Animal and Organoid Model Core

摘要 冠状病毒病2019年(新冠肺炎)，由严重急性呼吸综合征冠状病毒2号(SARS- CoV-2)在2019年底爆发为全球大流行，造成重大生命损失，宣布经济 中断和重大的长期医疗影响，目前仍在研究中。当前的COVID19 大流行突显了我们严重缺乏准备，尽管#年正在开发有效的疫苗 创纪录的时间，持续需要有效的抗病毒药物来平息与以下疾病有关的发病率和死亡率 感染变得很明显。尽管加快了识别和推出抗病毒药物的步伐，但几乎没有人 及时赶到诊所，防止了在美国观察到的大约70万人死亡， 全球有几百万人。此外，许多新出现和再次出现的病毒性疾病与大流行 已经确定了在未来可能带来与COVID19类似或更多的发病率和死亡率的可能性 大流行事件。这场大流行突显出有必要提前准备好具有大流行潜力的病毒。 为下一次疫情做准备。因此，这项提案的目标是确定新的、直接作用的抗病毒药物。 动物和有机体模型核心(核心D)的广泛、长期目标是开发/使用 用于测试项目1-6中产生的选定候选抗病毒化合物的有机和动物模型 这个U19应用程序。动物和有机体模型核心将与项目负责人合作 (项目1-6)、HTS核心(核心A)、药物化学核心(核心B)和吸收、分布、 新陈代谢、排泄和毒性(ADMET)/配方核心(核心C)以确定、修改和配方 在动物模型中进行体内测试的候选药物。主要目标将是开发有效的口服药物 针对冠状病毒、黄病毒和布尼亚病毒靶点的生物可用直接作用抗病毒化合物 本提案中所描述的。

SUMMARY Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), exploded into a global pandemic in late 2019 causing significant loss of life, pronounced economic disruption and major long-term medical impacts which are still being characterized. The current COVID19 pandemic highlighted our severe lack of preparedness and, despite an effective vaccine being developed in record time, the continued need for efficacious antiviral drugs to quell the morbidity and mortality associated with infection became evident. Despite an accelerated push to identify and bring forward anti-viral medicines, few made it to the clinic in time to prevent the approximately 700,000 deaths observed in the United States and several million across the globe. Moreover, many emerging and re-emerging viral diseases with pandemic potential have been identified which could bring similar or excess morbidity and mortality as COVID19 in a future pandemic event. This pandemic highlights the need to get ahead of viruses with pandemic potential to be ready for the next outbreak. As such, the goal of this proposal is to identify novel, direct-acting antivirals. The broad, long-range objectives of the Animal and Organoid Model Core (Core D) are to develop/employ organoid and animal models for testing of selected candidate anti-viral compounds generated in projects 1-6 of this U19 application. The Animal and Organoid Model Core will work in conjunction with the project leaders (projects 1-6), HTS core (Core A), medicinal chemistry core (Core B) and the absorption, distribution, metabolism, excretion and toxicity (ADMET)/formulation core (Core C) to identify, modify and formulate candidate hits for in vivo testing in the animal models. The primary goal will be the development of potent, orally bioavailable direct acting antiviral compounds against specific Coronavirus, Flavivirus and Bunyavirus targets described within this proposal.