Project 4 - Inhibitors of Flavivirus Replication

新出现的和流行的黄病毒属成员对世界范围内的公共卫生构成重大威胁。这个 全球范围的登革热病毒、日本脑炎病毒、西尼罗河病毒(WNV)、森林脑炎 病毒和ZIKV最近有所扩大。据估计，登革热病毒感染约4亿人，导致约100人患病 每年杀死约21,000人。黄热病病毒在34个非洲国家仍然是一个公共卫生问题 和13个南美国家。新出现的黄病毒包括鲍瓦桑病毒(POWV)(美国东北部 和Usutu病毒(欧洲)。人类只有一些黄病毒的疫苗可用，但它们 并不总是被使用。少数人在接种活的17D黄牛疫苗后患上多器官疾病 通常致命的发烧疫苗。目前还没有有效的针对黄病毒的小分子 治疗人类感染黄病毒的治疗学。的项目4中提出的研究目标 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 并直接作用于病毒成分。在目标1下，我们将开发四个核糖核苷类似物 由Core合成 B，已经获得了表明抗黄病毒活性的初步数据，通过 以B和C为核心的反复模拟合成-生物测试策略将测试化合物 原代小鼠和人巨噬细胞对一组黄病毒的抗病毒活性和细胞毒性 神经细胞。还将对耐药的作用方式和发展进行分析。在Aim 2下，记者 POWV和WNV病毒将被生成并用于高通量筛选~300,000个唯一 经反筛选验证的符合BSL3限制的化合物将得到进一步开发 根据目标1.符合进展标准的化合物将在黄病毒小鼠身上进行体内疗效测试 以及仓鼠感染模型和人类皮质类器官中。肠道微生物群对活性的影响 将与项目7合作评估铅黄病毒抗病毒化合物的影响。 POWV和WNV感染动物急、慢性病毒所致神经症状的治疗 有机化合物将与项目2合作进行评估。核心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。

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.