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 2019 年冠状病毒病 (COVID-19)，由严重急性呼吸系统综合症冠状病毒 2 (SARS- CoV-2）于 2019 年底爆发为全球大流行，造成重大生命损失，对经济造成显着影响 破坏和重大长期医疗影响仍在定性中。当前的新冠肺炎 大流行凸显了我们严重缺乏准备，尽管我们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降低与病毒相关的发病率和死亡率 感染变得明显。尽管加速推动抗病毒药物的识别和开发，但很少有人 及时到达诊所，避免了美国观察到的约 70 万人死亡， 全球有数百万人。此外，许多新出现和重新出现的大流行病毒性疾病 已确定未来可能带来与新冠病毒类似或过高的发病率和死亡率 流行病事件。这次大流行凸显了我们需要提前做好应对具有大流行潜力的病毒的准备 为下一次爆发。因此，该提案的目标是确定新型、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 用于测试项目 1-6 中产生的选定候选抗病毒化合物的类器官和动物模型 这个U19应用程序。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（Core A）、药物化学核心（Core B）以及吸收、分配、 代谢、排泄和毒性 (ADMET)/配方核心（核心 C），用于识别、修改和配制 在动物模型中进行体内测试的候选结果。主要目标是开发有效的口服药物 针对特定冠状病毒、黄病毒和布尼亚病毒目标的生物可利用的直接作用抗病毒化合物 本提案中进行了描述。