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.

抽象的 核心 1（病毒学） MAVDA 病毒学核心（MVC；核心 1）的建立是为了提供基于细胞的感染检测 评估针对一系列基本病毒酶活性的命中化合物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人员密切合作 将在易受 SARS 影响的细胞中对命中和先导抗病毒化合物进行早期剂量反应研究 CoV-2 和相关冠状病毒。 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流程至关重要，并将提供信息 集中迭代努力优化有前途的化合物，并为做出继续/不继续决策奠定基础 使用相关的体内模型将有前途的化合物推进机械和动物研究 新冠肺炎。 MVC 还具有选择和识别耐药病毒变体的附加功能， 可能会进一步告知先导化合物的作用模式，以及最大限度地提高抗药性障碍的努力 病毒逃避治疗。筛选具有大流行重要性的其他病毒（包括甲病毒）的能力 和黄病毒，也将提供给项目团队。 MVC 将是一个单一实体，由 Charles M. Rice（洛克菲勒大学；RU）、Stephen P. Goff 和 Yosef Sabo（哥伦比亚大学医学中心；CUMC）以及 David S. Perlin（发现与研究中心） 创新，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RNA病毒家族的数十种病毒。 其所在机构的基础设施以及生物安全 2 级和 3 级优先级工作的监管支持 使用具有低到高通量能力的最先进技术的病原体将提供关键的第一关 并为 MAVDA 项目 1-6 开发的化合物提供后续临床前评估支持。这些努力 形成一个中心支柱，可以快速有效地评估项目团队确定的化合物 具有抗病毒效力和对多种病毒感染的潜在体内功效，同时最大限度地减少细胞毒性。