Design, synthesis and degradation activity of PROTAC targeting SARS-CoV-2 main protease
10.12206/j.issn.2097-2024.202503063
- VernacularTitle:靶向SARS-CoV-2主蛋白酶的PROTAC设计、合成与蛋白降解活性研究
- Author:
Lai WEI
1
;
Guoqiang DONG
1
;
Chunquan SHENG
1
Author Information
1. Department of Medicinal Chemistry, School of Pharmacy, Naval Medical University, Shanghai 200433, China.
- Publication Type:Originalarticles
- Keywords:
SARS-CoV-2;
main protease;
PROTAC;
protein degradation activity;
antiviral drug
- From:
Journal of Pharmaceutical Practice and Service
2025;43(5):235-241
- CountryChina
- Language:Chinese
-
Abstract:
Objective To design and synthesize PROTAC degraders targeting the SARS-CoV-2 main protease （Mpro）based on PROTAC technology. Methods Compound 3w was used as the Mpro ligand, and the indole N atom in the solvent-exposed region was selected as the linker attachment site. A series of Mpro PROTACs were designed and synthesized by conjugating compound 3w with the CRBN ligand pomalidomide through alkane linkers of different lengths. The structures of the target compounds were confirmed by 1H NMR, 13C NMR, and HRMS. Western Blot analysis was employed to evaluate their degradation activity and explore its mechanism in Mpro-HEK-293T cells. Results Four novel Mpro PROTACs（A1-A4）were successfully synthesized. The most potent compound A4 demonstrated Mpro degradation activity with a DC50 value of 5.2 μmol/L, and its degradation mechanism was validated. Conclusion A novel class of Mpro PROTAC degraders were successfully designed and synthesized, and their protein degradation capability and mechanism of action were demonstrated. These results provided lead compounds for the research and development of antiviral degraders against SARS-CoV-2.
