Prime editor‐mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS‐CoV‐2 variants
Abstract The spike protein of SARS‐CoV‐2 hijacks the host angiotensin converting enzyme 2 (ACE2) to meditate its entry and is the primary target for vaccine development. Nevertheless, SARS‐CoV‐2 keeps evolving and the latest Omicron subvariants BQ.1 and XBB have gained exceptional immune evasion pot...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-10-01
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| Series: | MedComm |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mco2.356 |
| _version_ | 1797659171172122624 |
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| author | Wenwen Zhao Jifang Li Xiao Wang Wei Xu Bao‐Qing Gao Jiangchao Xiang Yaofeng Hou Wei Liu Jing Wu Qilian Qi Jia Wei Xiaoyu Yang Lu Lu Li Yang Jia Chen Bei Yang |
| author_facet | Wenwen Zhao Jifang Li Xiao Wang Wei Xu Bao‐Qing Gao Jiangchao Xiang Yaofeng Hou Wei Liu Jing Wu Qilian Qi Jia Wei Xiaoyu Yang Lu Lu Li Yang Jia Chen Bei Yang |
| author_sort | Wenwen Zhao |
| collection | DOAJ |
| description | Abstract The spike protein of SARS‐CoV‐2 hijacks the host angiotensin converting enzyme 2 (ACE2) to meditate its entry and is the primary target for vaccine development. Nevertheless, SARS‐CoV‐2 keeps evolving and the latest Omicron subvariants BQ.1 and XBB have gained exceptional immune evasion potential through mutations in their spike proteins, leading to sharply reduced efficacy of current spike‐focused vaccines and therapeutics. Compared with the fast‐evolving spike protein, targeting host ACE2 offers an alternative antiviral strategy that is more resistant to viral evolution and can even provide broad prevention against SARS‐CoV and HCoV‐NL63. Here, we use prime editor (PE) to precisely edit ACE2 at structurally selected sites. We demonstrated that residue changes at Q24/D30/K31 and/or K353 of ACE2 could completely ablate the binding of tested viruses while maintaining its physiological role in host angiotensin II conversion. PE‐mediated ACE2 editing at these sites suppressed the entry of pseudotyped SARS‐CoV‐2 major variants of concern and even SARS‐CoV or HCoV‐NL63. Moreover, it significantly inhibited the replication of the Delta variant live virus. Our work investigated the unexplored application potential of prime editing in high‐risk infectious disease control and demonstrated that such gene editing‐based host factor reshaping strategy can provide broad‐spectrum antiviral activity and a high barrier to viral escape or resistance. |
| first_indexed | 2024-03-11T18:09:59Z |
| format | Article |
| id | doaj.art-3f1cdc1af3d747359d28a9e3408e69b3 |
| institution | Directory Open Access Journal |
| issn | 2688-2663 |
| language | English |
| last_indexed | 2024-03-11T18:09:59Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj.art-3f1cdc1af3d747359d28a9e3408e69b32023-10-16T15:20:40ZengWileyMedComm2688-26632023-10-0145n/an/a10.1002/mco2.356Prime editor‐mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS‐CoV‐2 variantsWenwen Zhao0Jifang Li1Xiao Wang2Wei Xu3Bao‐Qing Gao4Jiangchao Xiang5Yaofeng Hou6Wei Liu7Jing Wu8Qilian Qi9Jia Wei10Xiaoyu Yang11Lu Lu12Li Yang13Jia Chen14Bei Yang15Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Shanghai ChinaShanghai Frontiers Science Center for Biomacromolecules and Precision Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Shanghai ChinaShanghai Frontiers Science Center for Biomacromolecules and Precision Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Shanghai ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) School of Basic Medical Sciences Fudan University Shanghai ChinaShanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai ChinaShanghai Frontiers Science Center for Biomacromolecules and Precision Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Shanghai ChinaShanghai Frontiers Science Center for Biomacromolecules and Precision Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Shanghai ChinaSchool of Physical Science and Technology ShanghaiTech University Shanghai ChinaShanghai Frontiers Science Center for Biomacromolecules and Precision Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Shanghai ChinaShanghai Frontiers Science Center for Biomacromolecules and Precision Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Shanghai ChinaCenter for Molecular Medicine Children's Hospital Fudan University Shanghai ChinaSchool of Physical Science and Technology ShanghaiTech University Shanghai ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) School of Basic Medical Sciences Fudan University Shanghai ChinaCenter for Molecular Medicine Children's Hospital Fudan University Shanghai ChinaShanghai Frontiers Science Center for Biomacromolecules and Precision Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Shanghai ChinaShanghai Frontiers Science Center for Biomacromolecules and Precision Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Shanghai ChinaAbstract The spike protein of SARS‐CoV‐2 hijacks the host angiotensin converting enzyme 2 (ACE2) to meditate its entry and is the primary target for vaccine development. Nevertheless, SARS‐CoV‐2 keeps evolving and the latest Omicron subvariants BQ.1 and XBB have gained exceptional immune evasion potential through mutations in their spike proteins, leading to sharply reduced efficacy of current spike‐focused vaccines and therapeutics. Compared with the fast‐evolving spike protein, targeting host ACE2 offers an alternative antiviral strategy that is more resistant to viral evolution and can even provide broad prevention against SARS‐CoV and HCoV‐NL63. Here, we use prime editor (PE) to precisely edit ACE2 at structurally selected sites. We demonstrated that residue changes at Q24/D30/K31 and/or K353 of ACE2 could completely ablate the binding of tested viruses while maintaining its physiological role in host angiotensin II conversion. PE‐mediated ACE2 editing at these sites suppressed the entry of pseudotyped SARS‐CoV‐2 major variants of concern and even SARS‐CoV or HCoV‐NL63. Moreover, it significantly inhibited the replication of the Delta variant live virus. Our work investigated the unexplored application potential of prime editing in high‐risk infectious disease control and demonstrated that such gene editing‐based host factor reshaping strategy can provide broad‐spectrum antiviral activity and a high barrier to viral escape or resistance.https://doi.org/10.1002/mco2.356broad spectrumHCoV‐NL63host factor reshapingprime editingSARS‐CoVSARS‐CoV‐2 VOCs |
| spellingShingle | Wenwen Zhao Jifang Li Xiao Wang Wei Xu Bao‐Qing Gao Jiangchao Xiang Yaofeng Hou Wei Liu Jing Wu Qilian Qi Jia Wei Xiaoyu Yang Lu Lu Li Yang Jia Chen Bei Yang Prime editor‐mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS‐CoV‐2 variants MedComm broad spectrum HCoV‐NL63 host factor reshaping prime editing SARS‐CoV SARS‐CoV‐2 VOCs |
| title | Prime editor‐mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS‐CoV‐2 variants |
| title_full | Prime editor‐mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS‐CoV‐2 variants |
| title_fullStr | Prime editor‐mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS‐CoV‐2 variants |
| title_full_unstemmed | Prime editor‐mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS‐CoV‐2 variants |
| title_short | Prime editor‐mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS‐CoV‐2 variants |
| title_sort | prime editor mediated functional reshaping of ace2 prevents the entry of multiple human coronaviruses including sars cov 2 variants |
| topic | broad spectrum HCoV‐NL63 host factor reshaping prime editing SARS‐CoV SARS‐CoV‐2 VOCs |
| url | https://doi.org/10.1002/mco2.356 |
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