Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry
Abstract Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42527-5 |
| _version_ | 1797452121775276032 |
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| author | Haofeng Wang Qi Yang Xiaoce Liu Zili Xu Maolin Shao Dongxu Li Yinkai Duan Jielin Tang Xianqiang Yu Yumin Zhang Aihua Hao Yajie Wang Jie Chen Chenghao Zhu Luke Guddat Hongli Chen Leike Zhang Xinwen Chen Biao Jiang Lei Sun Zihe Rao Haitao Yang |
| author_facet | Haofeng Wang Qi Yang Xiaoce Liu Zili Xu Maolin Shao Dongxu Li Yinkai Duan Jielin Tang Xianqiang Yu Yumin Zhang Aihua Hao Yajie Wang Jie Chen Chenghao Zhu Luke Guddat Hongli Chen Leike Zhang Xinwen Chen Biao Jiang Lei Sun Zihe Rao Haitao Yang |
| author_sort | Haofeng Wang |
| collection | DOAJ |
| description | Abstract Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition of these proteases and determine their complex structures with their respective targets. Furthermore, we show that applying inhibitors simultaneously that block both entry pathways has a synergistic antiviral effect. Notably, we devise a bispecific compound, 212-148, exhibiting the dual-inhibition ability of both TMPRSS2 and CTSL/CTSB, and demonstrate antiviral activity against various SARS-CoV-2 variants with different viral entry profiles. Our findings offer an alternative approach for the discovery of SARS-CoV-2 antivirals, as well as application for broad-spectrum treatment of viral pathogenic infections with similar entry pathways. |
| first_indexed | 2024-03-09T15:04:12Z |
| format | Article |
| id | doaj.art-a8a939a48a4d430796d03a0396af8a49 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T15:04:12Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a8a939a48a4d430796d03a0396af8a492023-11-26T13:44:52ZengNature PortfolioNature Communications2041-17232023-11-0114111410.1038/s41467-023-42527-5Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entryHaofeng Wang0Qi Yang1Xiaoce Liu2Zili Xu3Maolin Shao4Dongxu Li5Yinkai Duan6Jielin Tang7Xianqiang Yu8Yumin Zhang9Aihua Hao10Yajie Wang11Jie Chen12Chenghao Zhu13Luke Guddat14Hongli Chen15Leike Zhang16Xinwen Chen17Biao Jiang18Lei Sun19Zihe Rao20Haitao Yang21Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityGuangzhou LaboratoryShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversitySchool of Physical Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityGuangzhou LaboratoryShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityCAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of SciencesThe Fifth People’s Hospital of Shanghai, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences, Fudan UniversityThe Fifth People’s Hospital of Shanghai, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences, Fudan UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversitySchool of Chemistry and Molecular Biosciences, the University of QueenslandShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityCAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of SciencesGuangzhou LaboratoryShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityThe Fifth People’s Hospital of Shanghai, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences, Fudan UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityAbstract Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition of these proteases and determine their complex structures with their respective targets. Furthermore, we show that applying inhibitors simultaneously that block both entry pathways has a synergistic antiviral effect. Notably, we devise a bispecific compound, 212-148, exhibiting the dual-inhibition ability of both TMPRSS2 and CTSL/CTSB, and demonstrate antiviral activity against various SARS-CoV-2 variants with different viral entry profiles. Our findings offer an alternative approach for the discovery of SARS-CoV-2 antivirals, as well as application for broad-spectrum treatment of viral pathogenic infections with similar entry pathways.https://doi.org/10.1038/s41467-023-42527-5 |
| spellingShingle | Haofeng Wang Qi Yang Xiaoce Liu Zili Xu Maolin Shao Dongxu Li Yinkai Duan Jielin Tang Xianqiang Yu Yumin Zhang Aihua Hao Yajie Wang Jie Chen Chenghao Zhu Luke Guddat Hongli Chen Leike Zhang Xinwen Chen Biao Jiang Lei Sun Zihe Rao Haitao Yang Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry Nature Communications |
| title | Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry |
| title_full | Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry |
| title_fullStr | Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry |
| title_full_unstemmed | Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry |
| title_short | Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry |
| title_sort | structure based discovery of dual pathway inhibitors for sars cov 2 entry |
| url | https://doi.org/10.1038/s41467-023-42527-5 |
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