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.

登革热、黄热病和西尼罗河等黄病毒感染是一个重大的医学和社会经济问题