Development of Host- Oriented Therapeutics Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2),

针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的面向宿主的疗法的开发，

• 批准号: 10688262
• 负责人: RONALD N HARTY
• 金额: $ 29.24万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688262
• 关键词: 2019-nCoV; ACE2; Antiviral Agents; Antiviral Therapy; Arenavirus; Attenuated; Automobile Driving; Binding; Binding Proteins; Biological Assay; Biomedical Research; COVID-19 therapeutics; Cell Culture Techniques; Chemicals; Coronavirus; Data; Development; Disease Progression; Disease model; Ebola; Ebola virus; Epithelial Cells; Evaluation; Filovirus; Future; Goals; Hand; Human; In Vitro; Investigation; Lassa virus; Lead; Lung; Marburgvirus; Mediating; Membrane Proteins; Metabolic; Microsomes; Modeling; Mus; Oral; Pathogenicity; Pennsylvania; Pharmaceutical Chemistry; Phase; Plasma Proteins; Process; Property; Proteins; RNA Viruses; Rabies virus; Research Institute; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; SARS-CoV-2 spike protein; SARS-CoV-2 transmission; Scientist; Series; Small Business Technology Transfer Research; Solubility; Surface; Syndrome; Texas; Toxic effect; Universities; Variant; Viral; Viral Physiology; Viral Proteins; Virion; Virus; Virus Diseases; analog; anti-viral efficacy; antiviral drug development; combat; experience; gastrointestinal; in vivo; in vivo evaluation; inhibitor; lead candidate; lead optimization; meetings; mouse model; novel coronavirus; pandemic disease; pathogenic virus; recruit; respiratory; scale up; small molecule; therapeutic target; transmission process; virus host interaction

The ultimate goal of this Phase I application is to discover and develop host-oriented small molecule compounds targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 is a novel coronavirus driving the current global pandemic of severe respiratory syndrome in humans. Antiviral therapeutics are urgently needed to combat infection by SARS-CoV-2 and new variants that are continuing to emerge. We have discovered several chemical series that target modular interactions between specific host proteins containing WW-domains (e.g. Nedd4) and viral proteins containing PPxY motifs (e.g. Ebola VP40). Notably, emerging RNA virus pathogens such as Ebola, Marburg, Lassa, and rabies viruses all encode PPxY motifs that recruit host WW-domain containing proteins to facilitate efficient virus egress, spread, and transmission. Interestingly, the surface-exposed Spike glycoprotein (S) of SARS-CoV-2 also has a putative WW-domain binding motif (25PPAY28), that is not present in the S protein of SARS-CoV-1 or more attenuated coronavirus strains. The acquisition of this PPAY motif in the major surface protein of SARS-CoV-2 virions raises the intriguing possibility that it may contribute to the unique pathogenicity and/or transmission of SARS-CoV-2 via interactions with specific host WW-domain bearing proteins. In our ongoing studies on filoviruses and arenaviruses, we have used extensive SAR to identify a lead compound series capable of blocking egress and spread of live EBOV, MARV, and LAFV in cell culture, as well as blocking disease progression in vivo in a live MARV challenge model. Here, we hypothesize that “informed” SAR analyses of our in-hand PPxY/WW-domain inhibitors (e.g. lead candidate FC-10696) will lead to the discovery of analogs capable of blocking egress and disease progression of SARS-CoV-2, as well as related PPxY-containing variants that may emerge in the future. In support of our hypothesis, we present strong preliminary data showing that the PPxY motif within the S protein of SARS-CoV-2 virus can interact with host WW-domain containing proteins that are known to promote egress and spread of EBOV, MARV, and LAFV. Moreover, our current lead candidate PPxY budding inhibitors show activity in blocking egress of live SARS-CoV-2 virus infection in human lung epithelial cells. In this Phase I proposal, we will identify and evaluate host-oriented inhibitors as potential therapeutics for SARS-CoV-2 and related coronaviruses 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 of the Harty Lab at the University of Pennsylvania in the experimental aspects of virus-host interactions and antiviral therapy, and the lab of Olena Shtanko at Texas Biomedical Research Institute for evaluating compounds against live viruses under BSL-3 conditions. The three aims are (1) lead finding and optimization medicinal chemistry including ADME profiling, (2) evaluation for the ability to specifically inhibit egress of SARS-CoV-2 VLPs and PPxY- mediated S-host protein interactions, and (3) in vitro and in vivo analyses against authentic SARS-CoV-2 virus.

该阶段I应用的最终目标是发现和开发面向宿主的小分子化合物 靶向严重的急性呼吸综合症冠状病毒2（SARS-COV-2）感染。 SARS-COV-2是一部小说 冠状病毒驱动了人类严重呼吸道综合征的当前全球大流行。抗病毒疗法 迫切需要用SARS-COV-2和继续出现的新变体对抗感染。我们 已经发现了几个化学系列，这些化学系列靶向特定宿主蛋白之间的模块化相互作用 含有WW域（例如NEDD4）和含有PPXY基序的病毒蛋白（例如埃博拉病毒VP40）。尤其， 新兴的RNA病毒病原体，例如埃博拉病毒，马尔堡，Lassa和狂犬病病毒，都编码PPXY主题 招募宿主WW域含有蛋白质，以促进有效的病毒，扩散和传播。 有趣的是，SARS-COV-2的表面暴露的尖峰糖蛋白也有一个假定的WW域 结合基序（25ppay28），在SARS-COV-1或更多衰减的冠状病毒的S蛋白中不存在 菌株。在SARS-COV-2病毒的主要表面蛋白中获得此PPAY基序的获取可提高 有趣的可能性可能有助于通过SARS-COV-2通过 与特定宿主WW域轴承蛋白的相互作用。在我们正在进行的关于丝状病毒和的研究中 竞技病毒，我们使用了广泛的SAR来识别能够阻止出口和的铅化合物系列 活细胞培养中活的EBOV，MARV和LAFV的传播，并阻止活体内的疾病进展 MARV挑战模型。在这里，我们假设对我们的PPXY/WW-DOMAIN的“知情” SAR分析 抑制剂（例如，铅候选FC-10696）将导致发现能够阻止出口和的类似物 SARS-COV-2的疾病进展以及将来可能出现的相关含PPXY变体。 为了支持我们的假设，我们提出了强大的初步数据，表明S蛋白中的PPXY基序 SARS-COV-2病毒的结合可以与已知会促进流出的蛋白质的宿主WW结构域相互作用 并传播Ebov，Marv和LaFV。此外，我们目前的主要候选ppxy发芽抑制剂显示 阻断人肺上皮细胞中活体SARS-COV-2病毒感染出口的活性。在这个阶段第一 提案，我们将确定和评估面向宿主的抑制剂，作为SARS-COV-2和 通过结合科学家的药物和药物化学专业知识，相关的冠状病毒 Fox Chase化学多样性中心（FCCDC）具有Harty Lab的专业知识和经验 宾夕法尼亚大学在病毒宿主相互作用和抗病毒药疗法的实验方面以及 德克萨斯生物医学研究所的Olena Shtanko实验室评估现场病毒化合物 在BSL-3条件下。这三个目标是（1）铅发现和优化医学化学，包括 （2）评估特异性抑制SARS-COV-2 VLP和PPXY-的能力的评估 介导的S-宿主蛋白相互作用，以及（3）对正宗SARS-COV-2病毒的体外和体内分析。