Animal and Organoid Model Core

总结 2019冠状病毒病（COVID-19），由严重急性呼吸道综合征冠状病毒2（SARS- CoV-2）在2019年底爆发为全球大流行，造成重大生命损失， 破坏和重大的长期医疗影响，其特征仍在描述中。当前COVID 19 大流行突出表明我们严重缺乏准备，尽管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，以平息发病率和死亡率相关的 感染变得明显。尽管加快了识别和推出抗病毒药物的步伐， 及时赶到诊所，防止了在美国观察到的大约70万人死亡， 在地球仪上有几百万个。此外，许多新出现和重新出现的病毒性疾病， 已经确定了一种可能性，它可能在未来带来与COVID 19相似或更高的发病率和死亡率 大流行事件。这一大流行突出表明，有必要提前做好准备， 为下一次爆发做准备因此，该提案的目标是确定新的直接作用的抗病毒药物。 动物和类器官模型核心（核心D）的广泛，长期目标是开发/使用 类器官和动物模型，用于测试项目1-6中产生的选定候选抗病毒化合物， U19申请动物和类器官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， 代谢、排泄和毒性（ADMET）/制剂核心（核心C），以确定、修改和配制 在动物模型中进行体内测试的候选命中。主要目标将是开发有效的，口服的 针对特定冠状病毒、黄病毒和布尼亚病毒靶标的生物可利用的直接作用抗病毒化合物 在这个提案中描述。

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.