Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease
The papain-like protease (PL<sup>pro</sup>) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we repo...
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| Format: | Article |
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/10/8633 |
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| author | Qian Wang Guofeng Chen Jian He Jiameng Li Muya Xiong Haixia Su Minjun Li Hangchen Hu Yechun Xu |
| author_facet | Qian Wang Guofeng Chen Jian He Jiameng Li Muya Xiong Haixia Su Minjun Li Hangchen Hu Yechun Xu |
| author_sort | Qian Wang |
| collection | DOAJ |
| description | The papain-like protease (PL<sup>pro</sup>) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we report the structure-guide design of novel peptidomimetic inhibitors covalently targeting SARS-CoV-2 PL<sup>pro</sup>. The resulting inhibitors demonstrate submicromolar potency in the enzymatic assay (IC<sub>50</sub> = 0.23 μM) and significant inhibition of SARS-CoV-2 PL<sup>pro</sup> in the HEK293T cells using a cell-based protease assay (EC<sub>50</sub> = 3.61 μM). Moreover, an X-ray crystal structure of SARS-CoV-2 PL<sup>pro</sup> in complex with compound <b>2</b> confirms the covalent binding of the inhibitor to the catalytic residue cysteine 111 (C111) and emphasizes the importance of interactions with tyrosine 268 (Y268). Together, our findings reveal a new scaffold of SARS-CoV-2 PL<sup>pro</sup> inhibitors and provide an attractive starting point for further optimization. |
| first_indexed | 2024-03-11T03:40:54Z |
| format | Article |
| id | doaj.art-c9e06c42a91e4913af00a53646bcf667 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:40:54Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c9e06c42a91e4913af00a53646bcf6672023-11-18T01:39:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012410863310.3390/ijms24108633Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like ProteaseQian Wang0Guofeng Chen1Jian He2Jiameng Li3Muya Xiong4Haixia Su5Minjun Li6Hangchen Hu7Yechun Xu8School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaShanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, ChinaSchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, ChinaSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaThe papain-like protease (PL<sup>pro</sup>) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we report the structure-guide design of novel peptidomimetic inhibitors covalently targeting SARS-CoV-2 PL<sup>pro</sup>. The resulting inhibitors demonstrate submicromolar potency in the enzymatic assay (IC<sub>50</sub> = 0.23 μM) and significant inhibition of SARS-CoV-2 PL<sup>pro</sup> in the HEK293T cells using a cell-based protease assay (EC<sub>50</sub> = 3.61 μM). Moreover, an X-ray crystal structure of SARS-CoV-2 PL<sup>pro</sup> in complex with compound <b>2</b> confirms the covalent binding of the inhibitor to the catalytic residue cysteine 111 (C111) and emphasizes the importance of interactions with tyrosine 268 (Y268). Together, our findings reveal a new scaffold of SARS-CoV-2 PL<sup>pro</sup> inhibitors and provide an attractive starting point for further optimization.https://www.mdpi.com/1422-0067/24/10/8633SARS-CoV-2papain-like proteasecovalent inhibitorco-crystal structurein vitro assay |
| spellingShingle | Qian Wang Guofeng Chen Jian He Jiameng Li Muya Xiong Haixia Su Minjun Li Hangchen Hu Yechun Xu Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease International Journal of Molecular Sciences SARS-CoV-2 papain-like protease covalent inhibitor co-crystal structure in vitro assay |
| title | Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease |
| title_full | Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease |
| title_fullStr | Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease |
| title_full_unstemmed | Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease |
| title_short | Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease |
| title_sort | structure based design of potent peptidomimetic inhibitors covalently targeting sars cov 2 papain like protease |
| topic | SARS-CoV-2 papain-like protease covalent inhibitor co-crystal structure in vitro assay |
| url | https://www.mdpi.com/1422-0067/24/10/8633 |
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