Development of Inhibitors Targeting Flavivirus Methyltransferase

黄病毒甲基转移酶抑制剂的开发

• 批准号: 10636605
• 负责人: HONGMIN LI
• 金额: $ 76.74万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636605
• 关键词: 3-Dimensional; Adverse effects; Animal Model; Annual Reports; Antiviral Agents; Antiviral Therapy; Arbovirus Encephalitis; Binding; Biochemical; Biochemistry; Biological Assay; Cells; Cellular Assay; Cessation of life; Chemicals; Child; Country; Crystallography; Dengue Infection; Dengue Vaccine; Dengue Virus; Development; Disease; Disease Outbreaks; Drug Kinetics; Effectiveness; Enzymes; Epidemic; Flavivirus; Flavivirus Infections; Fluorescence; Fluorescence Resonance Energy Transfer; Genome; Human; Human Cell Line; In Vitro; Infection; Innate Immune Response; Insecta; Investigation; Japanese encephalitis virus; Label; Lead; Methods; Methylation; Methyltransferase; Microcephaly; Modeling; Molecular; Morbidity - disease rate; Newborn Infant; Organoids; Patients; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Poison; Populations at Risk; Positioning Attribute; Prevention; Public Health; RNA; RNA Caps; RNA replication; Research; Research Personnel; Resources; Risk; Serotyping; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Agents; Vaccination; Vaccines; Viral; Viral Physiology; Virus; Virus Diseases; Virus Replication; West Nile virus; Work; Yellow Fever Vaccine; Yellow Fever Virus Infection; Yellow fever virus; ZIKV infection; Zika Virus; analog; anti-viral efficacy; candidate validation; combat; cytotoxicity; design; drug candidate; drug testing; genomic RNA; high throughput screening; human pathogen; in vivo; inhibitor; innovation; insight; lead candidate; lead optimization; mortality; mouse model; nanomolar; novel; scaffold; screening; small molecule inhibitor; structural biology; synergism; tool; vaccine hesitancy; viral genomics; virology

Abstract: Flaviviruses are primarily insect-borne, associated with global morbidity and mortality, and found on every inhabited continent. Unfortunately, current therapeutic options for treating diseases associated with these viruses are limited. All flaviviruses encode methyltransferases (MTases)—flaviviral NS5 for both N-7 and 2'-O methylations of viral genomic RNA. The N-7 MTase function is essential for replication of the viral RNA genome, whereas 2'-O MTase function is required for the virus to evade the host innate immune response. These activities are conserved among the flaviviruses. For this project, our collaborative team will optimize the current lead compounds, perform high throughput screening (HTS) to identify additional lead candidates, chemically optimize the lead candidates, and define structure activity relationships. Optimizing current lead compounds using cutting- edge medicinal chemistry, the team will perform a large scale HTS campaign using innovative fluorescence chemical probes to identify additional small molecule inhibitors of flavivirus RNA capping MTases. We will perform an in-depth investigation of the model of action and antiviral efficacy using in vitro biochemistry, structural biology, virology, in vivo pharmacokinetics, and in vivo animal models, which will allow the development of novel, effective, broad-spectrum, and druglike therapeutic agents against both flaviviruses. Preliminary progress has been made in the identification of initial lead inhibitors of these MTases, demonstrating low nanomolar antiviral activity. We will advance these compounds to further develop potent antiviral compounds while conducting large- scale screening in parallel for additional structural scaffold discoveries. Complementary expertise among our investigators will synergize and expedite the progress of this research. Our collaborative objective is to provide first-in-class drug candidates for the treatment or prevention of these viral infections.

摘要： 黄病毒主要由昆虫传播，与全球发病率和死亡率相关，并且存在于每一个 有人居住的大陆不幸的是，目前用于治疗与这些病毒相关的疾病的治疗方案 是有限的。所有黄病毒编码甲基转移酶（MTases）-黄病毒NS 5，用于N-7和2 '-O 病毒基因组RNA的甲基化。N-7 MTase功能对于病毒RNA基因组的复制是必需的， 而2 ′-O MTase功能是病毒逃避宿主先天免疫应答所必需的。这些活动 在黄病毒中是保守的对于这个项目，我们的合作团队将优化当前的领先优势 化合物，进行高通量筛选（HTS），以确定其他先导候选物，化学优化 领导候选人，并定义结构活动关系。使用切割优化当前的铅化合物- 该团队将利用创新的荧光技术进行大规模的HTS活动， 化学探针来鉴定黄病毒RNA加帽MT酶的另外的小分子抑制剂。我们将 使用体外生物化学、结构和免疫学方法， 生物学、病毒学、体内药代动力学和体内动物模型，这将允许开发新的， 有效的、广谱的和类药物的治疗剂。初步进展已 在鉴定这些MT酶的初始先导抑制剂时， 活动我们将推进这些化合物，以进一步开发有效的抗病毒化合物，同时进行大规模- 规模筛选平行的额外的结构支架的发现。我们之间的互补专业知识 研究人员将协同并加快这项研究的进展。我们的合作目标是提供 用于治疗或预防这些病毒感染的一流候选药物。