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
  • 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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