Development of Broad Spectrum Direct Acting Antivirals Against Emerging Alphaviruses

针对新兴甲病毒的广谱直接作用抗病毒药物的开发

• 批准号: 10513688
• 负责人: Mark T Heise
• 金额: $ 710.04万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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/10513688
• 关键词: Address; Alphavirus; Alphavirus Infections; Animal Model; Antiviral Agents; Arthritis; Binding; Biochemistry; Biodistribution; Biology; Bioterrorism; Categories; Chemicals; Chikungunya virus; Collaborations; Coronavirus; Data; Development; Disease Outbreaks; Dose; Drug Combinations; Drug Kinetics; Drug Targeting; Drug resistance; Eastern Equine Encephalitis Virus; Encephalitis; Enzymatic Biochemistry; Enzymes; Family; Filovirus; Flavivirus; Formulation; Goals; In Vitro; Lead; Mayaro virus; Medical; Modeling; Molecular Virology; Outcome; Peptide Hydrolases; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Process; Property; Proteins; Public Health; RNA Helicase; RNA Viruses; RNA-Directed RNA Polymerase; Regimen; Risk; Site; Solubility; Specificity; Testing; Togaviridae; Toxic effect; Validation; Venezuelan Equine Encephalitis Virus; Viral; Viral Proteins; Virus; Western Equine Encephalitis Virus; Widespread Disease; anti-viral efficacy; antiviral drug development; base; biodefense; biothreat; drug development; effective therapy; efficacy study; experience; high throughput screening; human disease; improved; in silico; in vitro activity; in vivo; in vivo evaluation; inhibitor; lead optimization; lead series; member; mosquito-borne; novel; pandemic disease; pharmacokinetics and pharmacodynamics; pre-clinical; priority pathogen; programs; response; screening; small molecule; small molecule inhibitor; structural biology; treatment strategy

ABSTRACT Alphaviruses (Togaviridae genus) several medically important viruses, including chikungunya virus (CHIKV), Venezuelan equine encephalitis virus (VEEV), and Eastern equine encephalitis virus (EEEV). These re- emerging viruses are categorized as Biodefense Category B and C priority pathogens due to their pandemic risk or potential as bioterror threats. Despite the threat posed by these viruses, there are no approved antivirals for treating any alphavirus infection. Therefore, our highly experienced and interactive team will leverage our world class expertise in alphavirus biology, structural biology, high throughput screening, medicinal chemistry, and drug development to generate small molecule inhibitors targeting conserved viral enzymes with the goal of producing new, broad spectrum, direct acting anti-alphaviral drugs. The central premise of this effort is that small molecule-based inhibitors of essential viral proteins across multiple members of the Alphavirus family can be developed employing a platform that (a) integrates target identification and validation (Aim 1), (b) confirms and optimizes cellular antiviral activity and SAR against the given target (Aim 2a), (c) establishes and improves in vitro ADME and in vivo pharmacokinetics (Aim 2b), and progresses leads into in vivo efficacy and toxicity animal models (Aim 3). Collaboration with the Discovery Core B will functionally validate structurally conserved compound binding pockets in alphaviruses enzymes (RNA dependent RNA polymerase (RDRP; nsP4), the RNA helicase (nsP2), and the nsP2 protease). These analyses will inform the selection of viral targets for hit discovery using a combination of physical and in silico screening in coordination with Core B. Hit compounds that show robust target engagement will be optimized in collaboration with the Medicinal Chemistry Core (Core C) for target inhibition, stability, selectivity, solubility, permeability, pharmacokinetics, and antiviral activity in vitro against multiple alphaviruses (CHIKV, EEEV, and VEEV). As our goal is to identify broadly active compounds, lead compounds will also be tested agAainst additional alphaviruses (e.g. RRV, MAYV, ONNV, WEEV, and SINV) and other viruses in our program, including coronaviruses (Proj. 1 and 2), flaviviruses (Proj. 4), and filoviruses (Proj. 5). We will also collaborate with Enzymology Core D to identify their antiviral mechanism of action. Lead compounds with optimal in vivo biodistribution and stability will be tested for in vivo antiviral efficacy using our established models of alphavirus-induced arthritis (CHIKV) or encephalitis (VEEV or EEEV). Candidates with potent in vivo antiviral efficacy will be further optimized for formulation, toxicity, and advanced PK/PD.

抽象的 甲病毒（披盖病毒科属）几种重要的医学病毒，包括基孔肯雅病毒（CHIKV）、 委内瑞拉马脑炎病毒（VEEV）和东方马脑炎病毒（EEEV）。这些重新 新兴病毒因其大流行而被归类为生物防御 B 类和 C 类优先病原体 生物恐怖威胁的风险或潜力。尽管这些病毒构成威胁，但尚无批准的抗病毒药物 用于治疗任何甲病毒感染。因此，我们经验丰富且互动的团队将利用我们的 在甲病毒生物学、结构生物学、高通量筛选、药物化学、 和药物开发以产生针对保守病毒酶的小分子抑制剂，其目标是 生产新型、广谱、直接作用的抗甲病毒药物。这项努力的中心前提是 基于小分子的甲病毒家族多个成员的必需病毒蛋白抑制剂可以 使用一个平台进行开发，该平台 (a) 集成目标识别和验证（目标 1），(b) 确认 并针对给定目标优化细胞抗病毒活性和 SAR（目标 2a），(c) 建立并改进 体外 ADME 和体内药代动力学（目标 2b），并进一步研究体内功效和毒性 动物模型（目标 3）。与 Discovery Core B 的合作将在功能上验证结构保守 甲病毒酶中的复合结合口袋（RNA 依赖性 RNA 聚合酶（RDRP；nsP4）、RNA 解旋酶 (nsP2) 和 nsP2 蛋白酶）。这些分析将为热门发现的病毒靶标的选择提供信息 结合使用物理筛选和计算机筛选，并与 Core B 配合。命中显示的化合物 将与药物化学核心（核心 C）合作优化强大的目标参与度 抑制、稳定性、选择性、溶解度、渗透性、药代动力学和体外抗病毒活性 多种甲病毒（CHIKV、EEEV 和 VEEV）。由于我们的目标是识别具有广泛活性的化合物，因此 化合物还将针对其他甲病毒（例如 RRV、MAYV、ONNV、WEEV 和 SINV）进行测试 以及我们计划中的其他病毒，包括冠状病毒（项目 1 和 2）、黄病毒（项目 4）和丝状病毒 （项目 5）。我们还将与 Enzymology Core D 合作，以确定其抗病毒作用机制。带领 将使用我们的方法测试具有最佳体内生物分布和稳定性的化合物的体内抗病毒功效 建立了甲病毒诱导的关节炎（CHIKV）或脑炎（VEEV 或 EEEV）模型。候选人有 有效的体内抗病毒功效将在配方、毒性和先进的 PK/PD 方面得到进一步优化。