Development and optimization of novel anti -flavivirus compounds

新型抗黄病毒化合物的开发和优化

• 批准号: 8465809
• 负责人: Brian Geiss
• 金额: $ 27.78万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465809
• 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 Design; Drug Targeting; 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; Protein Methyltransferases; RNA; RNA Caps; Replicon; Research; Research Personnel; Research Project Grants; Resistance; Resolution; Resources; 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 effective; cytotoxicity; design; drug development; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; high throughput screening; human morbidity; human mortality; improved; inhibitor/antagonist; insight; molecular modeling; mortality; mouse model; novel; pathogen; pre-clinical; screening; small molecule; socioeconomics; structural biology; therapy development; viral RNA; virology

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素感染是主要的医学和社会经济 全球问题，目前尚未进行治疗黄病毒感染的有效的抗病毒治疗剂 可用的。因此，必须有效，选择性和成本效益的抗病毒化合物是 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）酶，可以用作有效的广谱化学治疗酶 治疗黄病毒感染的药物。 MTase酶在5'处生成盖结构 病毒RNA的结束是有效地翻译病毒基因组，对于病毒生长至关重要。 我们设计并成功地实施了一种简单而快速的体外高通量测定法 识别干扰MTase RNA帽结合的化合物。我们的初始验证屏幕 国家筛查实验室（NSRB）的分子库已确定多种化合物是 MTase抑制剂。在这个项目中，我们建议扩展这些结果，以识别和 优化一组化学多样的MTase帽结合抑制剂，以鉴定铅化合物 药物开发。特定目标1：我们将执行其他HTS，并将生化确定 抑制常数和抗病毒活性，用于其他命中化合物。特定目标2：使用结果 信息，我们将采用一个集成的硅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素MTase蛋白的亲和力和交叉选择性 和可接受的类似药物的特征。我们还将采用药物化学来设计和合成 必要时衍生物以改善生理化学特性。特定目标3：最佳抑制剂（在 将测试广度，效力和类似药物特征的术语）在细胞培养和 为了出现抗性抑制剂。铅化合物的抑制作用将是 在现有的小鼠模型中针对西尼罗河病毒确定。该项目利用了一个持续的 合作汇集了主要研究人员的专业知识（病毒学和计算生物学） 并将导致快速有效地识别黄病毒复制抑制剂的最终目标 描述具有类似药物特性的铅化合物适合临床前发育 黄病毒感染。该研究项目符合RMRCE综合研究的重点 治疗剂，并将直接与RPS 3.1和3.8互动，并利用CoreC的资源。