tetano
Editor, Senior Moderator
Cell Discov
. 2022 Jun 6;8(1):53.
doi: 10.1038/s41421-022-00419-w.
Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies
Miao-Miao Zhao[SUP] #[/SUP][SUP] 1 [/SUP], Yun Zhu[SUP] #[/SUP][SUP] 2 [/SUP], Li Zhang[SUP] #[/SUP][SUP] 3 [/SUP], Gongxun Zhong[SUP] #[/SUP][SUP] 4 5 [/SUP], Linhua Tai[SUP] 2 6 [/SUP], Shuo Liu[SUP] 3 [/SUP], Guoliang Yin[SUP] 2 6 [/SUP], Jing Lu[SUP] 1 [/SUP], Qiong He[SUP] 1 [/SUP], Ming-Jia Li[SUP] 1 [/SUP], Ru-Xuan Zhao[SUP] 1 [/SUP], Hao Wang[SUP] 1 [/SUP], Weijin Huang[SUP] 3 [/SUP], Changfa Fan[SUP] 7 [/SUP], Lei Shuai[SUP] 4 5 [/SUP], Zhiyuan Wen[SUP] 4 5 [/SUP], Chong Wang[SUP] 4 [/SUP], Xijun He[SUP] 4 5 [/SUP], Qiuluan Chen[SUP] 8 9 [/SUP], Banghui Liu[SUP] 8 9 [/SUP], Xiaoli Xiong[SUP] 8 9 [/SUP], Zhigao Bu[SUP] 10 11 [/SUP], Youchun Wang[SUP] 12 [/SUP], Fei Sun[SUP] 13 14 15 16 [/SUP], Jin-Kui Yang[SUP] 17 [/SUP]
Affiliations
Abstract
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.
. 2022 Jun 6;8(1):53.
doi: 10.1038/s41421-022-00419-w.
Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies
Miao-Miao Zhao[SUP] #[/SUP][SUP] 1 [/SUP], Yun Zhu[SUP] #[/SUP][SUP] 2 [/SUP], Li Zhang[SUP] #[/SUP][SUP] 3 [/SUP], Gongxun Zhong[SUP] #[/SUP][SUP] 4 5 [/SUP], Linhua Tai[SUP] 2 6 [/SUP], Shuo Liu[SUP] 3 [/SUP], Guoliang Yin[SUP] 2 6 [/SUP], Jing Lu[SUP] 1 [/SUP], Qiong He[SUP] 1 [/SUP], Ming-Jia Li[SUP] 1 [/SUP], Ru-Xuan Zhao[SUP] 1 [/SUP], Hao Wang[SUP] 1 [/SUP], Weijin Huang[SUP] 3 [/SUP], Changfa Fan[SUP] 7 [/SUP], Lei Shuai[SUP] 4 5 [/SUP], Zhiyuan Wen[SUP] 4 5 [/SUP], Chong Wang[SUP] 4 [/SUP], Xijun He[SUP] 4 5 [/SUP], Qiuluan Chen[SUP] 8 9 [/SUP], Banghui Liu[SUP] 8 9 [/SUP], Xiaoli Xiong[SUP] 8 9 [/SUP], Zhigao Bu[SUP] 10 11 [/SUP], Youchun Wang[SUP] 12 [/SUP], Fei Sun[SUP] 13 14 15 16 [/SUP], Jin-Kui Yang[SUP] 17 [/SUP]
Affiliations
- PMID: 35668062
- DOI: 10.1038/s41421-022-00419-w
Abstract
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.