Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses

总结：该II期申请的最终目标是开发新型小分子、广谱 针对由丝状病毒、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剂， PPxY L结构域基序用于感染的外出和传播。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，这些新兴的人类病原体的有效萌芽取决于 对宿主蛋白质的颠覆，如神经前体细胞表达的发育下调 蛋白4（Nedd 4），通过这些RNA病毒的基质蛋白中的PPxY L-结构域。确定和 干扰这些病毒-宿主相互作用的小分子抑制剂的开发应有效地阻断 病毒扩散、疾病进展和传播。在这些努力中，我们发现了几个化学系列 宿主Nedd 4/病毒PPxY复合物的小分子抑制剂对病毒外出很重要，这导致了一个 在马尔堡病毒攻击的小鼠模型中具有概念体内活性证明的类似物。如FDA 用于治疗这些大多数病毒感染的批准的治疗剂是不可用的， 鉴定可防止病毒传播的病毒宿主抑制剂将满足显著的未满足的需要。此外，委员会认为， 这些抑制剂将是广谱的，因此可能对新出现的病毒有效， 以及病毒变体。如下所述，我们将采用严格的多方面方法来识别、开发和 验证PPxY出芽抑制剂在I期鉴定为有效的广谱抗病毒药物。这个阶段的目的 II STTR赠款申请是为了优化我们的VP 40 PPxY-Nedd 4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准备IND指导研究。这将通过结合 福克斯蔡斯化学多样性研究所的科学家们的制药和药物化学专业知识 中心公司（FCCDC）在抗病毒治疗的实验方面具有专业知识和经验， 宾夕法尼亚大学的哈蒂实验室。我们将通过优化我们现有的抑制剂系列来实现这一目标， 以体内活性FC-10696为例，用于改善效力和口服药物性质（目的1），评价新的 基于两个有效系列的化合物，它们特异性抑制PPxY-Nedd 4相互作用的能力， 随后的VLP和替代病毒排出（目的2），鉴定具有合适药物性质的化合物， 使用体外和体内ADMET评价的选择性（目的3），并评价化合物的抗病毒活性 体外和体内抗真实BSL-4病毒的功效（目的4）。

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).