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: 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
• 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

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.

诸如登革热、黄热病和西尼罗河等黄病毒的感染是一种主要的医疗和社会经济问题 这是一个世界性的问题，但目前还没有有效的抗病毒疗法来治疗黄病毒感染 可用。因此，当务之急是有效的、选择性的和具有成本效益的抗病毒化合物 确认身份。这个项目的总体目标是发现新的黄病毒rna抑制剂。 可作为有效广谱化疗的甲基转移酶(MTase) 治疗黄病毒感染的药物。MTase酶在5‘端产生帽子结构 病毒RNA的末端，是病毒基因组高效翻译所必需的，也是病毒生长所必需的。 我们设计并成功地实现了一种简单、快速的体外高通量检测方法 确定干扰MTase结合的RNA帽的化合物。我们的初始验证屏幕 国家筛选实验室(NSRB)的分子库已经确定了一些化合物为 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 优化一组化学上不同的MTase帽结合抑制剂，以确定用于 药物开发。具体目标1：我们将进行额外的HTS，并将通过生化方法确定 附加HIT化合物的抑制常数和抗病毒活性。具体目标2：利用由此产生的 信息，我们将使用一系列集成的电子分子建模技术来识别 基于我们对RNA帽的结构知识的结构相关的小分子化合物 结合位置和电子分析将提高对黄病毒MTase蛋白的亲和力和交叉选择性 和可接受的类似毒品的特征。我们还将利用药物化学来设计和合成 必要时可使用衍生产品来改善物化性能。具体目标3：最好的抑制剂(in 广度、效力和类药物特性)将在细胞培养和 可能会出现耐药抑制药。对先导化合物的抑制作用将是 在现有的小鼠模型中确定了对西尼罗河病毒的抗药性。该项目利用正在进行的 将主要研究人员的专业知识(病毒学和计算生物学)结合在一起的协作 并将导致快速有效地识别黄病毒复制的抑制剂，最终目标是 描述了具有类药物性质的先导化合物，这些先导化合物适合临床前开发用于治疗 黄病毒感染。该研究项目符合RMRCE关于病毒的综合研究重点 治疗公司，并将直接与RPS 3.1和3.8互动，并利用Core C的资源。