Development and optimization of novel anti -flavivirus compounds

新型抗黄病毒化合物的开发和优化

基本信息

批准号：
7675657
负责人：
Brian Geiss
金额：
$ 26.17万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7675657
关键词：
Affinity Amino Acids Antiviral Agents Binding Binding Sites Biochemical Biological Biological Assay Biological Availability Categories Cell Culture Techniques Characteristics Collaborations Computational Biology Computer Simulation Culicidae Dengue Dengue Virus Development Disease Docking Drug Delivery Systems Drug Design Enzymes Evaluation Exhibits Family Flavivirus Flavivirus Infections Foundations Goals Growth Guanosine Guanosine Triphosphate Human In Vitro Infection Knowledge Laboratories Lead Libraries Life Medical Methodology Methyltransferase Modeling Molecular Models Morbidity - disease rate Mus Mutation National Institute of Allergy and Infectious Disease Pathogenesis Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Probability Process Property Protein Binding Proteins RNA RNA Caps Replicon Research Research Personnel Research Project Grants Resistance Resolution Resources Screening procedure Silicon Dioxide Structure Structure-Activity Relationship Techniques Testing Therapeutic Therapeutic Agents Translations Validation Viral Viral Genome Viral Hemorrhagic Fevers Virus West Nile virus Yellow Fever Yellow fever virus analog base biodefense chemotherapeutic agent cost cytotoxicity design drug development fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether high throughput screening human morbidity improved inhibitor/antagonist insight molecular modeling mortality mouse model novel pathogen pre-clinical small molecule socioeconomics therapy development viral RNA virology

项目摘要

Infection by flaviviruses such as dengue, yellow fever, and West Nile is a major medical and socioeconomic problem worldwide, yet effective antiviral therapeutics to treat flavivirus infection are not currently available. As such, it is imperative that potent, selective, and cost-effective antiviral compounds be identified. The overall goal of this project is the discovery of novel inhibitors of the flavivirus RNA methyltransferase (MTase) enzyme that can serve as effective broad-spectrum chemotherapeutic agents for the treatment of flavivirus infection. The MTase enzyme generates the cap structure at the 5' end of viral RNAs that is required for efficient translation of the viral genome and is essential for viral growth. We have designed and successfully implemented a simple and rapid in vitro high-throughput assay to identify compounds that interfere with RNA cap binding by the MTase. Our initial validation screen of molecule libraries at the National Screening Laboratory (NSRB) has identified a number of compounds as MTase inhibitors. In this project, we propose to expand on these results with the goal of identifying and optimizing a chemically diverse set of MTase cap-binding inhibitors in order to identify lead compounds for drug development. Specific Aim 1: We will perform additional HTS and will biochemically determine the inhibition constants and antiviral activity for additional hit compounds. Specific Aim 2: Using the resulting information, we will employ an integrated array of in silico molecular modeling techniques to identify structurally related small molecule compounds which based on our structural knowledge of the RNA cap binding site and in silico analysis will have improved affinity and cross selectivity for flavivirus MTase proteins and acceptable drug-like characteristics. We will also employ medicinal chemistry to design and synthesize derivatives when necessary to improve physiochemical properties. Specific Aim 3: The best inhibitors (in terms of breadth, potency and drug-like characteristics) will be tested for antiviral activity in cell culture and for the potential for emergence of resistance Inhibitors. Inhibitory effects for lead compounds will be determined against West Nile virus in an existing mouse model. This project takes advantage of an ongoing collaboration that brings together the expertise (virology and computational biology) of the lead investigators and will result in the rapid and efficient identification of inhibitors of flavivirus replication with the ultimate goal of describing lead compounds with drug-like properties suitable for preclinical development for the treatment flavivirus infection. This research Project fits within the RMRCE Integrated Research Focus on Viral Therapeutics, and will interact directly with RPs 3.1 and 3.8 and utilize the resources of Core C.

登革热、黄热病和西尼罗河等黄病毒感染是一种主要的医学和社会经济疾病这是一个世界范围内的问题，但目前还没有有效的抗病毒疗法来治疗黄病毒感染可用的。因此，迫切需要开发有效、选择性和具有成本效益的抗病毒化合物。确定。该项目的总体目标是发现黄病毒RNA的新型抑制剂甲基转移酶（MTase）可作为有效的广谱化疗药物用于治疗黄病毒感染的药物。 MTase 酶在 5' 处生成帽子结构病毒RNA的末端，是病毒基因组有效翻译所必需的，并且对于病毒生长至关重要。我们设计并成功实施了一种简单快速的体外高通量测定鉴定干扰 MTase 结合 RNA 帽的化合物。我们的初始验证屏幕国家筛选实验室 (NSRB) 的分子库已鉴定出许多化合物： MTase 抑制剂。在这个项目中，我们建议扩展这些结果，目标是确定和优化一组化学上多样化的 MTase 帽结合抑制剂，以确定先导化合物药物开发。具体目标 1：我们将进行额外的 HTS 并通过生化方法确定其他命中化合物的抑制常数和抗病毒活性。具体目标 2：使用结果信息，我们将采用一系列集成的计算机分子建模技术来识别结构相关的小分子化合物，基于我们对 RNA 帽的结构知识结合位点和计算机分析将提高黄病毒 MTase 蛋白的亲和力和交叉选择性和可接受的药物样特性。我们还将利用药物化学来设计和合成必要时使用衍生物以改善理化性质。具体目标 3：最好的抑制剂（在在广度、效力和药物样特征方面）将在细胞培养物中测试抗病毒活性，发现耐药抑制剂出现的可能性。对先导化合物的抑制作用将是在现有的小鼠模型中确定针对西尼罗河病毒。该项目利用了正在进行的汇集主要研究人员的专业知识（病毒学和计算生物学）的合作并将导致快速有效地鉴定黄病毒复制抑制剂，最终目标描述具有类似药物特性的先导化合物，适合用于治疗的临床前开发黄病毒感染。该研究项目符合 RMRCE 病毒综合研究重点治疗，将直接与 RP 3.1 和 3.8 交互并利用 Core C 的资源。