Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04
Abstract Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is current...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-04-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-024-00673-0 |
| _version_ | 1797209579586584576 |
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| author | Lijing Zhang Xuping Xie Hannan Luo Runtong Qian Yang Yang Hongtao Yu Jing Huang Pei-Yong Shi Qi Hu |
| author_facet | Lijing Zhang Xuping Xie Hannan Luo Runtong Qian Yang Yang Hongtao Yu Jing Huang Pei-Yong Shi Qi Hu |
| author_sort | Lijing Zhang |
| collection | DOAJ |
| description | Abstract Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04-binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpro’s C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics. |
| first_indexed | 2024-04-24T09:56:57Z |
| format | Article |
| id | doaj.art-b44f440683454d9aba992e81fbac8de0 |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-04-24T09:56:57Z |
| publishDate | 2024-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-b44f440683454d9aba992e81fbac8de02024-04-14T11:07:46ZengNature Publishing GroupCell Discovery2056-59682024-04-0110111410.1038/s41421-024-00673-0Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04Lijing Zhang0Xuping Xie1Hannan Luo2Runtong Qian3Yang Yang4Hongtao Yu5Jing Huang6Pei-Yong Shi7Qi Hu8Zhejiang UniversityDepartment of Biochemistry and Molecular Biology, University of Texas Medical BranchWestlake Laboratory of Life Sciences and BiomedicineWestlake Laboratory of Life Sciences and BiomedicineDivision of Life Sciences and Medicine, University of Science and Technology of ChinaWestlake Laboratory of Life Sciences and BiomedicineWestlake Laboratory of Life Sciences and BiomedicineDepartment of Biochemistry and Molecular Biology, University of Texas Medical BranchWestlake Laboratory of Life Sciences and BiomedicineAbstract Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04-binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpro’s C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics.https://doi.org/10.1038/s41421-024-00673-0 |
| spellingShingle | Lijing Zhang Xuping Xie Hannan Luo Runtong Qian Yang Yang Hongtao Yu Jing Huang Pei-Yong Shi Qi Hu Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04 Cell Discovery |
| title | Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04 |
| title_full | Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04 |
| title_fullStr | Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04 |
| title_full_unstemmed | Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04 |
| title_short | Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04 |
| title_sort | resistance mechanisms of sars cov 2 3clpro to the non covalent inhibitor wu 04 |
| url | https://doi.org/10.1038/s41421-024-00673-0 |
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