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.
