In a recent preprint reported by Frueh et al., an orally available CTSL inhibitor K777 exhibited anti-viral ability and efficiently reduced COVID-19-related pulmonary pathology in African green monkeys.183 Despite these achievements, the ubiquitous expression of CTSL raises concern about the side effects of CTSL inhibitors.184 Combined use of a CTSL inhibitor and other protease inhibitors or development of a CTSL inhibitor with multiple functions might be effective in preventing viral infection at a lower dose and in reducing side effects. This evidence concerns the gene CTSL and COVID-19.