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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

By Miao-Miao Zhao, Wei-Li Yang, Fang-Yuan Yang, Li Zhang, Weijin Huang, Wei Hou, Changfa Fan, Ronghua Jin, Yingmei Feng, Youchun Wang, Jinkui Yang

Posted 27 Oct 2020
medRxiv DOI: 10.1101/2020.10.25.20218990

To 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 increased CTSL expression in human cell lines and human ACE2 transgenic mice, while CTSL overexpression, in turn, enhanced pseudovirus infection. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in 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.

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