Diana Monteiro, PhD, and Thomas D. Grant, PhD, are studying how proteins critical to SARS-COV-2 viral replication function within cells of those infected.

Aiming to Better Understand the Biology of SARS-COV-2

Published January 13, 2021

Thomas D. Grant, PhD, assistant professor of structural biology, is co-principal investigator on a grant from the National Science Foundation (NSF) to study how small molecules bind to the SARS-COV-2 protease to understand drug binding and help aid drug design.

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The one-year, $200,000 grant is through the NSF’s Rapid Response Research (RAPID) funding mechanism which awards such grants quickly for emergency situations such as the current COVID-19 pandemic. 

The award was made by the Division of Biological Infrastructure, using funds from the Coronavirus Aid, Relief, and Economic Security Act.

Diana Monteiro, PhD, staff scientist at the Hauptman-Woodward Medical Research Institute, is principal investigator on the grant.

Novel Strategy Looks at Protein Interactions

The grant 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,” Grant says.

Grant and Monteiro are both affiliated with BioXFEL (Biology with X-ray Free Electron Lasers), a NSF Science and Technology Center composed of eight U.S. research universities that is headquartered at the University at Buffalo, and are collaborating with other groups in BioXFEL conducting further research on SARS-COV-2 with X-ray lasers supported by similar NSF RAPID awards.

Locating Surface Binding Hot Spots

“This project will use small and wide-angle X-ray scattering 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,” Grant says. “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.”

The 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 hot spots will provide information on potential binding interfaces as well as initial small molecule scaffolds that future efforts can use to target these interfaces, the researchers say.

Data from the 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.