Polymerase Inhibitors of Respiratory Syncytial Virus

呼吸道合胞病毒聚合酶抑制剂

• 批准号: 10199980
• 负责人: Richard K. Plemper
• 金额: $ 78.08万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10199980
• 关键词: 3-Dimensional; 5 year old; Address; Adherence; Adult; Advanced Development; Age; Air; Anabolism; Animal Model; Antibody Therapy; Antiviral Agents; Bioavailable; Biochemical; Biological Assay; Bronchiolitis; Cell Culture Techniques; Cells; Child; Clinical; Communicable Diseases; Companions; Complex; Data; Development; Disease; Disease Management; Docking; Dose; Drug Kinetics; Drug Screening; Drug or chemical Tissue Distribution; Elderly; Ensure; Epidemic; Failure; Foundations; Future; Generations; Goals; Health; Heart; Hospitalization; Hour; Human; Immunocompromised Host; Individual; Infant; Infection; Lead; Life; Liquid substance; Lung; Measurement; Mediating; Mitochondria; Modeling; Molecular Conformation; Molecular Mechanisms of Action; Mus; Nuclear; Oral; Organoids; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Physiological; Pilot Projects; Plasma; Polymerase; Population; Preparation; Process; Program Development; Property; Quantitative Structure-Activity Relationship; RNA chemical synthesis; RNA-Directed RNA Polymerase; Reporter; Research; Resistance; Resistance profile; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Ribonucleosides; Risk; Safety; Series; Solid; Structure; Technology; Testing; Therapeutic; Time; Tissue Model; Tissues; Transcript; Triage; United States; Uridine; Vaccines; Validation; Viral; Viral Load result; Viral load measurement; Virus; Virus Diseases; Virus Inhibitors; Vulnerable Populations; Work; airway epithelium; analog; anti-viral efficacy; base; clinical candidate; congenital heart disorder; crosslink; cytotoxicity; deep sequencing; design; disorder control; drug discovery; experience; flu; high risk; high throughput screening; human tissue; immunoprophylaxis; improved; in vivo; indexing; inhibitor/antagonist; innovation; insight; medical attention; mouse model; nanomolar; novel; novel therapeutics; patient population; pediatric patients; personalized approach; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; premature; prevent; programs; promoter; respiratory; respiratory virus; scaffold; screening; serial imaging; simulation; tripolyphosphate

Summary Respiratory syncytial virus (RSV) is the primary cause of infant hospitalization from infectious diseases in the United States. Regular re-infection of adults can occur throughout life during seasonal epidemics, but can be life-threatening especially to the elderly and the immunocompromised. Despite extensive research, no vaccine protection is available and current antibody therapy-based immunoprophylaxis remains reserved for high-risk patients. Recognizing the unmet clinical need for efficacious, applicable, and well-tolerated RSV therapeutics, it is the goal of this project to pursue a rigorous preclinical characterization and de-risking program of two orally efficacious RSV polymerase inhibitor classes that we have identified in previous work and pilot studies. Having pioneered RSV reporter virus technology and completed large-scale high-throughput anti-RSV drug screening campaigns, we have identified two structurally and mechanistically distinct hit classes that both inhibit the RSV RNA-dependent RNA polymerase (RdRP) complex, a novel uridine ribonucleoside analog and a non-competitive inhibitor of initiation of RdRP-mediated RNA synthesis at the promoter. Current leads show potent activity against RSV reporter strains and clinical isolates, nanomolar inhibitory concentrations in disease-relevant well-differentiated primary human airway epithelia cultures, good pharmacokinetic (PK) profiles with sustained plasma concentrations, and good preliminary tolerability. Pilot studies have established proof-of-concept of oral efficacy in the mouse model of RSV infection, reducing lung viral load and hallmark clinical signs of RSV bronchiolitis. This project will pursue the RSV polymerase target in a two-pronged strategy, developing the substrate-analog and non-competitive inhibitor classes simultaneously to proactively mitigate the risk of early stage failure or lay the experimental foundation for future use as companion drugs. The initial approach will be tailored individually to either series, designed to identify and address potential class-specific liabilities early in the process. The ribonucleoside analog lead has shown sustained tissue concentrations of the active triphosphate form and sterilizing oral anti-RSV efficacy. In preparation of formal development, this class will be subjected to mechanism of action characterization, resistance profiling against the RSV target, and assessment of off-target effects (aim 1). The first-generation non-competitive inhibitor lead has been successfully resistance, cytotoxicity, and mechanism profiled, but must be subjected to final structure and QSAR-guided synthetic optimization of potency and PK properties to uncover its full antiviral potential (aim 2). Emerging confirmed leads of either class will be de-risked using the mouse model of RSV infection, pathogenesis of compound-experienced RSV populations will be assessed, and PK profiles correlated with performance in primary human airway epithelium cultures to inform simulations of the impact of physiological, dynamic drug concentrations on antiviral efficacy and safety margin in relevant human tissue models (aim 3).

概括 呼吸道合胞病毒（RSV）是婴儿因传染病住院的主要原因 美国。在季节性流行期间，成年人一生中可能会定期再次感染，但也可能 尤其对于老年人和免疫功能低下的人来说，可能会危及生命。尽管进行了大量研究，但没有 疫苗保护是可用的，目前基于抗体治疗的免疫预防仍然保留用于 高危患者。认识到对有效、适用且耐受性良好的 RSV 的临床需求尚未得到满足 疗法，该项目的目标是追求严格的临床前表征和去风险 我们在之前的工作中确定了两种口服有效的 RSV 聚合酶抑制剂类别的计划 和试点研究。 首创RSV报告病毒技术并完成大规模高通量抗RSV 药物筛选活动中，我们已经确定了两种结构和机制不同的命中类别， 抑制 RSV RNA 依赖性 RNA 聚合酶 (RdRP) 复合物，这是一种新型尿苷核糖核苷类似物， 启动子处 RdRP 介导的 RNA 合成起始的非竞争性抑制剂。当前线索显示 对 RSV 报告菌株和临床分离株具有有效活性，纳摩尔抑制浓度 疾病相关的分化良好的原代人气道上皮培养物，良好的药代动力学 (PK) 具有持续血浆浓度和良好的初步耐受性的特征。试点研究已经确定 RSV 感染小鼠模型中口服功效的概念验证，可降低肺部病毒载量和标志 RSV 细支气管炎的临床症状。该项目将双管齐下地追求 RSV 聚合酶目标 策略，同时开发底物类似物和非竞争性抑制剂类别，以主动 减轻早期失败的风险或为将来用作伴随药物奠定实验基础。 最初的方法将针对这两个系列单独定制，旨在识别和解决潜在的问题 在此过程的早期阶段特定类别的负债。核糖核苷类似物先导物已显示出持续的组织 活性三磷酸盐形式的浓度和灭菌口服抗 RSV 功效。正式筹备中 开发过程中，此类药物将受到作用机制表征、耐药性分析 RSV 目标，以及脱靶效应评估（目标 1）。第一代非竞争性抑制剂先导 已成功地对耐药性、细胞毒性和机制进行了分析，但必须接受最终结构 和 QSAR 引导的效力和 PK 特性的综合优化，以揭示其全部抗病毒潜力（目标 2）。使用 RSV 感染小鼠模型可以降低任一类新出现的已确认线索的风险， 将评估经历过化合物的 RSV 群体的发病机制，以及与 原代人类气道上皮培养物的表现，以模拟生理、 相关人体组织模型中抗病毒功效和安全裕度的动态药物浓度（目标 3）。