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Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening

文献类型：期刊论文

作者Huang, Chao3,4; Jin, Yang2,3; Fu, Panpan2; Hu, Kongying; Wang, Mengxue2; Zai, Wenjing4; Hua, Ting4; Song, Xinluo4; Ye, Jianyu4; Zhang, Yiqing1
刊名ACTA PHARMACEUTICA SINICA B
出版日期2024-11-01
卷号14期号:11页码:4914-4933
关键词Anti-HBV HBV core protein Core protein assembly modulators Marine natural products HiBiT Lead compound Naamidine J derivative Bioactivity-driven synthesis
ISSN号2211-3835
DOI10.1016/j.apsb.2024.07.019
通讯作者Li, Xuwen(xwli@simm.ac.cn) ; Yuan, Zhenghong(zhyuan@shmu.edu.cn)
英文摘要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 mu mol/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. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词CRYSTAL-STRUCTURE ; IN-VITRO ; REPLICATION ; ANALOGS ; INHIBITION ; STRATEGIES ; RESISTANT
资助项目National Key Research and Development Program of China[2021YFF0502400] ; National Natural Science Foundation of China[82022069] ; Shanghai Municipal Health Commission (China) ; Hainan Provincial Major Science and Technology Project (China) ; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (China)[2023-PT310-02] ; CAMS Innovation Fund for Medical Sciences (China)[2019-12M-5-040] ; Shandong Laboratory Program (China)[SYS202205] ; CAS Youth Interdisciplinary Team ; Taishan Scholars Program (China)[tsqn202312302] ; [2022YFA1303600] ; [U23A20474] ; [GWVI-11.2-XD27] ; [ZDKJ2021028]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001364532100001
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/314777]  
专题中国科学院上海药物研究所
通讯作者Li, Xuwen; Yuan, Zhenghong
作者单位1.Guixi Hosp Tradit Chinese Med, Guixi 335400, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
4.Fudan Univ, Shanghai Frontiers Sci Ctr Pathogen Microbes & Inf, Sch Basic Med Sci, Res Unit Cure Chron Hepatitis B Virus Infect CAMS,, Shanghai 200032, Peoples R China
5.Shanghai Inst Infect Dis & Biosecur, Shanghai 200032, Peoples R China
推荐引用方式
GB/T 7714		 Huang, Chao,Jin, Yang,Fu, Panpan,et al. Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening[J]. ACTA PHARMACEUTICA SINICA B,2024,14(11):4914-4933.
APA Huang, Chao.,Jin, Yang.,Fu, Panpan.,Hu, Kongying.,Wang, Mengxue.,...&Yuan, Zhenghong.(2024).Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening.ACTA PHARMACEUTICA SINICA B,14(11),4914-4933.
MLA Huang, Chao,et al."Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening".ACTA PHARMACEUTICA SINICA B 14.11(2024):4914-4933.

入库方式： OAI收割

来源：上海药物研究所

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