Novel sites for Cathepsin L cleavage in SARS-CoV-2 spike guide treatment strategies
Abstract The spike (S) protein of SARS coronavirus 2 (SARS-CoV-2) is an ideal target for the development of specific vaccines or drugs. However, treatments targeting viruses with mutant S proteins that have recently emerged in many countries are limited. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered two novel sites (CS-1 and CS-2) in the S protein for cleavage by the protease Cathepsin L (CTSL). Both sites are highly conserved among all SARS-CoV-2 variants of concern. Cryo-electron microscopy structural studies revealed that CTSL cleavage increases the dynamics of the receptor binding domain of S and induces novel conformations. In our pseudovirus (PsV) infection experiment, alteration of the cleavage site significantly reduced the infection efficiency, and CTSL inhibitors markedly inhibited infection with PsVs of both the wild-type and emerged SARS-CoV-2 variants. Furthermore, six highly efficient CTSL inhibitors were found to effectively inhibit live virus infection in human cells in vitro, and two of these were further confirmed to prevent live virus infection in human ACE2 transgenic mice in vivo. Our work suggested that the CTSL cleavage sites in SARS-CoV-2 S are emerging new but effective targets for the development of mutation-resistant vaccines and drugs..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
ResearchSquare.com - (2022) vom: 29. Juli Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Jin-Kui [VerfasserIn] |
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| doi: |
10.21203/rs.3.rs-734963/v1 |
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| 520 | |a Abstract The spike (S) protein of SARS coronavirus 2 (SARS-CoV-2) is an ideal target for the development of specific vaccines or drugs. However, treatments targeting viruses with mutant S proteins that have recently emerged in many countries are limited. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered two novel sites (CS-1 and CS-2) in the S protein for cleavage by the protease Cathepsin L (CTSL). Both sites are highly conserved among all SARS-CoV-2 variants of concern. Cryo-electron microscopy structural studies revealed that CTSL cleavage increases the dynamics of the receptor binding domain of S and induces novel conformations. In our pseudovirus (PsV) infection experiment, alteration of the cleavage site significantly reduced the infection efficiency, and CTSL inhibitors markedly inhibited infection with PsVs of both the wild-type and emerged SARS-CoV-2 variants. Furthermore, six highly efficient CTSL inhibitors were found to effectively inhibit live virus infection in human cells in vitro, and two of these were further confirmed to prevent live virus infection in human ACE2 transgenic mice in vivo. Our work suggested that the CTSL cleavage sites in SARS-CoV-2 S are emerging new but effective targets for the development of mutation-resistant vaccines and drugs. | ||
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| 700 | 1 | |a Zhu, Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Gongxun |e verfasserin |4 aut | |
| 700 | 1 | |a Tai, Linhua |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shuo |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Guoliang |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Weijin |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Changfa |e verfasserin |4 aut | |
| 700 | 1 | |a Shuai, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Zhiyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chong |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xijun |e verfasserin |4 aut | |
| 700 | 1 | |a Bu, Zhigao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Youchun |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Fei |e verfasserin |4 aut | |
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