CV19: SALSI: Approaches to Inhibit the Main Protease Enzyme from Coronavirus causing COVID-19

To develop therapeutic approaches for addressing the COVID-19 pandemic. this project brings together researchers with multidisciplinary and complementary expertise in theoretical and computational biophysics (PI Vashisth. UNH). biophysical chemistry and NMR spectroscopy (co-PI Varga. UNH). and small- molecule drug discovery (co-PI Doug E. Frantz. UTSA). The partnership and collaboration are timely and strategic in that the first experimental structure of the protease enzyme and its potential inhibitors have just been reported. Dr. Vashisth has taken the lead in beginning modeling studies of this enzyme while Dr. Varga has begun mapping out key structural components via high-resolution NMR. To initiate our drug discovery efforts. Dr. Frantz will synthesize several known small molecule inhibitors of SARS-CoV-2 protease enzyme (Mpro) that will be interrogated by NMR HSQC methods to understand the structural perturbations induced by binding and impact on enzymatic activity. The detailed structural biology data generated by these preliminary studies will then guide future medicinal chemistry efforts to discover and develop novel small molecule inhibitors of Mpro as potential treatments of COVID-19.