Structural basis for the inhibition of coronaviral main proteases by PF-00835231
The main protease (M<sup>pro</sup>) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M<sup>pro</sup>. Here, we r...
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| Format: | Article |
| Language: | English |
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China Science Publishing & Media Ltd.
2024-07-01
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| Series: | Acta Biochimica et Biophysica Sinica |
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| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2024122 |
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| author | Zhou Xuelan Lu Xiaolu Lin Cheng Zou Xiaofang Li Wenwen Zeng Xiangyi Wang Jie Zeng Pei Wang Weiwei Zhang Jin Jiang Haihai Li Jian |
| author_facet | Zhou Xuelan Lu Xiaolu Lin Cheng Zou Xiaofang Li Wenwen Zeng Xiangyi Wang Jie Zeng Pei Wang Weiwei Zhang Jin Jiang Haihai Li Jian |
| author_sort | Zhou Xuelan |
| collection | DOAJ |
| description | The main protease (M<sup>pro</sup>) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M<sup>pro</sup>. Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M<sup>pro</sup> and seven M<sup>pro</sup> mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M<sup>pro</sup>s. In addition, the crystal structures of SARS-CoV-2 M<sup>pro</sup>, SARS-CoV M<sup> pro</sup>, MERS-CoV M<sup>pro</sup>, and seven SARS-CoV-2 M<sup>pro</sup> mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M<sup>pro</sup>s. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M<sup> pro</sup> inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses. |
| format | Article |
| id | doaj-art-bdeea7c65123491995b0c38948917a99 |
| institution | Kabale University |
| issn | 1672-9145 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | China Science Publishing & Media Ltd. |
| record_format | Article |
| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj-art-bdeea7c65123491995b0c38948917a992025-01-17T05:58:27ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452024-07-01561813182210.3724/abbs.202412220d259ccStructural basis for the inhibition of coronaviral main proteases by PF-00835231Zhou Xuelan0Lu Xiaolu1Lin Cheng2Zou Xiaofang3Li Wenwen4Zeng Xiangyi5Wang Jie6Zeng Pei7Wang Weiwei8Zhang Jin9Jiang Haihai10Li Jian11["College of Pharmacy, Gannan Medical University, Ganzhou 341000, China"]["College of Pharmacy, Gannan Medical University, Ganzhou 341000, China"]["Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen 518118, China"]["Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou 341000, China"]["Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou 341000, China"]["Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou 341000, China"]["Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou 341000, China"]["Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou 341000, China"]["Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201204, China"]["School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"]["School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"]["College of Pharmacy, Gannan Medical University, Ganzhou 341000, China"]The main protease (M<sup>pro</sup>) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M<sup>pro</sup>. Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M<sup>pro</sup> and seven M<sup>pro</sup> mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M<sup>pro</sup>s. In addition, the crystal structures of SARS-CoV-2 M<sup>pro</sup>, SARS-CoV M<sup> pro</sup>, MERS-CoV M<sup>pro</sup>, and seven SARS-CoV-2 M<sup>pro</sup> mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M<sup>pro</sup>s. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M<sup> pro</sup> inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.https://www.sciengine.com/doi/10.3724/abbs.2024122coronavirusmain proteasePF-00835231crystal structureinhibition |
| spellingShingle | Zhou Xuelan Lu Xiaolu Lin Cheng Zou Xiaofang Li Wenwen Zeng Xiangyi Wang Jie Zeng Pei Wang Weiwei Zhang Jin Jiang Haihai Li Jian Structural basis for the inhibition of coronaviral main proteases by PF-00835231 Acta Biochimica et Biophysica Sinica coronavirus main protease PF-00835231 crystal structure inhibition |
| title | Structural basis for the inhibition of coronaviral main proteases by PF-00835231 |
| title_full | Structural basis for the inhibition of coronaviral main proteases by PF-00835231 |
| title_fullStr | Structural basis for the inhibition of coronaviral main proteases by PF-00835231 |
| title_full_unstemmed | Structural basis for the inhibition of coronaviral main proteases by PF-00835231 |
| title_short | Structural basis for the inhibition of coronaviral main proteases by PF-00835231 |
| title_sort | structural basis for the inhibition of coronaviral main proteases by pf 00835231 |
| topic | coronavirus main protease PF-00835231 crystal structure inhibition |
| url | https://www.sciengine.com/doi/10.3724/abbs.2024122 |
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