Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

SUMMARYTo discover new drugs to combat coronavirus disease 2019 (COVID-19), an understanding of the molecular basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated and was positively correlated with disease course and severity in COVID-19 patients. Correspondingly, SARS-CoV-2 pseudovirus infection increasedCTSLexpression in human cell lines and humanACE2transgenic mice, whileCTSLoverexpression, in turn, enhanced pseudovirus infection. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdownin vitroand application of CTSL inhibitor drugsin vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity and prevented SARS-CoV-2 pseudovirus infection. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.