Ensitrelvir is an orally bioavailable inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), also known as 3C-like protease (3CLpro), with an IC50 value of 0.013 ?M.1 It is selective for Mpro over HIV-1 protease and the human proteases caspase-2, chymotrypsin, thrombin, and cathepsin B, -D, -G, and -L (IC50s = >100 ?M for all). Ensitrelvir reduces the cytopathic effects of SARS-CoV-2 clinical isolates, including Alpha, Beta, Gamma, Delta, and Omicron strains, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV), in Vero E6 cells expressing human transmembrane serine protease 2 (TMPRSS2; EC50s = 0.29-1.4 ?M). Oral administration of ensitrelvir decreases lung viral titers in a mouse model of SARS-CoV-2 Gamma variant infection when administered at doses ranging from 2 to 32 mg/kg at the time of, and 12 hours after, infection.
1.Unoh, Y., Uehara, S., Nakahara, K., et al.Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19J. Med. Chem.65(9)6499-6512(2022)