Virology Core

病毒学核心

• 批准号: 10513915
• 负责人: Charles M Rice
• 金额: $ 528.97万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 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/10513915
• 关键词: 2019-nCoV; Academic Medical Centers; Alphavirus; Animals; Antiviral Agents; Biological Assay; COVID-19; COVID-19 susceptibility; COVID-19 treatment; Catalogs; Cells; Collaborations; Coronavirus; Data; Development; Distant; Dose; Drug Kinetics; Effectiveness; Engineering; Ensure; Essential Drugs; Evaluation; Family; Flavivirus; Goals; Health; Infection; Infrastructure; Institution; Lead; Meridians; Methods; Outcome; Outcome Study; Pharmaceutical Chemistry; Pharmacology; Process; Prodrugs; RNA Viruses; Replicon; Reporter; Research Project Grants; Resistance; Rice; SARS-CoV-2 variant; Site; Standardization; System; Techniques; Therapeutic; Time; Toxic effect; Universities; Validation; Variant; Viral; Virion; Virus; Virus Diseases; base; cytotoxicity; drug discovery; effectiveness evaluation; flexibility; follow-up; in vivo; in vivo Model; innovation; insight; lead optimization; member; metropolitan; novel; pandemic coronavirus; pandemic disease; preclinical evaluation; priority pathogen; programs; response; screening; small molecule; structural biology; virology; virtual

Abstract Core 1 (Virology) The MAVDA Virology Core (MVC; Core 1) has been established to provide cell-based infection assays to evaluate the effectiveness of hit and lead compounds targeting a range of essential viral enzymatic activities as identified by MAVDA Project Leaders. Working in close collaboration with all Project Teams and Cores, the MVC will conduct early-stage dose-response studies of hit and lead antiviral compounds in cells susceptible to SARS- CoV-2 and related coronaviruses. The MVC will also determine cytotoxicity and predicted therapeutic windows for these compounds. The data provided by the MVC is essential for the drug discovery pipeline and will inform central iterative efforts to optimize promising compounds and form the basis for making go/no-go decisions for moving promising compounds forward into mechanistic and animal studies using relevant in vivo models of COVID-19. The MVC also has the added capability of selecting for and identifying resistant viral variants that may further inform modes of action for lead compounds, as well as efforts to maximize resistance barriers against viral escape from therapy. Capacity to screen additional viruses of pandemic importance, including alphaviruses and flaviviruses, will also be made available to Project Teams. The MVC will be a single entity headed by Charles M. Rice (The Rockefeller University; RU), Stephen P. Goff and Yosef Sabo (Columbia University Medical Center; CUMC) and David S. Perlin (Center for Discovery & Innovation, Hackensack Meridian Health; CDI-HMH). Their combined labs possess decades of expertise in developing and implementing cell-based assays using natural virus isolates and engineered reporter systems from dozens of viruses in the corona-, flavi-, paramyxo-, bunya-, toga-, filo-, and picorna- RNA virus families. The infrastructures of their host institutions and regulatory support for working with biosafety level 2 and 3 priority pathogens using state-of-the-art techniques with low to high-throughput capabilities will provide critical first pass and follow up pre-clinical evaluation support for compounds developed by MAVDA Projects 1-6. These efforts form a central pillar upon which compounds identified by Project teams can be rapidly and efficiently evaluated for antiviral potency and potential in vivo efficacy for a variety of viral infections while minimizing cellular toxicity.

摘要 核心1（病毒学） 已建立MAVDA病毒学核心（MVC;核心1），以提供基于细胞的感染测定， 评估靶向一系列基本病毒酶活性的hit和先导化合物的有效性， 由MAVDA项目负责人确定。MVC与所有项目团队和核心紧密合作， 将在对SARS敏感的细胞中进行早期剂量反应研究， CoV-2和相关的冠状病毒。MVC还将确定细胞毒性和预测的治疗窗口 对于这些化合物。MVC提供的数据对于药物发现管道至关重要， 中央迭代工作，以优化有前途的化合物，并形成基础，使去/不去的决定， 使用相关的体内模型，将有前途的化合物向前推进到机制和动物研究中， 2019冠状病毒病。MVC还具有选择和鉴定耐药病毒变体的附加能力， 可能进一步为先导化合物的作用方式提供信息，以及最大限度地提高耐药性障碍的努力。 病毒逃避治疗筛查包括甲病毒在内的其他大流行性病毒的能力 和黄病毒，也将提供给项目小组。 MVC将是由Charles M.领导的单一实体。Rice（The Rockefeller University; RU），Stephen P. Goff和Yosef Sabo（哥伦比亚大学医学中心; CUMC）和大卫S.柏林（Center for Discovery & Innovation，Hackensack Meridian Health; CDI-HMH）。他们的联合实验室拥有数十年的专业知识， 使用天然病毒分离物和工程报告系统开发和实施基于细胞的测定 来自冠状病毒、黄病毒、副粘病毒、布尼亚病毒、托加病毒、丝状病毒和小核糖核酸病毒科的几十种病毒。 东道机构的基础设施以及对生物安全2级和3级优先事项工作的监管支持 使用具有低到高通量能力的最新技术的病原体将提供关键的第一次通过 并为MAVDA项目1-6开发的化合物提供后续临床前评价支持。这些努力 形成一个中心支柱，在此基础上，可以快速有效地评估项目小组确定的化合物 对于各种病毒感染的抗病毒效力和潜在的体内功效，同时使细胞毒性最小化。