Download MendeleyCovalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors.
Wang, X., Xiong, L., Zhu, Y., Liu, S., Zhao, W., Wu, X., Seydimemet, M., Li, L., Ding, P., Lin, X., Liu, J., Wang, X., Duan, Z., Lu, W., Suo, Y., Cui, M., Yue, J., Jin, R., Zheng, M., Xu, Y., Mei, L., Hu, H., Lu, X.(2024) J Am Chem Soc 146: 33983-33996
- PubMed: 39574309
- DOI: https://doi.org/10.1021/jacs.4c12992
- Primary Citation of Related Structures:
8Z46, 8Z4W - PubMed 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 (3CL pro , Nsp5) and the papain-like protease (PL pro ) 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 3CL pro inhibitor with an IC 50 of 0.34 μM, and LU10 , whose crystal structure showed a distinct binding mode within the 3CL pro active site. The X-ray cocrystal structure of SARS-CoV-2 PL pro 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.
Organizational Affiliation:
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
