| Autor: |
Miao-Miao Zhao, Yun Zhu, Li Zhang, Gongxun Zhong, Linhua Tai, Shuo Liu, Guoliang Yin, Jing Lu, Qiong He, Ming-Jia Li, Ru-Xuan Zhao, Hao Wang, Weijin Huang, Changfa Fan, Lei Shuai, Zhiyuan Wen, Chong Wang, Xijun He, Qiuluan Chen, Banghui Liu, Xiaoli Xiong, Zhigao Bu, Youchun Wang, Fei Sun, Jin-Kui Yang |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Cell discovery. 8(1) |
| ISSN: |
2056-5968 |
| Popis: |
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence of variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered that the S protein contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 and CS-2). Both sites are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed that CTSL cleavage promoted S to adopt receptor-binding domain (RBD) “up” activated conformations, facilitating receptor-binding and membrane fusion. We confirmed that CTSL cleavage is essential during infection of all emerged SARS-CoV-2 variants (including the recently emerged Omicron variant) by pseudovirus (PsV) infection experiment. Furthermore, we found CTSL-specific inhibitors not only blocked infection of PsV/live virus in cells but also reduced live virus infection of ex vivo lung tissues of both human donors and human ACE2-transgenic mice. Finally, we showed that two CTSL-specific inhibitors exhibited excellent In vivo effects to prevent live virus infection in human ACE2-transgenic mice. Our work demonstrated that inhibition of CTSL cleavage of SARS-CoV-2 S protein is a promising approach for the development of future mutation-resistant therapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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