Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies
Chamandi S. Dampalla, Yunjeong Kim, Alexandria Zabiegala, Dennis J. Howard, Harry Nhat Nguyen, Trent K. Madden, Hayden A. Thurman, Anne Cooper, Lijun Liu, K.P. Battaile, Scott W. Lovell, Kyeong‐Ok Chang, William C. Groutas · Journal of Medicinal Chemistry · 2024
Zoonotic coronaviruses are known to produce severe infections in humans and have been the cause of significant morbidity and mortality worldwide. SARS-CoV-2 was the largest and latest contributor of fatal cases, even though MERS-CoV has the highest case-fatality ratio among zoonotic coronaviruses. These infections pose a high risk to public health worldwide warranting efforts for the expeditious discovery of antivirals. Hence, we hereby describe a novel series of inhibitors of coronavirus 3CL pro embodying an N -substituted 2-pyrrolidone scaffold envisaged to exploit favorable interactions with the S3–S4 subsites and connected to an invariant Leu-Gln P 2–P1 recognition element. Several inhibitors showed nanomolar antiviral activity in enzyme and cell-based assays, with no significant cytotoxicity. High-resolution crystal structures of inhibitors bound to the 3CL pro were determined to probe and identify the molecular determinants associated with binding, to inform the structure-guided optimization of the inhibitors, and to confirm the mechanism of action of the inhibitors.