Project 2 - Novel Therapeutics for Emerging Alphavirus

项目 2 - 新兴甲病毒的新疗法

基本信息

批准号：
10580024
负责人：
DANIEL N STREBLOW
金额：
$ 101.31万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-07 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580024
关键词：
Acute Alphavirus Alphavirus Infections Americas Animal Model Anti-Inflammatory Agents Antiviral Agents Antiviral Therapy Arthralgia Arthritis Arthritogenic Asia Biochemical Biological Assay Biological Availability Categories Cell Culture Techniques Cell Line Chemicals Chikungunya virus Chronic Clinical Collaborations Combined Modality Therapy Computer Analysis Computer Models Culicidae Development Disease Disease Outbreaks Drug Kinetics Drug resistance Eastern Equine Encephalitis Virus Eastern Equine Encephalomyelitis Economics Encephalitis Epidemic Europe Flavivirus Goals Health Human Immune Immune system In Vitro Infection Inflammatory Lead Licensing Life Life Cycle Stages Maps Molecular Target National Institute of Allergy and Infectious Disease Neurologic Nucleosides Pathogenicity Pathology Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phylogenetic Analysis Prodrugs Property Proteins RNA Viruses RNA-Directed RNA Polymerase Regimen Research Resistance Resolution Ross river virus Severity of illness Solubility Specificity Structure Tenosynovitis Testing Therapeutic Treatment Efficacy Vaccines Venezuelan Equine Encephalitis Virus Viral Viral Drug Resistance Viral Physiology Virus Virus Replication Western Equine Encephalitis Virus Work aging population analog arthropod-borne cell type combat cytotoxicity disability drug development drug discovery drug resistance development helicase high throughput screening improved in silico in vivo inhibitor lead optimization mortality mouse model mutant nervous system disorder novel novel therapeutic intervention novel therapeutics nucleoside analog nucleoside inhibitor pre-clinical prevent priority pathogen screening small molecule small molecule inhibitor structural biology synergism targeted treatment transmission process viral resistance

项目摘要

PROJECT SUMMARY Mosquito-transmitted alphaviruses cause outbreaks of incapacitating acute and chronic arthritis and life- threatening encephalitis. The arthritogenic alphaviruses include the re-emerging chikungunya (CHIKV), Mayaro, and Ross River viruses. Since 2004, CHIKV has infected millions of people and expanded into Europe, Asia, and Americas. As arthritis can endure for months to years after infection with an arthritogenic alphavirus, large epidemics have severe economic consequences. The encephalitic alphaviruses include Eastern, Venezuelan (VEEV), and Western equine encephalitis viruses that are endemic to the Americas and infection can lead to mortality or long-term neurological sequelae. There are currently no approved alphavirus- specific vaccines or antiviral agents. In collaboration with Southern Research, we used HTS to identify non- toxic small molecules that inhibit CHIKV and VEEV replication. Additionally, we identified chemically distinct compound classes that display broad inhibitory activity against alphaviruses, as well as other pathogenic human viruses (e.g., flaviviruses). We also mapped resistance mutants against two highly active compounds and identified the alphavirus nsP2 helicase domain and the nsP3 macrodomain as potential antiviral targets. In addition to this work, in collaboration with the Emory Institute for Drug Development, we identified novel nucleosides, which target RNA-dependent RNA polymerases, with potent antiviral activity against alphavirus infection. Thus, we have identified potent antiviral compounds against three distinct molecular targets essential for alphavirus replication. The goal of this highly interactive Project 2 of the Antiviral Drug Discovery and Development Center (AD3C) is to develop new therapeutic strategies that inhibit alphavirus replication, prevent selection for drug resistance, and reduce alphavirus disease severity. In Specific Aim 1, lead compounds will be optimized in collaboration with Core A and Core B by iterative medicinal chemistry, cell culture-based antiviral and cytotoxicity assays, and in vivo pharmacokinetic studies to improve their efficacy, selectivity, solubility, and bioavailability. In Specific Aim 2, we will work with the other AD3C Projects to define the breadth of antiviral activity and cell type specificity, molecular targets through resistance mapping and structural/computational analyses and identify synergy profiles for compounds with potent activity. In Specific Aim 3, optimized compounds will be evaluated for in vivo efficacy using well-established pre-clinical mouse models of alphavirus infection. Since therapies that target different aspects of the viral life cycle are likely to show improved efficacy and limit the development of drug resistance, combination therapies also will be tested. Last of all, since alphavirus-induced disease includes inflammatory immune pathology, we will evaluate the therapeutic potential of combining antiviral therapy with anti-inflammatory regimens. This work will promote the development of new antiviral therapeutic strategies that have the potential to improve human health.

项目概要蚊子传播的甲病毒会导致急性和慢性关节炎的爆发以及生命危险威胁脑炎。引起关节炎的甲病毒包括重新出现的基孔肯雅病毒（CHIKV）、马亚罗病毒和罗斯河病毒。自 2004 年以来，CHIKV 已感染数百万人并蔓延至欧洲、亚洲和美洲。由于关节炎在感染致关节炎药物后可以持续数月至数年甲病毒，大规模流行病会造成严重的经济后果。脑炎甲病毒包括美洲流行的东部、委内瑞拉 (VEEV) 和西部马脑炎病毒感染可导致死亡或长期神经系统后遗症。目前还没有批准的甲病毒- 特定疫苗或抗病毒药物。我们与 Southern Research 合作，使用 HTS 来识别非抑制 CHIKV 和 VEEV 复制的有毒小分子。此外，我们还发现了化学上不同的对甲病毒以及其他致病病毒表现出广泛抑制活性的化合物类别人类病毒（例如黄病毒）。我们还绘制了针对两种高活性化合物的抗性突变体并确定甲病毒 nsP2 解旋酶结构域和 nsP3 宏结构域作为潜在的抗病毒靶点。在除了这项工作之外，我们还与埃默里药物开发研究所合作，发现了新的核苷，靶向 RNA 依赖性 RNA 聚合酶，对甲病毒具有有效的抗病毒活性感染。因此，我们已经鉴定出针对三个不同分子靶标的有效抗病毒化合物用于甲病毒复制。这个高度互动的抗病毒药物发现项目 2 的目标开发中心（AD3C）致力于开发新的治疗策略，抑制甲病毒复制，预防选择耐药性，并降低甲病毒病的严重程度。在具体目标 1 中，先导化合物将通过迭代药物化学、基于细胞培养的方法与核心 A 和核心 B 合作进行优化抗病毒和细胞毒性测定以及体内药代动力学研究，以提高其功效、选择性、溶解度和生物利用度。在具体目标 2 中，我们将与其他 AD3C 项目合作来定义范围抗病毒活性和细胞类型特异性，通过抗性图谱确定分子靶标结构/计算分析并确定具有有效活性的化合物的协同作用特征。具体来说目标 3，将使用成熟的临床前小鼠评估优化化合物的体内功效甲病毒感染模型。由于针对病毒生命周期不同方面的疗法可能会显示出改善的疗效并限制耐药性的发展，联合疗法也将得到测试。最后，由于甲病毒引起的疾病包括炎症免疫病理学，我们将评估抗病毒治疗与抗炎疗法相结合的治疗潜力。这项工作将促进开发有潜力改善人类健康的新抗病毒治疗策略。