In vivo virology core

核心7：体内病毒学 总结 SARS-CoV-2在目前的大流行中继续导致严重的发病率和死亡率，未来的RNA病毒 流行病或大流行是不可避免的。为了降低患者死亡率，开发抗病毒药物 治疗是关键。然而，目前可用的SARS-CoV-2抗病毒治疗的疗效有限。 此外，我们必须获得一个针对所有RNA病毒的化合物库， 在未来大流行的最早阶段， 这将挽救数百万人的生命，并减少与疾病有关的长期残疾。 QCRG流行病应对计划的目标是确定和开发口服药物 具有合适的安全性特征的候选人，可广泛用于门诊。体内病毒学核心发挥作用 在QCRG药物发现平台中的命中到铅和铅优化阶段发挥重要作用， 与项目1-6和体外病毒学和药物化学核心密切相关。我们的目标是确定 抗病毒药物对冠状病毒、黄病毒、披膜病毒、小核糖核酸病毒的治疗效果 和布尼亚病毒目在病毒感染的晚期动物模型中的作用。 我们已经组建了一个研究团队，他们在先进的动物模型方面拥有数十年的经验， 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化合物， 动物模型采用最大耐受剂量的单浓度预防性治疗。的化合物 显示出体外抗病毒活性（由体外病毒学核心建立），并具有良好的 将检测体内PK和毒性特征（药物化学核心）抑制病毒复制的能力 以及用冠状病毒、黄病毒、肠道病毒、披膜病毒和布尼亚病毒攻击的小鼠的疾病。 对于在单剂量治疗中具有体内抗病毒活性的化合物，我们将确定剂量反应、时间和剂量效应。 攻毒后给药的治疗活性，以及对多种菌株的活性谱， 病毒（目标1）。我们预计将确定8-12或8-10种冠状病毒和其他大流行性疾病的先导化合物- 潜在的RNA病毒。接下来，在目标2中，我们将确定抗病毒药物的耐药模式和适应性。 此外，体外鉴定的有益化合物组合（体外病毒学核心）将 在适当的动物模型中进行药物组合研究，包括已知的病毒抑制剂和 对方.我们期望成为抗病毒药物开发的关键组成部分，并期望与项目合作。 和核心，以获得3-6个优化的电极导线，这些电极导线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.