Project 2 - Novel Therapeutics for Emerging Alphavirus

项目 2 - 新兴甲病毒的新疗法

• 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
• 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

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.

项目总结 蚊子传播的甲型病毒会导致急性和慢性关节炎和生命丧失能力的爆发- 有威胁的脑炎。致关节炎的甲型病毒包括重新出现的基孔肯雅病毒(CHIKV)， Mayaro和罗斯河病毒。自2004年以来，CHIKV已感染数百万人，并扩大到 欧洲、亚洲和美洲。因为关节炎在感染一种致关节炎物质后可以持续几个月到几年 甲型病毒，大规模流行会造成严重的经济后果。脑炎甲型病毒包括 东部、委内瑞拉(VEEV)和西部马脑炎病毒，美洲和 感染可能导致死亡或长期的神经后遗症。目前没有批准的甲型病毒- 特定的疫苗或抗病毒药物。在与Southern Research的合作中，我们使用HTS来识别非 抑制CHIKV和VEEV复制的有毒小分子。此外，我们发现了不同的化学成分 对甲型病毒和其他致病性病毒表现出广泛抑制活性的化合物类 人类病毒(例如，黄病毒)。我们还定位了抗性突变体对两种高活性化合物的抗性 并确定了甲型病毒nsP2解旋酶结构域和NSP3大分子结构域为潜在的抗病毒靶点。在……里面 除了这项工作，我们与埃默里药物开发研究所合作，确定了新的 以RNA依赖的RNA聚合酶为靶标的核苷，具有强大的抗甲病毒活性 感染。因此，我们已经确定了针对三个不同的分子靶点的有效抗病毒化合物 用于甲型病毒复制。这个高度互动的项目2的目标是抗病毒药物发现和 开发中心(AD3C)正在开发新的治疗策略，以抑制甲型病毒复制，防止 选择抗药性，并降低甲型病毒病的严重程度。在具体目标1中，先导化合物将 通过迭代药物化学，以细胞培养为基础，与核心A和核心B合作进行优化 抗病毒和细胞毒性试验，以及体内药代动力学研究，以提高其疗效，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项目一起定义广度 抗病毒活性和细胞类型特异性，通过耐药性图谱和分子靶点 进行结构/计算分析，确定具有强大活性的化合物的协同作用特征。具体而言 目的3，优化的化合物将通过建立良好的临床前小鼠进行体内疗效评估 甲型病毒感染模型。因为针对病毒生命周期不同方面的治疗方法可能会 显示出改善的疗效和限制耐药性的发展，联合治疗也将得到测试。 最后，由于甲型病毒诱导的疾病包括炎性免疫病理，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 开发有可能改善人类健康的新的抗病毒治疗策略。