Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors

分类： 药物科学 >> 药物设计 提交时间： 2024-12-30

Wang, Xudong Xiong, Liwei Zhu, Ying Liu, Sixiu Zhao, Wenfeng Wu, Xinyuan Seydimemet, Mengnisa Li, Linjie Ding, Peiqi Lin, Xian Liu, Jiaxiang Wang, Xuan Duan, Zhiqiang Lu, Weiwei Suo, Yanrui Cui, Mengqing Yue, Jinfeng Jin, Rui Zheng, Mingyue Xu, Yechun

摘要： The 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.

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