Animal and Organoid Model Core

动物和类器官模型核心

• 批准号: 10514322
• 负责人: John Ross Teijaro
• 金额: $ 365.76万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514322
• 关键词: 2019-nCoV; Animal Model; Animal Testing; Animals; Antiviral Agents; Arbovirus Infections; COVID-19; COVID-19 pandemic; Cavia; Cessation of life; Clinic; Coronavirus; Development; Disease Outbreaks; Drug Kinetics; Ebola virus; Economics; Environment; Event; Excretory function; Family; Ferrets; Flavivirus; Formulation; Future; Goals; Growth; In Vitro; Infection; Intravenous; Kinetics; Lead; Life; Medical; Medicine; Mesocricetus auratus; Metabolism; Middle East Respiratory Syndrome Coronavirus; Modality; Modeling; Morbidity - disease rate; Mus; Oral; Organoids; Orthobunyavirus; Pathogenicity; Pathologic; Pharmaceutical Chemistry; Physiological; Process; Property; Proteins; RNA; RNA Interference; Readiness; Route; SARS coronavirus; SARS-CoV-2 infection; Testing; Time; Toxic effect; United States; Vaccines; Variant; Viral; Virus; Virus Diseases; Work; absorption; aged; base; efficacy study; guinea pig model; hemorrhagic fever virus; in vivo; in vivo evaluation; inhibitor; intraperitoneal; mortality; mouse model; novel; pandemic disease; pandemic preparedness; prevent

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.

概括 冠状病毒疾病2019年（COVID-19），由严重的急性呼吸综合征冠状病毒2（SARS-- COV-2），在2019年底爆炸为全球大流行，导致了重大生命丧失，明显的经济 仍在表征的破坏和重大的长期医疗影响。当前的COVID19 大流行强调了我们严重缺乏准备，尽管有有效的疫苗 创纪录的时间，持续需要有效的抗病毒药物来平息与之相关的发病率和死亡率 感染变得明显。尽管加速了识别和提出抗病毒药物的推动力，但很少 及时到达了诊所，以防止在美国观察到的大约700,000人死亡和 全球数百万。此外，许多大流行的新兴和重新出现病毒疾病 已经确定了可能在未来带来与Covid19相似或过剩的发病率和过量死亡率的潜力 大流行事件。这种大流行凸显了有必要领先具有大流行潜力的病毒 对于下一次爆发。因此，该提案的目的是确定新颖的直接作用抗病毒药。 动物和器官模型核心（核心D）的广泛，远程目标是发展/采用 在项目1-6的项目1-6中生成的选定候选抗病毒化合物测试的器官和动物模型 此U19应用程序。动物和类器官模型核心将与项目负责人一起使用 （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）/配方核心（核心C）识别，修改和配方 候选人在动物模型中进行体内测试。主要目标是开发有效的口头 可生物利用的直接作用抗病毒化合物针对特定的冠状病毒，黄牛病毒和BUNYAVIRUS靶标 在此提案中描述。