Core E – Structural Biology

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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.