Discovery, Optimization, and Evaluation of Non-Nucleoside SARS-CoV-2 NSP14 Inhibitors
Michael W. Miller, Cindy Meyer, Aitor Garzia, Hans-Heinrich Hoffmann, Tanweer A. Khan, Melissa S. Egbertson, Robert Walter Myers, Nigel J. Liverton, Stacia Kargman, J-A Davis, Oleg M. Ganichkin, Julius Nitsche, Stefan Steinbacher, Shlomi Dagan, Joseph Fraser Glickman, Charles M. Rice, Thomas Tuschl, Peter T. Meinke, David J. Huggins · Journal of Medicinal Chemistry · 2025
We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity. Thermal shift assay data and available crystal structures led us to develop a model of the novel inhibitory ternary complex (NSP14, SAH, inhibitor), which was validated with a crystal structure of the complex. The advances described here enabled a successful proof-of-concept study that validated SARS-CoV-2 NSP14 as a novel drug target for COVID-19 and represent the first demonstration of pharmacological inhibition of viral methyltransferases as a viable avenue for an antiviral therapeutic.