2. Academic Validation
  3. Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors

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

  • J Am Chem Soc. 2024 Dec 11;146(49):33983-33996. doi: 10.1021/jacs.4c12992.
Xudong Wang 1 2,  Liwei Xiong 3,  Ying Zhu 4,  Sixiu Liu 1 2,  Wenfeng Zhao 1,  Xinyuan Wu 1 2,  Mengnisa Seydimemet 4,  Linjie Li 1,  Peiqi Ding 3,  Xian Lin 5,  Jiaxiang Liu 1,  Xuan Wang 1,  Zhiqiang Duan 1,  Weiwei Lu 1,  Yanrui Suo 1 2,  Mengqing Cui 1,  Jinfeng Yue 1,  Rui Jin 1,  Mingyue Zheng 1 2,  Yechun Xu 1 2 4 3,  Lianghe Mei 5,  Hangchen Hu 1 2 3,  Xiaojie Lu 1 2 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, P. R. China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, P. R. China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
  • 5 Suzhou Institute of Materia Medica, No. 108 Yuxin Road, Suzhou, Jiangsu 215123, P. R. China.
PMID: 39574309 DOI: 10.1021/jacs.4c12992
Abstract

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 μM, 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 μM 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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