ovalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors
ovalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors
he COVID-19 pandemic, exacerbated by persistent viral mutations, underscored the urgent need for diverse inhibitors targeting multiple viral proteins. In this study, we utilized covalent DNA-encoded libraries to discover innovative triazine-based covalent inhibitors for the 3-chymotrypsin-like protease (3CLpro, Nsp5) and the papain-like protease (PLpro) domains of Nsp3, as well as novel non-nucleoside covalent inhibitors for the nonstructural protein 12 (Nsp12, RdRp). Optimization through molecular docking and medicinal chemistry led to the development of LU9, a nonpeptide 3CLpro inhibitor with an IC50 of 0.34 mu M, and LU10, whose crystal structure showed a distinct binding mode within the 3CLpro active site. The X-ray cocrystal structure of SARS-CoV-2 PLpro in complex with XD5 uncovered a previously unexplored binding site adjacent to the catalytic pocket. Additionally, a non-nucleoside covalent Nsp12 inhibitor XJ5 achieved a potency of 0.12 mu M following comprehensive structure-activity relationship analysis and optimization. Molecular dynamics revealed a potential binding mode. These compounds offer valuable chemical probes for target validation and represent promising candidates for the development of SARS-CoV-2 antiviral therapies.
he COVID-19 pandemic, exacerbated by persistent viral mutations, underscored the urgent need for diverse inhibitors targeting multiple viral proteins. In this study, we utilized covalent DNA-encoded libraries to discover innovative triazine-based covalent inhibitors for the 3-chymotrypsin-like protease (3CLpro, Nsp5) and the papain-like protease (PLpro) domains of Nsp3, as well as novel non-nucleoside covalent inhibitors for the nonstructural protein 12 (Nsp12, RdRp). Optimization through molecular docking and medicinal chemistry led to the development of LU9, a nonpeptide 3CLpro inhibitor with an IC50 of 0.34 mu M, and LU10, whose crystal structure showed a distinct binding mode within the 3CLpro active site. The X-ray cocrystal structure of SARS-CoV-2 PLpro in complex with XD5 uncovered a previously unexplored binding site adjacent to the catalytic pocket. Additionally, a non-nucleoside covalent Nsp12 inhibitor XJ5 achieved a potency of 0.12 mu M following comprehensive structure-activity relationship analysis and optimization. Molecular dynamics revealed a potential binding mode. These compounds offer valuable chemical probes for target validation and represent promising candidates for the development of SARS-CoV-2 antiviral therapies.
Wang, Xudong、Wang, Xuan、Suo, Yanrui、Liu, Sixiu、Wu, Xinyuan、Hu, Hangchen、Zhao, Wenfeng、Lu, Weiwei、Yue, Jinfeng、Ding, Peiqi、Lin, Xian、Xiong, Liwei、Liu, Jiaxiang、Zheng, Mingyue、Mei, Lianghe、Cui, Mengqing、Lu, Xiaojie、Zhu, Ying、Jin, Rui、Xu, Yechun、Seydimemet, Mengnisa、Li, Linjie、Duan, Zhiqiang
药学基础医学生物科学研究方法、生物科学研究技术
Papain-Like Proteaseselective Inhibitorsdesignpotent
Papain-Like Proteaseselective Inhibitorsdesignpotent
Wang, Xudong,Wang, Xuan,Suo, Yanrui,Liu, Sixiu,Wu, Xinyuan,Hu, Hangchen,Zhao, Wenfeng,Lu, Weiwei,Yue, Jinfeng,Ding, Peiqi,Lin, Xian,Xiong, Liwei,Liu, Jiaxiang,Zheng, Mingyue,Mei, Lianghe,Cui, Mengqing,Lu, Xiaojie,Zhu, Ying,Jin, Rui,Xu, Yechun,Seydimemet, Mengnisa,Li, Linjie,Duan, Zhiqiang.ovalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors[EB/OL].(2024-12-30)[2025-08-02].https://chinaxiv.org/abs/202412.00349.点此复制
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