME，我们将合成优化的化合物，这些化合物具有潜在的，有选择性且具有类似药物的特性，适合于EBOV感染的治疗和/或预防性。