Midwest AViDD Center

中西部 AViDD 中心

• 批准号: 10522804
• 负责人: Reuben S Harris
• 金额: $ 6643.12万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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/10522804
• 关键词: 2019-nCoV; Address; Antiviral Agents; Arenavirus; Award; Back; Bolivian Hemorrhagic Fever Virus; COVID-19 pandemic; Cells; Cessation of life; Chemicals; Chemistry; Clinical; Collaborations; Communication; Computational Biology; Coronavirus; Country; DNA; Development; Digestion; Disease Outbreaks; Drug Targeting; Ebola virus; Education and Outreach; Educational workshop; Emergency Situation; Equilibrium; Family; Filovirus; Flaviviridae; Flavivirus; Fostering; Future; Goals; Infection prevention; International; Lassa virus; Lead; Mentors; Midwestern United States; National Institute of Allergy and Infectious Disease; Oral; Outcome; Peer Review; Peptide Hydrolases; Pharmaceutical Preparations; Process; Publications; RNA Helicase; RNA Viruses; Research; Research Personnel; SARS-CoV-2 pathogenesis; Services; Site; Specificity; Technology; Training; Training and Education; Viral; Viral Proteins; Virus; Virus Replication; Zika Virus; antiviral drug development; drug development; experience; helicase; high throughput screening; industry partner; inhibitor; innovation; meetings; multidisciplinary; nanobodies; next generation; novel; nuclease; outreach; pandemic disease; pathogen; prevent; programs; public education; research and development; response; screening; structural biology; symposium; virology; virtual screening

Overall – Midwest AViDD Center ABSTRACT The Midwest Anti-Viral Drug Development (AViDD) Center was formalized as a direct response to NIAID U19 RFA RFA-AI-21-050 “Emergency Awards: AViDD Centers for Pathogens of Pandemic Concern”. The Co- PIs of the Midwest AViDD Center are Reuben Harris and Fang Li, who have deep experience in functional and structural virology, respectively, and in leading multidisciplinary teams to successful outcomes. The majority of our center investigators were already working together in various capacities when this RFA was announced, and the RFA catalyzed the nucleation of our comprehensive multidisciplinary center focused on innovative antiviral drug development. The primary target of the Midwest AViDD Center is SARS-CoV-2 (SARS2), with all five Projects targeting essential viral processes (two for cell entry and projects for proteolytic cleavage, nucleolytic digestion, and RNA helicase activity). We purposely selected a balance of well-established antiviral drug targets (entry, protease), as well as less conventional targets with equally promising long-term potential (nuclease, helicase). All five Projects require integrated and highly collaborative support from five distinct service Cores for administration, screening, chemistry, structural and computational biology, and virology. A major strength of the Midwest AViDD Center is a 3-pronged screening approach [ultra-High Throughput Screening (uHTS), DNA- Encoded Chemistry Technology (DEC-Tec), and Virtual Screening (VS)] to maximize chemical space and obtain favorable starting points for antiviral drug development. Each Project will also pursue inhibitors of the same assigned target for an additional RNA virus of pandemic potential – the arenaviruses Lassa virus (LASV) and Machupo virus (MACV), the filovirus Ebola virus (EBOV), and the flavivirus Zika virus (ZIKV). Each Project therefore has a built-in capacity to assess inhibitor specificity throughout the course of drug development. Thus, the overall activities of the Midwest AViDD Center are organized into two specific aims. The first aim is dedicated to research and development, where our five Projects and five Cores leverage a combination of established and innovative approaches to develop novel, high potency, and orally available inhibitors of essential viral proteins required for pathogenesis of SARS2 and the other viruses with pandemic potential. The second is dedicated to interdisciplinary training, education, and outreach. Interdisciplinary training is vital for both addressing the current COVID-19 pandemic as well as for preparing for the next one. Education and outreach are also essential to achieve immediate and long-term impacts. Major deliverables will therefore be novel antiviral lead compounds for further development by industry partners and, equally important, a well-trained group of antiviral researchers including next generation experts and leaders. Both deliverables will have lasting, long-term impacts, hopefully contributing to ending the current pandemic and becoming better prepared for future viral outbreaks and stopping them before reaching pandemic levels.

总体-中西部AViDD中心 摘要 中西部抗病毒药物开发（AViDD）中心正式成立，作为对NIAID的直接回应 U19 RFA RFA-AI-21-050“紧急奖励：大流行病病原体的AViDD中心”。该公司- 中西部AViDD中心的PI是Reuben Harris和Fang Li，他们在功能和 结构病毒学，分别，并在领导多学科团队取得成功的结果。大多数 当RFA宣布时，我们中心的研究人员已经在以各种身份合作， RFA促进了我们的综合性多学科中心的形成，该中心专注于创新的抗病毒药物 药物开发中西部AViDD中心的主要目标是SARS-CoV-2（SARS 2），所有五个 针对基本病毒过程的项目（两个用于细胞进入的项目和蛋白水解裂解、溶核 消化和RNA解旋酶活性）。我们有目的地选择了一个平衡的完善的抗病毒药物的目标， （进入，蛋白酶），以及具有同样有前途的长期潜力的不太常规的靶（核酸酶， 解旋酶）。所有五个项目都需要来自五个不同服务核心的集成和高度协作的支持， 施用、筛选、化学、结构和计算生物学以及病毒学。一个主要的优势， 中西部AViDD中心是一个三管齐下的筛选方法[超高重复率筛选（uHTS），DNA- 编码化学技术（DEC-Tec）和虚拟筛选（VS）]，以最大限度地提高化学空间， 抗病毒药物开发的有利起点。每个项目还将寻求相同的抑制剂 为具有大流行潜力的另一种RNA病毒--沙粒病毒拉沙病毒（LASV）指定了靶标， 马丘波病毒（MACV）、丝状病毒埃博拉病毒（EBOV）和黄病毒寨卡病毒（ZIKV）。每个项目 因此，在整个药物开发过程中具有评估抑制剂特异性的内在能力。因此，在本发明中， 中西部AViDD中心的全部活动被组织成两个具体目标。第一个目标是 我们的五个项目和五个核心利用了现有的 和创新的方法来开发新的，高效的和口服的抑制剂， SARS 2和其他具有大流行潜力的病毒发病机制所需的蛋白质。二是 致力于跨学科的培训、教育和推广。跨学科培训对双方都至关重要 应对当前的COVID-19疫情以及为下一次疫情做准备。教育和外联 也是实现短期和长期影响的关键。因此，主要的可交付成果将是新型抗病毒药物 领先的化合物，供行业合作伙伴进一步开发，同样重要的是， 包括下一代专家和领导者在内的抗病毒研究人员。这两个可交付成果都将具有持久的、长期的 影响，希望有助于结束目前的大流行，并为未来的病毒传播做好更好的准备。 并在达到大流行水平之前加以阻止。