Project 4 - Inhibitors of Flavivirus Replication

项目 4 - 黄病毒复制抑制剂

• 批准号: 10513945
• 负责人: Margo A Brinton
• 金额: $ 291.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513945
• 关键词: Acute; African; Animal Model; Animals; Antiviral Agents; Binding; Biological Assay; Biological Testing; Blood; Blood - brain barrier anatomy; Brain; Canada; Cell model; Cells; Chronic; Collaborations; Containment; Country; Data; Dengue; Dengue Virus; Development; Disease; Dose; Drug resistance; Encephalitis Viruses; Europe; Flavivirus; Flavivirus Infections; G-Quartets; Genome; Goals; Hamsters; Human; In Vitro; Individual; Infection; Japanese encephalitis virus; Lead; Libraries; Modeling; Mus; Neurologic; Neurons; Oral; Organoids; Persons; Pharmaceutical Preparations; Polymerase; Powassan virus; Public Health; RNA; RNA Viruses; Reporter; Research; Resistance; Ribonucleosides; Serial Passage; South American; Testing; Tick-Borne Encephalitis Virus; Tissues; Treatment Efficacy; Vaccination; Viral; Viral Load result; Virus; West Nile virus; Yellow Fever Vaccine; Yellow fever virus; Zika Virus; analog; anti-viral efficacy; cell type; clinical candidate; cytotoxicity; drug development; experimental study; genome sequencing; gut microbiome; high throughput screening; human stem cells; in vivo; in vivo evaluation; inhibitor; macrophage; meetings; member; mutant; pandemic disease; screening; small molecule therapeutics; stem cell differentiation; stem cells; therapeutic evaluation; tripolyphosphate; vaccine access; viral RNA; viral resistance; whole genome

Emerging and endemic members of the genus Flavivirus pose significant worldwide public health threats. The global ranges of dengue viruses, Japanese encephalitis virus, West Nile virus (WNV), tick-borne encephalitis virus and ZIKV have recently expanded. Dengue virus is estimated to infect ~400 million, cause illness in ~100 million, and kill ~21,000 people a year. Yellow fever virus remains a public health concern in 34 African countries and 13 South American countries. Newly emerging flaviviruses include Powassan virus (POWV) (northeast US and Canada) and Usutu virus (Europe). Vaccines are available for humans for only some flaviviruses, but they are not always used. A few individuals develop multiorgan disease after vaccination with the live 17D yellow fever vaccine which is typically fatal. There are currently no effective flavivirus-specific small molecule therapeutics for treatment of humans with flavivirus infections. The goal of the research proposed in Project 4 of the AC/DC is to develop clinical candidate compounds that can be delivered orally, have broad anti-flavivirus activity and directly act on a viral component. Under Aim 1, we will develop four ribonucleoside analogs synthesized by Core B, for which preliminary data indicating anti-flavivirus activity has already been obtained, by a reiterative analog synthesis-biological testing strategy with Cores B and C. Compounds will be tested for antiviral activity against a panel of flaviviruses and cytotoxicity in primary mouse and human macrophages and neural cells. Mode of action and development of drug resistance will also be analyzed. Under Aim 2, reporter POWV and WNV viruses will be generated and used in high throughput screening of ~300,000 unique compounds under BSL3 containment by Core F. Hits validated by counter-screening will be further developed under Aim 1. Compounds meeting the advancement criteria will be tested for in vivo efficacy in flavivirus mouse and hamster infection models and in human cortical organoids. The effect of the gut microbiome on the activity of lead flavivirus antiviral compounds will be assessed in collaboration with Project 7. The impact of antiviral treatment on acute and chronic virus-induced neurological signatures in POWV and WNV infected animals and organoids will be evaluated in collaboration with Project 2. Core D will provide whole genome sequencing of viral mutants generated during viral resistance profiling of lead compounds.

黄病毒属的新兴和地方性成员对全球公共卫生构成重大威胁。这 全球登革热病毒、日本脑炎病毒、西尼罗河病毒 (WNV)、蜱传脑炎 病毒和 ZIKV 最近有所扩大。登革热病毒估计会感染约 4 亿人，导致约 100 人患病 百万，每年杀死约 21,000 人。黄热病病毒仍然是 34 个非洲国家的公共卫生问题 和13个南美国家。新出现的黄病毒包括波瓦桑病毒 (POWV)（美国东北部） 和加拿大）和乌苏图病毒（欧洲）。人类可以获得针对某些黄病毒的疫苗，但它们 并不总是被使用。少数人在接种活 17D 黄色疫苗后出现多器官疾病 发烧疫苗通常是致命的。目前尚无有效的黄病毒特异性小分子 用于治疗人类黄病毒感染的疗法。项目4提出的研究目标 AC/DC 旨在开发可口服、具有广泛抗黄病毒作用的临床候选化合物 活性并直接作用于病毒成分。在目标 1 下，我们将开发四种核糖核苷类似物 由Core合成 B，已获得表明抗黄病毒活性的初步数据，通过 使用核心 B 和 C 的重复模拟合成-生物测试策略。将测试化合物 对一组黄病毒的抗病毒活性以及对原代小鼠和人类巨噬细胞的细胞毒性 神经细胞。还将分析作用方式和耐药性的发展。在目标 2 下，记者 将生成 POWV 和 WNV 病毒并用于约 300,000 个独特病毒的高通量筛选 Core F 控制的 BSL3 化合物。通过反筛选验证的命中将进一步开发 目标 1. 符合进展标准的化合物将在黄病毒小鼠中测试体内功效 和仓鼠感染模型以及人类皮质类器官。肠道微生物组对活性的影响 将与项目 7 合作评估主要黄病毒抗病毒化合物的影响。 对 POWV 和 WNV 感染动物的急性和慢性病毒诱导的神经特征进行治疗 将与项目 2 合作评估类器官。Core D 将提供病毒的全基因组测序 在先导化合物的病毒抗性分析过程中产生的突变体。