Ensitrelvir as a potential treatment for COVID-19

First-generation therapeutics have improved clinical outcomes in patients infected with SARS-CoV-2. However, viral evolution has produced variants and subvariants capable of resisting many of these drugs and novel treatment strategies are urgently needed.A corporate compound library screen identified ensitrelvir (formerly S-217622), a non-covalent, non-peptidic, orally bioavailable small-molecule protease inhibitor as a potential treatment for SARS-CoV-2. Ensitrelvir cleaves the active site of the 3C-like protease (3CLpro), which is conserved across SARS-CoV-2 variants and subvariants, with no human cell protease with similar specificity.Ensitrelvir demonstrates strong in vitro antiviral activity against the SARS-CoV-2 Omicron subvariants BA.4 and BA.5, which have driven new waves of infection throughout 2022, suggesting a potential therapeutic option for patients with COVID-19. This manuscript reviews what is known about ensitrelvir and explores how this drug may be used in the future to address the SARS-CoV-2 pandemic.