Targeting SARS-CoV-2 main protease for the discovery of a broad-spectrum COVID-19 inhibitor by intensive multi-tiered validation.
10.1016/j.apsb.2025.09.033
- Author:
Min ZHANG
1
;
Changjian WANG
1
;
Lu FENG
2
;
Qi YANG
3
;
Yipeng CAO
4
;
Yao ZHAO
5
;
Junhua ZHANG
1
;
Yuefei WANG
1
;
Zihe RAO
2
;
Boli ZHANG
1
Author Information
1. State Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
2. State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China.
3. Guangzhou Laboratory, Guangzhou 510005, China.
4. Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
5. National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen 518112, China.
- Publication Type:Journal Article
- Keywords:
Allosteric inhibitor;
Broad-spectrum antiviral activity;
COVID-19;
Chebulagic acid (CHLA);
Main protease (Mpro);
Molecular interaction;
SARS-CoV-2;
X-ray crystallography
- From:
Acta Pharmaceutica Sinica B
2025;15(11):5789-5802
- CountryChina
- Language:English
-
Abstract:
SARS-CoV-2 and its emerging variants continue to pose a significant global public health threat. The SARS-CoV-2 main protease (Mpro) is a critical target for the development of antiviral agents that can inhibit viral replication and transcription. In this study, we identified chebulagic acid (CHLA), isolated from Terminalia chebula Retz., as a potent non-peptidomimetic and non-covalent Mpro inhibitor. CHLA exhibited intermolecular interactions and provided significant protection to Vero E6 cells against a range of SARS-CoV-2 variants, including the wild-type, Delta, Omicron BA.1.1, BA.2.3, BA.4, and BA.5, with EC50 values below 2 μmol/L. Moreover, in vivo studies confirmed the antiviral efficacy of CHLA in K18-hACE2 mice. Notably, CHLA bound to a unique groove at the interface between Mpro domains I and II, which was revealed by the high-resolution crystal structure (1.4 Å) of the Mpro-CHLA complex, shrinking the substrate binding pocket of Mpro and inducing Mpro aggregation. CHLA was proposed to act as an allosteric inhibitor. Pharmacokinetic profiling and safety assessments underscore CHLA's potential as a promising broad-spectrum antiviral candidate. These findings report a novel binding site on Mpro and identify antiviral activity of CHLA, providing a robust framework for lead compounds discovery and elucidating the underlying molecular mechanisms of inhibition.
