In Vitro Evaluation and Characterization of Novel Lead Therapeutic Candidates for Encephalitic Alphavirus Treatment

治疗脑炎甲病毒的新型先导候选药物的体外评价和表征

基本信息

批准号：
10563180
负责人：
Donghoon Chung
金额：
$ 54.59万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-06 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10563180
关键词：
Adverse effects Alphavirus Americas Amidines Antiviral Agents Biological Assay Bioterrorism Blood Cell Line Cells Collaborations Complex DNA-Directed RNA Polymerase Development Documentation Eastern Equine Encephalitis Virus Encephalitis Evaluation FDA approved Funding Human In Vitro Infection Lead Measures Mitochondria Modeling Molecular Target Monitor Mus N-terminal Neurons Outcomes Research Pharmaceutical Chemistry Preparation RNA chemical synthesis RNA-Directed RNA Polymerase Reporting Research Project Grants Resistance Resistance development Safety Series Structure System Testing Therapeutic Therapeutic Index Toxic effect Treatment Protocols Venezuelan Venezuelan Equine Encephalitis Virus Viral Viral Physiology Virus Western Equine Encephalitis Virus cytotoxicity design drug discovery experimental study fitness follow-up high throughput screening in vitro Assay in vitro activity in vivo in vivo Model in vivo evaluation indexing lead candidate lead optimization lead series meter neurotropic novel novel therapeutics pre-Investigational New Drug meeting programs prototype replicase response scaffold therapeutic candidate viral RNA virology

项目摘要

Program Abstract- Project 3 Encephalitic alphaviruses (i.e., Venezuelan, Western, and Eastern Equine Encephalitis viruses) can cause devastating encephalitis in humans and equids. Several drug discovery efforts have been pursued to fulfill the unmet needs for effective antivirals for these viruses; however, they are still not available for treatment. Here we propose the development of a therapeutic candidate for encephalitic alphaviruses based on our two novel lead series. Prototypes within each series showed potent antiviral activity in vitro and in vivo without adverse effects. In Aim 1, we will evaluate newly designed compounds in vitro for their potentials as anti-VEEV, EEEV therapeutics to support the lead optimization of Research Project 1 and contribute to the selection of leads to be tested in vivo in Research Project 2. In Aim 2, we will contribute to experimental studies and documentation for the Non-Clinical Virology Study Report for the selected lead candidate in preparation for the informal and Pre- IND meetings in collaboration with Leidos. We will experimentally establish that the alphaviral RNA replicase is the target of the lead candidate compounds, using in vitro viral RNA synthesis assays. Specifically, we will evaluate the anti-V/W/EEEV activity in biologically relevant systems, and importantly, measure the Inhibitory Quotient to demonstrate antiviral activity in human blood. We will also determine the in vitro safety and therapeutic index of the lead candidate compounds and define the resistance threshold of resistant viruses.

项目摘要-项目3 脑炎甲病毒（即委内瑞拉、西方和东方马脑炎病毒）可引起人类和马科动物的毁灭性脑炎。为了实现这一目标，我们进行了多项药物发现工作针对这些病毒的有效抗病毒药物的需求未得到满足；然而，他们仍然无法接受治疗。在这里我们提议基于我们的两个新先导药物开发脑炎甲病毒的治疗候选药物系列。每个系列中的原型在体外和体内均显示出有效的抗病毒活性，且没有副作用。在目标 1 中，我们将在体外评估新设计的化合物作为抗 VEEV、EEEV 的潜力治疗支持研究项目 1 的先导化合物优化并有助于选择待开发的先导化合物在研究项目 2 中进行了体内测试。在目标 2 中，我们将为以下方面的实验研究和记录做出贡献：选定的主要候选人的非临床病毒学研究报告，为非正式和预审做准备与 Leidos 合作召开 IND 会议。我们将通过实验确定甲病毒RNA复制酶是使用体外病毒 RNA 合成测定来确定主要候选化合物的靶标。具体来说，我们将评估生物相关系统中的抗 V/W/EEEV 活性，重要的是，测量抑制证明人体血液中抗病毒活性的商数。我们还将确定体外安全性和主要候选化合物的治疗指数并定义耐药病毒的耐药阈值。