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: 10545109
• 负责人: RONALD N HARTY
• 金额: $ 30.65万
• 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/10545109
• 关键词: 2019-nCoV; ACE2; Antiviral Agents; Antiviral Therapy; Arenavirus; Attenuated; Automobile Driving; Binding; Binding Proteins; Biological Assay; Biomedical Research; COVID-19 therapeutics; Caco-2 Cells; Cell Culture Techniques; Chemicals; Coronavirus; Data; Development; Disease Progression; Disease model; Ebola; Ebola virus; Epithelial Cells; Evaluation; Filovirus; Foxes; Future; Glycoproteins; Goals; Hand; Human; In Vitro; Investigation; Lassa virus; Lead; Lung; Marburgvirus; Mediating; Membrane Proteins; Metabolic; 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 transmission; Scientist; Series; Small Business Technology Transfer Research; Solubility; Surface; Syndrome; Texas; Toxic effect; Universities; Variant; 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.

该一期申请的最终目标是发现和开发面向主体的小分子化合物 针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 感染的 SARS-CoV-2 是一种新型感染。 冠状病毒推动了当前人类严重呼吸综合征的全球流行。 迫切需要对抗 SARS-CoV-2 和不断出现的新变种的感染。 发现了几种针对特定宿主蛋白之间的模块化相互作用的化学系列 包含 WW 结构域（例如 Nedd4）和包含 PPxY 基序的病毒蛋白（例如埃博拉 VP40）。 埃博拉病毒、马尔堡病毒、拉沙病毒和狂犬病病毒等新兴 RNA 病毒病原体均编码 PPxY 基序， 宿主招募含有 WW 结构域的蛋白质以促进有效的病毒排出、传播和传播。 ，SARS-CoV-2 表面暴露的刺突糖蛋白 (S) 也具有假定的 WW 结构域 结合基序 (25PPAY28)，不存在于 SARS-CoV-1 或更弱的冠状病毒的 S 蛋白中 在 SARS-CoV-2 病毒粒子的主要表面蛋白中获得该 PPAY 基序会提高 有趣的可能性是，它可能通过以下方式促进 SARS-CoV-2 的独特致病性和/或传播： 在我们正在进行的丝状病毒研究中，与特定宿主 WW 结构域的相互作用。 沙粒病毒，我们使用了广泛的 SAR 来识别能够阻止出口和的先导化合物系列 活 EBOV、MARV 和 LAFV 在细胞培养物中的传播，以及在活体内阻断疾病进展 MARV 挑战模型。在这里，我们勇敢地对我们现有的 PPxY/WW 域进行“知情”SAR 分析。 抑制剂（例如主要候选药物 FC-10696）将导致发现能够阻止出口和 SARS-CoV-2 的疾病进展，以及未来可能出现的相关包含 PPxY 的变体。 为了支持我们的假设，我们提供了强有力的初步数据，表明 S 蛋白中的 PPxY 基序 SARS-CoV-2 病毒可以与含有已知促进流出的宿主 WW 结构域的蛋白质相互作用 此外，我们目前的主要候选 PPxY 出芽抑制剂显示。 在第一阶段中，具有阻断人肺上皮细胞中活 SARS-CoV-2 病毒感染流出的活性。 根据提案，我们将确定和评估面向宿主的抑制剂作为 SARS-CoV-2 的潜在疗法， 相关的冠状病毒通过结合科学家的制药和药物化学专业知识 Fox Chase 化学多样性中心 (FCCD) 拥有 Harty 实验室的专业知识和经验 宾夕法尼亚大学在病毒与宿主相互作用和抗病毒治疗的实验方面，以及 德克萨斯生物医学研究所的 Olena Shtanko 实验室用于评估针对活病毒的化合物 BSL-3 条件下的三个目标是 (1) 先导药物发现和优化药物化学，包括 ADME 分析，(2) 评估特异性抑制 SARS-CoV-2 VLP 和 PPxY- 流出的能力 介导的 S 宿主蛋白相互作用，以及 (3) 针对真正的 SARS-CoV-2 病毒的体外和体内分析。