Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses

针对出血热病毒的小分子疗法的开发

• 批准号: 10368115
• 负责人: RONALD N HARTY
• 金额: $ 101.54万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368115
• 关键词: Ames Assay; Animal Model; Antiviral Agents; Antiviral Therapy; Applications Grants; Arenavirus; Arrhythmia; Binding Proteins; Biological Assay; Biomedical Research; Bioterrorism; Businesses; Canis familiaris; Categories; Cell Culture Techniques; Chemicals; Complement; Complex; Cytochrome P450; Data; Development; Disease; Disease Progression; Dose; Drug Interactions; Ebola; Ebola virus; Ensure; Evaluation; Exhibits; FDA approved; Filovirus; Foxes; Funding; Generations; Goals; Hand; Human; Imaging Techniques; In Vitro; Infection; Isoenzymes; Lassa Fever; Lassa virus; Lead; Legal patent; Manuals; Manuscripts; Marburgvirus; Mediating; Metabolic; Metabolic Activation; Methods; Midazolam; Modification; Mus; Oral; Pathogenicity; Patients; Pennsylvania; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma Proteins; Population; Process; Property; Proteins; Publishing; RNA Viruses; Rattus; Research Institute; Safety; Scientist; Series; Small Business Technology Transfer Research; Solubility; Technology; Texas; Therapeutic; Therapeutic Agents; Time; Toxic effect; Ubiquitination; United States National Institutes of Health; Universities; Variant; Viral; Virus; Virus Diseases; Virus Inhibitors; analog; anti-viral efficacy; antiviral drug development; base; drug candidate; drug discovery; emerging human pathogen; experience; hemorrhagic fever virus; improved; in vivo; in vivo evaluation; inhibitor; lead candidate; lead optimization; live cell imaging; meetings; mouse model; nerve stem cell; nonhuman primate; novel; patch clamp; pathogen; plasma protein Z; precursor cell; prevent; research clinical testing; small molecule; small molecule inhibitor; small molecule therapeutics; therapeutic target; transcriptome; transcriptome sequencing; transmission process; ubiquitin-protein ligase; unvaccinated; viral transmission; virus host interaction; virus identification; voucher

Summary: The ultimate goal of this Phase II application is to develop novel small molecule, broad-spectrum therapeutics against viral infections caused by filoviruses, arenaviruses, and other viruses that depend on the PPxY L-domain motif for egress and spread of infection. Some of these viruses, including Ebola (EBOV), Marburg (MARV), and Lassa fever (LAFV) viruses, are highly pathogenic and classified as Category A bioterror pathogens. We and others have determined that efficient budding of these emerging human pathogens depends on the subversion of host proteins, such as neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4), by PPxY L-domains in the matrix proteins of these RNA viruses. The identification and development of small molecule inhibitors that interfere with these virus-host interactions should effectively block virus egress, disease progression, and transmission. In these efforts we have discovered several chemical series of small molecule inhibitors of the host Nedd4/virus PPxY complex important for viral egress which led to one analog possessing proof of concept in vivo activity in a Marburg virus challenged mouse model. As FDA approved therapeutic agents for the treatment of these most of these viral infections are not available, our identification of virus-host inhibitors that may prevent virus spread will fill a significant unmet need. Moreover, these inhibitors will be broad-spectrum, and therefore will likely be effective against newly emerging viruses as well as viral variants. As described below, we will use a rigorous multifaceted approach to identify, develop, and validate PPxY budding inhibitors identified in Phase I as potent, broad-spectrum antivirals. The goal of this Phase II STTR grant application is to optimize our lead inhibitors of VP40 PPxY-Nedd4 interactions to generate full- fledged predevelopment drug candidates ready for IND directed studies. This will be accomplished by combining the pharmaceutical and medicinal chemistry expertise of the scientists at the Fox Chase Chemical Diversity Center, Inc. (FCCDC) with the expertise and experience in the experimental aspects of antiviral therapy of the Harty Lab at the University of Pennsylvania. We will realize this goal by optimizing our existing series of inhibitors, exemplified by in vivo active FC-10696, for improved potency and oral drug properties (Aim 1), evaluating new compounds based on two potent series for their ability to specifically inhibit PPxY-Nedd4 interactions and subsequent VLP and surrogate virus egress (Aim 2), identifying compounds having suitable drug properties and selectivity using in vitro and in vivo ADMET evaluation (Aim 3), and evaluating compounds for their antiviral efficacy against authentic BSL-4 viruses in vitro and in vivo (Aim 4).

摘要：本次二期申请的最终目标是开发新型小分子、广谱药物 针对丝状病毒、沙粒病毒和其他依赖于病毒的病毒引起的病毒感染的治疗 PPxY L 结构域基序用于感染的流出和传播。其中一些病毒，包括埃博拉病毒 (EBOV)、 马尔堡病毒 (MARV) 和拉沙热病毒 (LAFV) 具有高致病性，被列为 A 类生物恐怖病毒 病原体。我们和其他人已经确定，这些新出现的人类病原体的有效萌芽取决于 宿主蛋白的颠覆，例如神经前体细胞表达的发育下调 蛋白 4 (Nedd4)，由这些 RNA 病毒基质蛋白中的 PPxY L 结构域产生。身份识别和 开发干扰这些病毒与宿主相互作用的小分子抑制剂应该可以有效阻止 病毒的排出、疾病进展和传播。在这些努力中，我们发现了几种化学系列 宿主 Nedd4/病毒 PPxY 复合物的小分子抑制剂对病毒流出很重要，这导致了一种 类似物在马尔堡病毒攻击的小鼠模型中具有体内活性的概念证明。作为FDA 目前还没有批准用于治疗大多数病毒感染的治疗药物，我们的 鉴定出可以阻止病毒传播的病毒宿主抑制剂将填补一个重大的未满足的需求。而且， 这些抑制剂将是广谱的，因此可能对新出现的病毒有效 以及病毒变种。如下所述，我们将使用严格的多方面方法来识别、开发和 验证 I 期鉴定的 PPxY 出芽抑制剂是否为有效的广谱抗病毒药物。本阶段的目标 II STTR 拨款申请是为了优化我们的 VP40 PPxY-Nedd4 相互作用的主要抑制剂，以产生完整的 成熟的预开发候选药物已准备好进行 IND 指导研究。这将通过结合来完成 Fox Chase Chemical Diversity 科学家的制药和药物化学专业知识 Center, Inc. (FCCCDC) 在抗病毒治疗实验方面拥有专业知识和经验 宾夕法尼亚大学哈蒂实验室。我们将通过优化我们现有的系列抑制剂来实现这一目标， 以体内活性 FC-10696 为例，用于改善效力和口服药物特性（目标 1），评估新的 基于两个有效系列的化合物，它们能够特异性抑制 PPxY-Nedd4 相互作用，并且 随后的 VLP 和替代病毒流出（目标 2），识别具有合适药物特性的化合物，并 使用体外和体内 ADMET 评估（目标 3）进行选择性，并评估化合物的抗病毒作用 在体外和体内对抗真正的 BSL-4 病毒的功效（目标 4）。