In vivo virology core

核心7：体内病毒学 摘要 SARS-CoV-2在当前的大流行中继续造成严重的发病率和死亡率，以及未来的RNA病毒 流行病或大流行是不可避免的。为提高患者死亡率，开发抗病毒药物 治疗是至关重要的。然而，目前可用的SARS-CoV-2抗病毒治疗效果有限。 此外，当务之急是我们有权获得对抗所有核糖核酸病毒的化合物。 大流行潜力准备在未来大流行的最早阶段部署到临床试验中，以挽救 减少数百万人的生命，减少与疾病相关的长期残疾。 QCRG大流行应对计划的目标是确定和开发口服药物 具有适合在门诊环境中广泛使用的安全配置文件的候选人。体内病毒学的核心作用 在Hit-to-Lead和Lead优化阶段在QCRG药物发现平台中发挥重要作用，工作 与项目1-6以及体外病毒学和药物化学核心密切合作。我们的目标是确定 抗病毒药物对冠状病毒、黄病毒、冠状病毒、小核糖核酸病毒的治疗效果 和布尼亚病毒属在病毒感染的高级动物模型中。 我们已经组建了一支在高级动物模型方面拥有数十年经验的研究团队 针对目标病毒家族的抗病毒对策分析。我们将首先分析命中的化合物 动物模型采用单一浓度预防性治疗最大耐受量。一种化合物 在体外显示抗病毒活性(由体外病毒学核心建立)，并具有良好的 PK和体内毒性(药物化学核心)，将测试它们抑制病毒复制的能力 以及用冠状病毒、黄病毒、肠道病毒、托加病毒和布尼亚病毒挑战的小鼠的疾病。 对于体内具有抗病毒活性的化合物，我们将确定单次给药的剂量反应、时间 给药后对治疗活性的挑战，以及对多种菌株和 病毒(目标1)。我们预计将确定冠状病毒和其他大流行的8-12或8-10先导化合物- 分别是潜在的RNA病毒。接下来，在目标2中，我们将确定抗病毒耐药性模式和适合度 抗药性突变此外，在体外(体外病毒学核心)确定的有益化合物组合，将 在适当的动物模型中进行药物组合研究，既有已知的病毒抑制剂，也有 彼此之间。我们预计将成为抗病毒开发的关键组件，并希望与项目迭代 和核心，以获得3-6个优化的线索，这些线索将转移到我们的行业合作伙伴罗氏进行临床 发展。

CORE 7: IN VIVO VIROLOGY SUMMARY SARS-CoV-2 continues to cause severe morbidity and mortality in the current pandemic, and future RNA virus epidemics or pandemics are inevitable. To improve patient mortality rates, the development of antiviral therapeutics is critical. However, currently available SARS-CoV-2 antiviral treatments are limited in efficacy. Furthermore, it is imperative that we have access to an arsenal of compounds against all RNA viruses of pandemic potential ready to be deployed into clinical trials at the earliest stages of future pandemics to save millions of lives and reduce long-term disabilities associated with disease. The goal of the QCRG Pandemic Response Program is the identification and development of oral drug candidates with suitable safety profiles for broad use in the outpatient setting. The In Vivo Virology Core plays an essential role in the QCRG Drug Discovery Platform in the Hit-to-Lead and Lead Optimization stages, working closely with Projects 1-6 and the In Vitro Virology and Medicinal Chemistry Cores. Our goal is to determine the therapeutic efficacy of antiviral hits and leads against coronaviruses, flaviviruses, togaviruses, picornaviruses and Bunyavirales in advanced animal models of viral infection. We have assembled a team of investigators with decades of experience in advanced animal models for the analysis of antiviral countermeasures against the target viral families. We will first analyze hit compounds in animal models using single concentration prophylactic treatment of maximal tolerated dose. Compounds that show antiviral activity against viruses in vitro (established by the In Vitro Virology core) and have a favorable PK and toxicity profile in vivo (Medicinal Chemistry Core), will be tested for their ability to inhibit viral replication and disease in mice challenged with coronaviruses, flaviviruses, enteroviruses, togaviruses, and bunyaviruses. For compounds with antiviral activity in vivo in single-dose treatments, we will determine dose responses, time of administration post-challenge for therapeutic activity, and spectrum of activity against multiple strains and viruses (Aim 1). We expect to identify 8-12 or 8-10 Lead Compounds for coronaviruses and other pandemic- potential RNA viruses, respectively. Next, in Aim 2, we will determine antiviral resistance patterns and fitness of resistant mutantsIn addition, beneficial compound combinations identified in vitro (In Vitro Virology Core), will be tested in drug combinations studies in the appropriate animal model, both with known virus inhibitors and with each other. We anticipate being a key component for antiviral development and expect to iterate with Projects and Cores to obtain 3-6 Optimized Leads that will be transferred to our industry partner Roche for clinical development.