DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS AGAINST RNA VIRUSES

针对 RNA 病毒的小分子疗法的开发

• 批准号: 8903846
• 负责人: RONALD N HARTY
• 金额: $ 30万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903846
• 关键词: Antiviral Agents; Antiviral Therapy; Applications Grants; Arenavirus; Biological Assay; Biological Models; Bioterrorism; Businesses; Cell Separation; Cell Survival; Chemicals; Clinical; Computer Simulation; Data; Data Reporting; Development; Disease Progression; Drug Kinetics; Ebola virus; Filovirus; Foxes; Frankfurt-Marburg Syndrome Virus; Future; Goals; Half-Life; Henipavirus; Human; Imaging Techniques; In Vitro; Inhibitory Concentration 50; Intellectual Property; Lassa Fever; Lead; Life; Literature; Mediating; Metabolic; Metabolism; Microsomes; Midazolam; Modification; Mus; Paramyxovirus; Peer Review; Pennsylvania; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma Proteins; Positioning Attribute; Preparation; Property; Protein Binding; Proteins; Publications; Publishing; RNA Viruses; Rhabdoviridae; Scientist; Small Business Technology Transfer Research; Structure-Activity Relationship; Technology; Testing; Therapeutic; Toxic effect; Toxicity Tests; Universities; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; Virus-like particle; absorption; analog; base; cellular imaging; design; disease transmission; drug development; drug discovery; experience; improved; in vivo; inhibitor/antagonist; meetings; neural precursor cell; novel; particle; pathogen; prevent; programs; protein structure; public health relevance; small molecule; virus host interaction

 DESCRIPTION (provided by applicant): The ultimate goal of this project is to produce a broad-spectrum drug for the treatment of viral infections caused by filoviruses (Ebola and Marburg), arenaviruses (Lassa fever), and rhabdoviruses (rabies). We and others have determined that efficient budding of these emerging human pathogens is dependent on the subversion of host proteins, such as Nedd4, and that PPxY late (L) budding domains expressed by the matrix proteins of these RNA viruses are critical for such interactions. As disruption of virus budding would prevent virus dissemination, we will evaluate the ability of small molecule inhibitors to disrupt host Nedd4-viral PPxY interactions, thereby preventing virus budding. Our collaborators, Drs. Michael Lee and Mark Olson (USAMRIID, Ft. Detrick, MD), have used a known protein structure containing a Nedd4-PPxY interaction to perform an in silico screen to find potential competitive blockers. This effort led to an initial active small molecule hit that ws subsequently improved with additional SAR analog testing. The goal of this Phase I STTR grant application is to expand this novel finding by designing and preparing additional analogs to understand SAR and initial ADME properties to support a future drug discovery program in Phase II. We will accomplish this by combining the pharmaceutical and medicinal chemistry expertise of the Fox Chase Chemical Diversity Center, Inc. (www.fc-cdci.com, FCCDC) with the expertise and experience of the Harty Lab at the University of Pennsylvania in the clinical and experimental aspects of antiviral therapy. In this SAR development proposal, we will design and prepare novel analogs suitable for composition of matter intellectual property protection to understand SAR and increase potency in our assays (Aim 1). We will use BiMC and VLP budding assays to test analogs for their efficacy at specifically inhibiting the PPxY-Nedd4 interaction and subsequent egress of filovirus particles (Aim 2). In this aim we will also test analogs for their ability to block PPxY-mediated budding of live viruses including VSV, rabies, Ebola (Kikwit), Marburg (Ci67), and Lassa fever. We will seek to understand potential drug property issues by obtaining in vitro absorption, distribution, metabolism and distribution (ADME) data and pharmacokinetic (PK) parameters in mice (IV administration) for advanced lead compounds (Aim 3). As L-domain containing matrix proteins are required for efficient virus-cell separation of many RNA viruses, including filoviruses, arenaviruses, rhabdoviruses, paramyxoviruses, and henipaviruses, we predict that targeting this virus-host interaction domain will serve as the basis for the development of new and powerful broad-spectrum antiviral drugs. Once we achieve the aims of this proposal, we will be ideally positioned to transition into a full drug discovery and development program as part of the more extensive STTR Phase II period where we will seek to find one or more PPxY inhibitors to evaluate in detailed IND-directed pharmacokinetic, pharmacodynamic and toxicity studies.

 描述（由申请人提供）：该项目的最终目标是生产一种广谱药物，用于治疗丝状病毒（埃博拉病毒和马尔堡病毒）、沙粒病毒（拉沙热）和弹状病毒（狂犬病）引起的病毒感染。我们和其他人已经确定，这些新兴人类病原体的有效出芽依赖于宿主蛋白（例如 Nedd4）的颠覆，并且这些 RNA 病毒的基质蛋白表达的 PPxY 晚期 (L) 出芽结构域对于这种相互作用至关重要。由于破坏病毒出芽会阻止病毒传播，因此我们将评估小分子抑制剂破坏宿主 Nedd4-病毒 PPxY 相互作用的能力，从而防止病毒出芽。我们的合作者，博士。 Michael Lee 和 Mark Olson（USAMRIID，马里兰州德特里克堡）使用一种已知的含有 Nedd4-PPxY 相互作用的蛋白质结构进行计算机筛选，以寻找潜在的竞争性阻断剂。这项努力导致了最初的活性小分子命中，随后通过额外的 SAR 模拟测试得到了改善。第一阶段 STTR 拨款申请的目标是通过设计和制备额外的类似物来了解 SAR 和初始 ADME 特性，以支持未来第二阶段的药物发现计划，从而扩展这一新发现。我们将通过将 Fox Chase Chemical Diversity Center, Inc. (www.fc-cdci.com, FCCDC) 的制药和药物化学专业知识与宾夕法尼亚大学 Harty 实验室在抗病毒治疗的临床和实验方面的专业知识和经验相结合来实现这一目标。在此 SAR 开发提案中，我们将设计和制备适合物质成分知识产权保护的新型类似物，以了解 SAR 并提高我们检测的效力（目标 1）。我们将使用 BiMC 和 VLP 出芽测定来测试类似物在特异性抑制 PPxY-Nedd4 相互作用和随后丝状病毒颗粒流出方面的功效（目标 2）。为此，我们还将测试类似物阻断 PPxY 介导的活病毒出芽的能力，包括 VSV、狂犬病、埃博拉病毒 (Kikwit)、马尔堡病毒 (Ci67) 和拉沙热。我们将通过获得先进先导化合物的体外吸收、分布、代谢和分布 (ADME) 数据以及小鼠体内的药代动力学 (PK) 参数（IV 给药）来寻求了解潜在的药物特性问题（目标 3）。由于许多RNA病毒（包括丝状病毒、沙粒病毒、弹状病毒、副粘病毒和亨尼帕病毒）的有效病毒-细胞分离需要含有L结构域的基质蛋白，因此我们预测，针对该病毒-宿主相互作用结构域将成为开发新型强效广谱抗病毒药物的基础。一旦我们实现了该提案的目标，我们将处于理想的位置，可以过渡到完整的药物发现和开发计划，作为更广泛的 STTR II 期的一部分，我们将寻求找到一种或多种 PPxY 抑制剂，以在详细的 IND 指导的药代动力学、药效学和毒性研究中进行评估。