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

该RAPID奖由生物基础设施部（DBI）使用《冠状病毒援助、救济和经济安全（CARES）法案》的资金颁发。该奖项授予Hauptman-Woodward医学研究所，以支持一种新策略的研究，该策略通过使用x射线散射技术获得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者的细胞内发挥作用，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、快速感染检测和快速结构解决方案对于及时和积极应对此次大流行至关重要。这些研究的结果将为我们了解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。来自弱势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可用的存储库迅速传播，以便其他研究人员可以在自己的研究中利用实验结果。研究结果也将发表在同行评议的期刊上，并在科学会议上分享。该项目将使用小散射和宽散射x射线技术（SWAXS）为NSP5蛋白酶和NSP13解旋酶（以及潜在的NSP15）提供蛋白质-配体相互作用的大型结构信息数据库，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，将为学界提供有关分子相互作用调节病毒功能的有价值的结构信息。这些研究将首先关注与主要病毒蛋白酶NSP5结合的配体，NSP5负责释放在大多蛋白序列中编码的各种蛋白质。研究人员还将对NSP13进行分析，NSP13是一种已知与许多参与先天免疫反应的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结合界面的信息，以及未来可用于靶向这些界面的初始小分子支架。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.