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 α病毒（togaviridae属）几种医学上重要的病毒，包括chikungunya病毒（Chikv）， 委内瑞拉马脑炎病毒（VEEV）和东马脑炎病毒（EEEV）。这些重新 由于其大流行，新兴病毒被归类为B和C优先病原体 风险或潜在的生物越威胁。尽管这些病毒构成了威胁，但没有批准的抗病毒药 用于治疗任何α病毒感染。因此，我们经验丰富且互动的团队将利用我们的 世界一流的α病毒生物学，结构生物学，高通量筛查，药物化学的专业知识， 和药物开发以产生针对保守病毒酶的小分子抑制剂的目标 产生新的，广泛的，直接作用的抗菌药物。这项工作的主要前提是 基于小分子的小分子抑制剂在α家族的多个成员中基本病毒蛋白的抑制剂可以 使用（a）整合目标识别和验证的平台开发（目标1），（b）确认 并优化针对给定靶标（AIM 2A）的细胞抗病毒活性和SAR，（c）建立和改进 体外ADME和体内药代动力学（AIM 2B），并且进展会导致体内功效和毒性 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的 α病毒酶（RNA依赖性RNA聚合酶（RDRP; NSP4），RNA）中的复合结合口袋 解旋酶（NSP2）和NSP2蛋白酶）。这些分析将为您选择的HIT发现靶标的选择 在与核心B协调中使用物理和硅筛进行筛选的组合。 可与药物化学核心（核心C）合作优化稳健的目标参与目标 抑制，稳定性，选择性，溶解度，渗透率，药代动力学和抗病毒活性在体外 多个α病毒（Chikv，Eeev和Veev）。因为我们的目标是识别广泛活跃的化合物，铅 化合物还将进行附加α病毒测试（例如RRV，Mayv，Onnv，Weev和Sinv） 以及我们程序中的其他病毒，包括冠状病毒（Proj。1和2），黄病毒（Proj。4）和丝状病毒 （Proj。5）。我们还将与酶学核心D合作，以确定其抗病毒作用机理。带领 使用我们的体内生物分布和稳定性的最佳化合物将使用我们 已建立的α病毒诱导关节炎（CHIKV）或脑炎（VEEV或EEEV）的模型。候选人 有效的体内抗病毒疗效将进一步优化用于制剂，毒性和晚期PK/PD。