Antiviral Efficacy and Resistance Core

抗病毒功效和耐药性核心

• 批准号: 10513869
• 负责人: John Damon Chodera
• 金额: $ 659.93万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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/10513869
• 关键词: Antiviral resistance; Structure; anti-viral efficacy

SARS-CoV-2 continues to cause severe morbidity and mortality in the current pandemic and future RNA virus pandemics are inevitable. Clinical-trial-ready antivirals are lacking for all RNA viruses of pandemic potential. It is imperative that the world have access to an arsenal of compounds ready to be deployed into clinical trials at the earliest stages of future pandemics. Beyond coronaviruses; flaviviruses and picornaviruses have caused frequent and ongoing epidemics around the world and there are currently no effective therapeutics available. These viral families have proven to be major threats to the human population and novel IND-ready therapeutics will be critical for our future pandemic preparedness. The ASAP AViDD Center is dedicated to the development of novel chemical matter with antiviral activity against these three viral families. The focus on targets refractory to antiviral resistance by Project 1: Antiviral Targeting to Suppress Drug Resistance and the Target Enabling Packages (TEPs) developed by Project 2: Target Enablement are highly innovative approaches that will allow the ASAP consortium to efficiently develop novel antivirals with the potential for sustained clinical success. The Antiviral Efficacy and Resistance Core plays an essential role in the ASAP Center, firstly as the primary site for in vitro screening and primary cell models, with support from Johan Neyts {KU Leuven) as a secondary in vitro screening laboratory. We will also perform comprehensive in vitro and in vivo antiviral resistance analysis and drug combination studies. Finally, we will work closely with Projects 1-6, the NIAID, and industry partners to select leads to move into in vivo analysis and determine the therapeutic efficacy of antiviral leads against these three viral families in advanced animal models of viral infection. We have assembled a team of investigators in our core with decades of experience in cell culture and advanced animal models for the analysis of antiviral countermeasures against the target viral families. A major goal of the ASAP Center is the identification and development of 3 oral antiviral drug candidates with suitable safety profiles for broad use in the outpatient setting. We have placed an emphasis on the identification of novel antiviral targets using advanced resistance-refractory target selection, Al-based fragment-based screening, structural enablement of these targets, and a comprehensive efficacy and resistance analysis. The Antiviral Efficacy and Resistance Core will be integrated into the ASAP platform by working with the consortium, the NIAID, and industry partners to select 45-50 of our top antiviral leads to test in our advanced animal models of viral infection. We will then advance up to 15 advanced leads into comprehensive in vivo efficacy analysis, and finally select 3 leads to move into in vivo resistance mutation analysis and drug combination studies using well-established methods in our laboratories. Project Summary/

SARS-CoV-2继续在当前大流行和未来的RNA病毒中造成严重的发病率和死亡率 大流行是不可避免的。所有具有大流行潜力的RNA病毒都缺乏可用于临床试验的抗病毒药物。它 当务之急是让世界能够获得一批准备部署到临床试验中的化合物 未来大流行的早期阶段。除了冠状病毒；黄病毒和小核糖核酸病毒也引起了 世界各地频繁和持续的流行病，目前还没有有效的治疗方法。 这些病毒家族已被证明是对人类人口的主要威胁和新的IND就绪 治疗将对我们未来的大流行防备至关重要。 ASAP AViDD中心致力于开发具有抗病毒活性的新化学物质 针对这三个病毒家族。项目一：抗病毒药物耐药靶点的重点 抑制耐药性的目标和由项目2开发的目标使能包(TEP)： Target Enablement是高度创新的方法，将使ASAP财团能够高效地开发 具有持续临床成功潜力的新型抗病毒药物。抗病毒疗效和耐药核心 在ASAP中心起着至关重要的作用，首先是作为体外筛选和原代细胞的主要场所 模型，在Johan Neyts(KU鲁汶)的支持下作为二次体外筛选实验室。我们还将 进行全面的体外和体内抗病毒耐药性分析和药物联合研究。最后， 我们将与项目1-6、NIAID和行业合作伙伴密切合作，选择进入体内的线索 抗病毒药物对这三个病毒家族晚期疗效的分析与判定 病毒感染的动物模型。我们已经在我们的核心组建了一支调查团队，拥有数十年的 在细胞培养和先进动物模型分析抗病毒对策方面的经验 目标病毒家庭。 ASAP中心的一个主要目标是确定和开发3种口服抗病毒药物候选药物 适合在门诊环境中广泛使用的安全配置文件。我们把重点放在了 基于铝基的新型抗病毒靶向筛选技术 基于片段的筛查，这些靶点的结构使能，以及全面的疗效和 阻力分析。抗病毒功效和耐药性核心将通过以下方式整合到ASAP平台 与财团、NIAID和行业合作伙伴合作，选择45-50条我们的顶级抗病毒药物进行测试 我们先进的病毒感染动物模型。然后我们将把最多15个高级线索推进到 综合体内疗效分析，最终选择3个先导进入体内耐药突变 使用我们实验室中成熟的方法进行分析和药物组合研究。 项目总结/