3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV–infected mice

Optimized small-molecule 3C-like protease inhibitors show potency against human coronaviruses in both cell culture and a mouse model. Targeting coronavirus 3CLpro Coronavirus 3C-like proteases (3CLpro) are attractive therapeutic targets because they play a vital role in coronavirus replication. Rathnayake et al. now report a series of optimized coronavirus 3CLpro inhibitors that blocked replication of the human coronaviruses MERS-CoV and SARS-CoV-2 in cultured cells. Administration of a lead compound to a MERS-CoV mouse model demonstrated proof-of-concept efficacy. These findings suggest that this lead compound should be investigated further as a potential therapeutic for human coronavirus infection. Pathogenic coronaviruses are a major threat to global public health, as exemplified by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emerged SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). We describe herein the structure-guided optimization of a series of inhibitors of the coronavirus 3C-like protease (3CLpro), an enzyme essential for viral replication. The optimized compounds were effective against several human coronaviruses including MERS-CoV, SARS-CoV, and SARS-CoV-2 in an enzyme assay and in cell-based assays using Huh-7 and Vero E6 cell lines. Two selected compounds showed antiviral effects against SARS-CoV-2 in cultured primary human airway epithelial cells. In a mouse model of MERS-CoV infection, administration of a lead compound 1 day after virus infection increased survival from 0 to 100% and reduced lung viral titers and lung histopathology. These results suggest that this series of compounds has the potential to be developed further as antiviral drugs against human coronaviruses.