2. Academic Validation
  3. 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

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

  • Signal Transduct Target Ther. 2021 Mar 27;6(1):134. doi: 10.1038/s41392-021-00558-8.
Miao-Miao Zhao  # 1,  Wei-Li Yang  # 1,  Fang-Yuan Yang  # 1,  Li Zhang  # 2,  Wei-Jin Huang 2,  Wei Hou 3,  Chang-Fa Fan 4,  Rong-Hua Jin 3,  Ying-Mei Feng 5,  You-Chun Wang 6,  Jin-Kui Yang 7
Affiliations

Affiliations

  • 1 Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
  • 2 Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, China.
  • 3 Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China.
  • 4 Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, China.
  • 5 Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China. [email protected].
  • 6 Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, China. [email protected].
  • 7 Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 33774649 DOI: 10.1038/s41392-021-00558-8
Abstract

To discover new drugs to combat COVID-19, an understanding of the molecular basis of 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 after SARS-CoV-2 Infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus Infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus Infection in human cells. 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 after SARS-CoV-2 pseudovirus Infection and prevented Infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

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