Discovery and mechanistic study of Imperatorin that inhibits HBsAg expression and cccDNA transcription

作者全名：Ren, Fang; Zhao, Shiqiao; He, Xin; Lo, Hanghong; Wong, Vincent Kam Wai; Law, Betty Yuen Kwan; Wu, Anguo; Zhang, Juan

作者地址：[Ren, Fang; Zhao, Shiqiao; Zhang, Juan] Chongqing Hosp Tradit Chinese Med, Dept Clin Lab, Chongqing, Peoples R China; [Ren, Fang; Zhao, Shiqiao; Zhang, Juan] Chongqing Key Lab Sichuan Chongqing Coconstruct D, Chongqing, Peoples R China; [He, Xin] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Chinese Minist Educ, Chongqing, Peoples R China; [Lo, Hanghong; Wong, Vincent Kam Wai; Law, Betty Yuen Kwan] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Taipa, Macao, Peoples R China; [Wu, Anguo] Southwest Med Univ, Sch Pharm, Sichuan Key Med Lab New Drug Discovery & Drug Abi, Key Lab Med Electrophysiol,Minist Educ, Luzhou, Peoples R China; [Zhang, Juan] Chongqing Tradit Chinese Med Hosp, Dept Lab Med, Chongqing 400021, Peoples R China

通信作者：Zhang, J (通讯作者)，Chongqing Tradit Chinese Med Hosp, Dept Lab Med, Chongqing 400021, Peoples R China.

来源：JOURNAL OF MEDICAL VIROLOGY

ESI学科分类：MICROBIOLOGY

WOS号：WOS:001232031300016

JCR分区：Q1

影响因子：6.8

年份：2024

卷号：96

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：covalently closed circular (ccc) DNA; CREB; ERK; hepatitis B surface antigen; imperatorin

摘要：Chronic hepatitis B virus (HBV) infection remains a significant global health challenge due to its link to severe conditions like HBV-related cirrhosis and hepatocellular carcinoma (HCC). Although current treatments effectively reduce viral levels, they have limited impact on certain HBV elements, namely hepatitis B surface antigen (HBsAg) and covalently closed circular DNA (cccDNA). This highlights the urgent need for innovative pharmaceutical and biological interventions that can disrupt HBsAg production originating from cccDNA. In this study, we identified a natural furanocoumarin compound, Imperatorin, which markedly inhibited the expression of HBsAg from cccDNA, by screening a library of natural compounds derived from Chinese herbal medicines using ELISA assay and qRT-PCR. The pharmacodynamics study of Imperatorin was explored on HBV infected HepG2-NTCP/PHHs and HBV-infected humanized mouse model. Proteome analysis was performed on HBV infected HepG2-NTCP cells following Imperatorin treatment. Molecular docking and bio-layer interferometry (BLI) were used for finding the target of Imperatorin. Our findings demonstrated Imperatorin remarkably reduced the level of HBsAg, HBV RNAs, HBV DNA and transcriptional activity of cccDNA both in vitro and in vivo. Additionally, Imperatorin effectively restrained the actions of HBV promoters responsible for cccDNA transcription. Mechanistic study revealed that Imperatorin directly binds to ERK and subsequently interfering with the activation of CAMP response element-binding protein (CREB), a crucial transcriptional factor for HBV and has been demonstrated to bind to the PreS2/S and X promoter regions of HBV. Importantly, the absence of ERK could nullify the antiviral impact triggered by Imperatorin. Collectively, the natural compound Imperatorin may be an effective candidate agent for inhibiting HBsAg production and cccDNA transcription by impeding the activities of HBV promoters through ERK-CREB axis.

基金机构：National Natural Science Foundation of China; Chongqing Natural Science Foundation [CSTB2022NSCQ-MSX1560]; Chongqing Postdoctoral Science Foundation [2022CQBSHTB2016]; China Postdoctoral Science Foundation [2023T160770, 2021MD703920]; Chongqing Science and Technology Foundation [cstc2021jxjl130038]; College Project of Chengdu University of Traditional Chinese Medicine [1576]; [82304994]

基金资助正文：This work was supported by National Natural Science Foundation of China (Grant No. 82304994 to F. R.); Chongqing Natural Science Foundation (CSTB2022NSCQ-MSX1560 to F. R.); Chongqing Postdoctoral Science Foundation (2022CQBSHTB2016 to F. R.); China Postdoctoral Science Foundation (2023T160770, 2021MD703920 to F. R.); Chongqing Science and Technology Foundation (cstc2021jxjl130038 to J. Z.); and College Project of Chengdu University of Traditional Chinese Medicine (1576).