Core E – Structural Biology

核心 E — 结构生物学

• 批准号: 10513940
• 负责人: Jason Scott McLellan
• 金额: $ 169.98万
• 依托单位: EMORY UNIVERSITY
• 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/10513940
• 关键词: 2019-nCoV; Address; Affinity; Amino Acids; Antiviral Agents; Area; Binding; Biological Assay; Biophysics; COVID-19 pandemic; Calorimetry; Collection; Complex; Consult; Coronavirus; Cryoelectron Microscopy; Crystallization; Data; Data Set; Development; Drops; Drug Design; Electron Microscope; Electrons; Entropy; Formulation; Image; Insecta; Intervention; Kinetics; Knowledge; Laboratories; Lead; Mammalian Cell; Mission; Molecular Conformation; Molecular Mechanisms of Action; Oral; Pharmaceutical Preparations; Plasmids; Polymerase; Process; Production; Property; Protein Engineering; Proteins; RNA Viruses; Research Personnel; Research Project Grants; Resistance; Resolution; Respiratory syncytial virus; Roentgen Rays; SARS coronavirus; Services; Structure; Surface; Surface Plasmon Resonance; Techniques; Texas; Thermodynamics; Titrations; Universities; Validation; Variant; Viral Proteins; Work; X-Ray Crystallography; austin; base; biophysical properties; biophysical techniques; design; detector; drug development; experience; flexibility; improved; in silico; inhibitor; insight; instrument; lead optimization; novel; pandemic disease; particle; pathogenic virus; protein expression; protein purification; protein structure; rational design; screening; small molecule; structural biology; synchrotron radiation; virology

Project Summary – Core E There is an urgent need for the development of orally bioavailable antivirals that are safe and highly efficacious against coronaviruses such as SARS-CoV-2 as well as other RNA viruses with pandemic potential. The development of effective small-molecule antivirals can be greatly accelerated by a thorough understanding of their biophysical binding constants, mechanisms of action, and structural basis of binding, which will be provided by Core E: Protein Expression and Structural Biology. This core will be led by Dr. Jason McLellan at the University of Texas at Austin, who is an expert in structural virology and the development of structure-based interventions for viral pathogens. His laboratory has expertise in the determination of viral protein structures, including the first structure of the respiratory syncytial virus (RSV) polymerase complex, as well as extensive experience in structure-based design and biophysical characterization of protein interactions. The primary mission of Core E of the Antiviral Countermeasures Development Center (AC/DC) is to determine X-ray or cryo-EM structures of lead compounds identified by the Research Projects in complex with their viral protein targets. The resulting atomic-level information will be used to rationally design or optimize lead compounds in silico, as well as determine molecular mechanisms of action. Core E will also provide protein expression and purification support to Research Projects that need highly active and pure proteins for compound validation or novel screening approaches. Additionally, Core E will perform biophysical binding studies to determine thermodynamic and kinetic binding constants for lead compounds via isothermal titration calorimetry and surface plasmon resonance. These techniques can be used to identify candidates that bind directly to the target protein as well as enable compound optimization aimed at improving specific binding parameters. Collectively, the services provided by Core E will accelerate the development of orally bioavailable antivirals against SARS-CoV-2 and other RNA viruses with pandemic potential as well as provide novel insights into the structure, function, and inhibition of important viral proteins.

项目摘要 - 核心E 迫切需要开发安全且高度安全的生物利用抗病毒药 有效针对冠状病毒（例如SARS-COV-2）以及其他大流行的RNA病毒 潜在的。有效的小分子抗病毒药的发展可以通过直接加速 了解它们的生物物理结合常数，作用机理和结合的结构基础， 核心E将提供：蛋白质表达和结构生物学。该核心将由博士领导。 德克萨斯大学奥斯汀分校的杰森·麦克莱伦（Jason McLellan）是结构性病毒学专家和 开发基于结构的病毒病原体的干预措施。他的实验室在 病毒蛋白结构的测定，包括呼吸综合病毒（RSV）的第一个结构 聚合酶复合物以及基于结构设计和生物物理的丰富经验 蛋白质相互作用的表征。 抗病毒对策开发中心（AC/DC）的核心E的主要任务是 确定复杂研究项目确定的铅化合物的X射线或冷冻EM结构 及其病毒蛋白靶标。由此产生的原子级信息将用于合理设计或 优化有机硅中的铅化合物，并确定作用的分子机制。核心也会 为需要高度活跃的研究项目提供蛋白质表达和纯化支持，并且 用于复合验证或新型筛选方法的纯蛋白质。此外，核心E将执行 生物物理结合研究以确定铅的热力学和动力学结合常数 通过等温滴定量热法和表面等离子体共振的化合物。这些技术可以是 用于识别直接与靶蛋白结合的候选者以及启用化合物优化 旨在改善特定的结合参数。总体而言，核心E提供的服务将 加快针对SARS-COV-2和其他RNA病毒的口服生物利用抗病毒药的发展 具有大流行潜力，并提供了对结构，功能和抑制的新见解 重要的病毒蛋白。