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

Miao-Miao Zhao,Wei-Jin Huang,Jin-Kui Yang,Ying-Mei Feng,Chang-Fa Fan,Fang-Yuan Yang,Li Zhang,Wei Hou,Wei-Li Yang,You-Chun Wang,Rong-Hua Jin

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.

Highlights

The recent outbreak of novel coronavirus (SARS-CoV-2) disease (COVID-19) has imposed a severe public health burden worldwide.To prevent and treat this disease, effective methods, such as vaccines and drugs, are urgently needed
cathepsin L (CTSL) and CTSL/cathepsin B (CTSB) increased in COVID-19 patients than to SARS-2-S-driven entry, we compared several human cell lines, in healthy individuals, and in severe patients than in nonsevere including human hepatoma cells (Huh7), human embryonic patients. These results indicated that CTSL or CTSL/CTSB were kidney cells (HEK293T), human lung adenocarcinoma cells associated with the SARS-CoV-2 infection
Huh[7] cells were infected with different range after discharge (Fig. 1f). These results indicated that CTSL doses of SARS-CoV-2 pseudovirus, as indicated by the luciferase was significantly associated with SARS-CoV-2 infection

Summary

Introduction

The recent outbreak of novel coronavirus (SARS-CoV-2) disease (COVID-19) has imposed a severe public health burden worldwide. To prevent and treat this disease, effective methods, such as vaccines and drugs, are urgently needed. Vaccination is underway in some countries, the impact of SARS-CoV-2 mutations and the degree of protection that a vaccine could have are some of the main issues under debate.[1] On the other hand, the drug is more convenient and acceptable to people. There is currently no efficient drug that can be used. The United States Food and Drug Administration (FDA) has approved remdesivir for the treatment of COVID-19 under an emergency use authorization. It is believed that remdesivir may be useful but not universally effective.[2] broadening the spectrum of therapeutic targets is important

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