Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors
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 (3CL<sup>pro</sup>, Nsp5) and the papain-like protease (PL<sup>pro</sup>) 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 <b>LU9</b>, a nonpeptide 3CL<sup>pro</sup> inhibitor with an IC<sub>50</sub> of 0.34 μM, and <b>LU10</b>, whose crystal structure showed a distinct binding mode within the 3CL<sup>pro</sup> active site. The X-ray cocrystal structure of SARS-CoV-2 PL<sup>pro</sup> in complex with <b>XD5</b> uncovered a previously unexplored binding site adjacent to the catalytic pocket. Additionally, a non-nucleoside covalent Nsp12 inhibitor <b>XJ5</b> 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.
Authors
- Xiaojie Lu (ORCID: https://orcid.org/0000-0002-3600-288X)
- Yechun Xu (ORCID: https://orcid.org/0000-0002-1581-6155)
- Rui Jin (ORCID: https://orcid.org/0000-0003-4544-6535)
- Hangchen Hu (ORCID: https://orcid.org/0000-0002-1063-9292)
- Weiwei Lu (ORCID: https://orcid.org/0000-0002-9940-5125)
- Lianghe Mei
- Jinfeng Yue
- Mengnisa Seydimemet
- Sixiu Liu (ORCID: https://orcid.org/0000-0001-7094-5892)
- Xinyuan Wu (ORCID: https://orcid.org/0009-0000-7565-6811)
- Yanrui Suo
- Mingyue Zheng (ORCID: https://orcid.org/0000-0002-3323-3092)
- Peng Ding (ORCID: https://orcid.org/0000-0002-9348-8134)
- Zhiqiang Duan (ORCID: https://orcid.org/0009-0003-4097-4336)
- Xuan Wang (ORCID: https://orcid.org/0000-0003-4986-0231)
- Xudong Wang (ORCID: https://orcid.org/0000-0002-3402-7995)
- Liwei Xiong
- Ying Zhu (ORCID: https://orcid.org/0009-0002-3142-284X)
- Wenfeng Zhao (ORCID: https://orcid.org/0000-0003-2517-4747)
- Jiaxiang Liu
- Mengqing Cui
- Linjie Li (ORCID: https://orcid.org/0000-0002-9817-1793)
- Xian Lin
Institutions
- Nanjing University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- Shanghai Institute of Materia Medica (CN)
- Institute for Advanced Study (DE)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1021/jacs.4c12992
- Citations
- 20
- Primary Topic
- Advanced biosensing and bioanalysis techniques
- Type
- article
- Field-Weighted Citation Impact
- 4.68
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Nanjing University of Chinese Medicine
- Nanjing University
- University of Chinese Academy of Sciences
- State Key Laboratory of Drug Research
- Science and Technology Innovation Plan Of Shanghai Science and Technology Commission