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，而未来的 RNA 病毒 流行病或流行病是不可避免的。为了降低患者死亡率，抗病毒药物的研发 治疗至关重要。然而，目前可用的 SARS-CoV-2 抗病毒治疗效果有限。 此外，我们必须获得针对所有 RNA 病毒的化合物库。 大流行的潜力已准备好在未来大流行的最早阶段部署到临床试验中，以拯救 数百万人的生命并减少与疾病相关的长期残疾。 QCRG 流行病应对计划的目标是识别和开发口服药物 具有适当安全性的候选者，可在门诊环境中广泛使用。体内病毒学核心 在 QCRG 药物发现平台的 Hit-to-Lead 和 Lead Optimization 阶段发挥着重要作用， 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、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高级动物模型中的应用。 我们组建了一支在先进动物模型方面拥有数十年经验的研究人员团队 针对目标病毒家族的抗病毒对策分析。我们将首先分析中的热门化合物 动物模型使用最大耐受剂量的单一浓度预防性治疗。化合物 在体外表现出抗病毒活性（由体外病毒学核心建立）并具有良好的 体内 PK 和毒性特征（药物化学核心）将测试其抑制病毒复制的能力 以及受到冠状病毒、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 攻击后的治疗活性和针对多种菌株的活性谱和 病毒（目标 1）。我们期望识别冠状病毒和其他流行病的 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测试，包括已知的病毒抑制剂和 彼此。我们预计成为抗病毒开发的关键组成部分，并期望与项目进行迭代 和核心以获得 3-6 个优化的先导化合物，这些先导化合物将转移给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.