RAPID Collaborative Proposal: High-resolution structure determination of Coronavirus ligands by high-throughput WAXS

该奖项由生物基础设施部（DBI）使用冠状病毒援助，救济和经济安全（CARES）法案的资金进行。授予Hauptman-Woodward医学研究所的奖项支持了一种新策略的研究，该策略通过使用X射线散射技术产生溶液中蛋白质相互作用的结构信息并具有高通量。研究人员将利用他们的快速分析来了解对SARS-COV-2病毒复制至关重要的蛋白质如何在感染个体的细胞内发挥作用，以及这些蛋白质如何与潜在的治疗药物化合物相互作用。 高通量、快速命中检测和快速结构解决方案对于及时和积极应对这一流行病至关重要。 这些研究的结果将为我们理解SARS-COV-2生物学提供重要信息，并可能有助于为治疗方法的选择和开发提供信息。 来自代表性不足群体的学生也将通过BioXFEL学者计划参与这项活动，以帮助进行数据分析。 这些研究的数据将通过公开的数据库迅速传播，以便其他研究人员可以在自己的研究中利用实验结果。 该研究结果也将发表在同行评审的期刊上，并在科学会议上分享。该项目将使用小而宽散射X射线技术（SWAXS）来提供NSP 5蛋白酶和NSP 13解旋酶（以及潜在的NSP 15）的蛋白质-配体相互作用的结构信息的大型数据库，包括结合诱导的结构变化。 高通量SWAXS筛选方法在SARS-CoV-2蛋白中的成功应用将为研究SARS-CoV-2蛋白的分子间相互作用提供有价值的结构信息。 这些研究最初将集中在配体与主要病毒蛋白酶NSP 5的结合上，NSP 5负责释放编码在大的多蛋白序列中的各种蛋白质。 还将进行分析以研究NSP 13，一种已知与参与先天免疫反应的许多人类蛋白质相互作用的蛋白质。 寻找表面结合热点将提供潜在的结合界面以及初始的小分子支架的信息，未来的努力可以用来针对这些接口。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

This RAPID award is made by the Division of Biological Infrastructure (DBI) using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act. The award to Hauptman-Woodward Medical Research Institute supports research with a novel strategy that yields structural information on protein interactions in solution and with high-throughput by using x-ray scattering techniques. The researchers will use their rapid analyses to understand how proteins critical to SARS-COV-2 viral replication function within cells of infected individuals, and how these proteins interact with potential therapeutic drug compounds. High-throughput, rapid hit detection and fast structure solutions are essential for a timely and aggressive response to this pandemic. Results from these studies will contribute vital information to our understanding of SARS-COV-2 biology and may help to inform on the selection and development of therapeutic treatments. Students from under-represented groups will also participate in this activity through the BioXFEL Scholars program to help with data analysis. Data from these studies will be rapidly disseminated through publicly available repositories so that other researchers can leverage the experimental outcomes in their own studies. The study findings will also be published in peer-reviewed journals and shared at scientific meetings.This project will use small and wide-scattering X-ray techniques (SWAXS) to deliver a large database of structural information on protein-ligand interactions for the NSP5 protease and then NSP13 helicase (and potentially NSP15), including binding-induced structural changes. The successful application of high-throughput SWAXS screening approach to SARS-CoV-2 proteins will provide the community with valuable structural information on molecular interactions modulating viral function. These studies will focus initially on the ligand binding with the main viral protease, NSP5, responsible for the release of various proteins encoded in the large polyprotein sequence. Analyses will also be performed to investigate NSP13, a protein known to interact with many human proteins involved in the innate immune response. Finding surface binding hotspots will provide information on potential binding interfaces as well as initial small molecule scaffolds that future efforts can use to target these interfaces.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.