Polymerase Inhibitors of Respiratory Syncytial Virus

呼吸道合胞病毒聚合酶抑制剂

• 批准号: 10666509
• 负责人: Richard K. Plemper
• 金额: $ 68.94万
• 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/10666509
• 关键词: 3-Dimensional; 5 year old; Address; Adherence; Adult; Advanced Development; Age; Air; Anabolism; Animal Model; Antibody Therapy; Antiviral Agents; Biochemical; Biological Assay; Biological Availability; 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; Eligibility Determination; 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; Molecular Conformation; 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; Seasons; 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; clinical candidate; congenital heart disorder; cytotoxicity; deep sequencing; design; disorder control; drug discovery; experience; high risk; high throughput screening; human tissue; immunoprophylaxis; improved; in vivo; indexing; inhibitor; 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; risk mitigation; scaffold; 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）是婴儿住院的主要原因。 美国。在季节性流行期间，定期重新感染成年人可以在整个生命中发生，但可以 对老年人和免疫功能受损的威胁生命。尽管进行了广泛的研究，但没有 提供疫苗保护，目前基于抗体疗法的免疫预防仍保留 高危患者。认识到对有效，适用和耐受性良好的RSV的未满足的临床需求 治疗学，该项目的目标是追求严格的临床前表征和降级风险 我们在以前的工作中确定的两个口头有效的RSV聚合酶抑制剂类别的程序 和试点研究。 拥有开创性的RSV报告病毒技术，并完成了大规模的高通量抗RSV 药物筛查运动，我们已经确定了两个结构和机械上不同的命中型，这两者都 抑制RSV RNA依赖性RNA聚合酶（RDRP）复合物，一种新型的尿苷核糖核苷类似物和 RDRP介导的RNA合成在启动子上的非竞争性抑制剂。当前的潜在客户显示 针对RSV报告菌株和临床分离株，纳摩尔抑制浓度的有效活性 与疾病相关的良好分化的原发性人类气道上皮培养物，良好的药代动力学（PK） 具有持续的血浆浓度和良好初步耐受性的曲线。试点研究已经建立 在RSV感染的小鼠模型中口服功效的概念证明，减少肺部病毒负荷和标志 RSV支气管炎的临床体征。该项目将在两种方面追求RSV聚合酶目标 策略，同时开发底物 - 分析和非竞争性抑制剂类别 减轻早期失败的风险或为将来用作伴侣药物的实验基础。 最初的方法将分别量身定制为任何一个系列，旨在识别和解决潜力 在此过程的早期，班级特定的负债。核糖核苷模拟铅已显示出持续的组织 活性三磷酸形式的浓度和对口服抗RSV疗效进行消毒。准备正式 发展，该类将受到动作表征的机理，抵抗分析 RSV靶标和脱靶效应的评估（AIM 1）。第一代非竞争抑制剂铅 已经成功地抗性，细胞毒性和机制，但必须经受最终结构 以及QSAR引导的效力和PK特性的合成优化，以发现其全部抗病毒电位（AIM 2）。新兴级别的确认潜在客户将使用RSV感染的小鼠模型去危险， 将评估具有化合物经验的RSV种群的发病机理，PK曲线与与 在原发性人类气道上皮培养物中的表现，以告知模拟生理影响的影响 相关人体组织模型中抗病毒功效和安全边缘的动态药物浓度（AIM 3）。

项目成果

4'-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication.

• DOI: 10.1126/science.abj5508
• 发表时间: 2022-01-14
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Sourimant, Julien;Lieber, Carolin M.;Aggarwal, Megha;Cox, Robert M.;Wolf, Josef D.;Yoon, Jeong-Joong;Toots, Mart;Ye, Chengin;Sticher, Zachary;Kolykhalov, Alexander A.;Martinez-Sobrido, Luis;Bluemling, Gregory R.;Natchus, Michael G.;Painter, George R.;Plemper, Richard K.
• 通讯作者: Plemper, Richard K.

Accelerated Discovery of Potent Fusion Inhibitors for Respiratory Syncytial Virus.

加速发现呼吸道合胞病毒的强效融合抑制剂。

• DOI: 10.1021/acsinfecdis.9b00524
• 发表时间: 2020
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Pribut,Nicole;Kaiser,ThomasM;Wilson,RobertJ;Jecs,Edgars;Dentmon,ZackeryW;Pelly,StephenC;Sharma,Savita;Bartsch3rd,PerryW;Burger,PieterB;Hwang,SoyonS;Le,Thalia;Sourimant,Julien;Yoon,Jeong-Joong;Plemper,RichardK;Liotta,D
• 通讯作者: Liotta,D

Small-molecule polymerase inhibitor protects non-human primates from measles and reduces shedding.

• DOI: 10.1038/s41467-021-25497-4
• 发表时间: 2021-09-02
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Wittwer K;Anderson DE;Pfeffermann K;Cox RM;Wolf JD;Santibanez S;Mankertz A;Plesker R;Sticher ZM;Kolkykhalov AA;Natchus MG;Pfaller CK;Plemper RK;von Messling V
• 通讯作者: von Messling V

Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets.

• DOI: 10.1038/s41564-020-00835-2
• 发表时间: 2021-01
• 期刊: Nature microbiology
• 影响因子: 28.3
• 作者: Cox RM;Wolf JD;Plemper RK
• 通讯作者: Plemper RK

Therapeutic targeting of measles virus polymerase with ERDRP-0519 suppresses all RNA synthesis activity.

• DOI: 10.1371/journal.ppat.1009371
• 发表时间: 2021-03
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Cox RM;Sourimant J;Govindarajan M;Natchus MG;Plemper RK
• 通讯作者: Plemper RK