GC376 is an inhibitor of 3C- and 3C-like proteases. It inhibits recombinant poliovirus, foot and mouth disease virus (FMDV), and human rhinovirus (HRV) 3C proteases (ICs = 1.77, 1.16, and 0.2 µM, respectively). GC376 also inhibits recombinant Norwalk virus, MD145 virus, transmissible gastroenteritis virus (TGEV), and severe acute respiratory syndrome coronavirus (SARS-CoV) 3C-like proteases (ICs = 0.49, 0.96, 0.82 and 4.35 µM, respectively). It reduces the cytopathic effect of SARS-CoV-2 in infected Vero E6 cells (EC = 3.37 µM). GC376 also reduces liver viral titers by 9.86- and 21.99-fold in a model of murine hepatitis virus (MHV A59) infection when administered at doses of 50 and 100 mg/kg per day, respectively.