Core E – Structural Biology

项目摘要-核心E 迫切需要开发安全且高度有效的口服生物可用抗病毒药物。 对冠状病毒如SARS-CoV-2以及其他具有大流行的RNA病毒有效 潜力。有效的小分子抗病毒药物的开发可以通过彻底的 了解它们的生物物理结合常数、作用机制和结合的结构基础； 它将由核心E：蛋白质表达和结构生物学提供。这个核心将由Dr。 德克萨斯大学奥斯汀分校的杰森·麦克莱伦是结构病毒学和 开发针对病毒病原体的基于结构的干预措施。他的实验室在 病毒蛋白结构的测定，包括呼吸道合胞病毒(RSV)的第一结构 聚合酶复合体，以及在基于结构的设计和生物物理方面的丰富经验 蛋白质相互作用的表征。 反病毒对策开发中心(AC/DC)的核心E的主要任务是 确定研究项目确定的复合体中先导化合物的X-射线或低温电子显微镜结构 它们的病毒蛋白靶标。由此产生的原子级信息将被用于合理地设计或 优化硅胶中的先导化合物，以及确定分子作用机制。核心E也将 为需要高活性和高活性的研究项目提供蛋白质表达和纯化支持 用于化合物验证的纯蛋白质或新的筛选方法。此外，酷睿E将执行 测定铅的热力学和动力学结合常数的生物物理结合研究 通过等温滴定、量热法和表面等离子激元共振测定化合物。这些技术可以是 用于识别直接与目标蛋白结合的候选者，以及实现化合物优化 旨在改进特定的结合参数。总体而言，Core E提供的服务将 加快开发口服生物可用抗SARS-CoV-2和其他RNA病毒的药物 具有大流行的可能性，并提供了对结构、功能和抑制的新见解 重要的病毒蛋白。

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.