Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening.
10.1016/j.apsb.2024.07.019
- Author:
Chao HUANG
1
;
Yang JIN
2
;
Panpan FU
3
;
Kongying HU
1
;
Mengxue WANG
3
;
Wenjing ZAI
1
;
Ting HUA
1
;
Xinluo SONG
1
;
Jianyu YE
1
;
Yiqing ZHANG
4
;
Gan LUO
1
;
Haiyu WANG
1
;
Jiangxia LIU
1
;
Jieliang CHEN
1
;
Xuwen LI
2
;
Zhenghong YUAN
1
Author Information
1. Key Laboratory of Medical Molecular Virology (MOE/NHC), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai 200032, China.
2. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
4. Guixi Hospital of Chinese Medicine, Guixi 335400, China.
- Publication Type:Journal Article
- Keywords:
Anti-HBV;
Bioactivity-driven synthesis;
Core protein assembly modulators;
HBV core protein;
HiBiT;
Lead compound;
Marine natural products;
Naamidine J derivative
- From:
Acta Pharmaceutica Sinica B
2024;14(11):4914-4933
- CountryChina
- Language:English
-
Abstract:
Due to the limitations of current anti-HBV therapies, the HBV core (HBc or HBcAg) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound 8a, a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound 11a (IC50 = 0.24 μmol/L). Furthermore, 11a was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 in vitro for anti-HBV activity. Treatment with 11a in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative 11a could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.
