Psoralen inhibits hepatitis B viral replication by down-regulating the host transcriptional machinery of viral promoters

Xinna Ma; Heng Li; Ying Gong; Feifei Liu; Xiankun Tong; Fenghua Zhu; Xiaoqian Yang; Li Yang; Jianping Zuo

doi:10.1016/j.virs.2022.01.027

April 2022

Xinna Ma, Heng Li, Ying Gong, Feifei Liu, Xiankun Tong, Fenghua Zhu, Xiaoqian Yang, Li Yang and Jianping Zuo. Psoralen inhibits hepatitis B viral replication by down-regulating the host transcriptional machinery of viral promoters[J]. Virologica Sinica, 2022, 37(2): 256-265. doi: 10.1016/j.virs.2022.01.027

Citation: Xinna Ma, Heng Li, Ying Gong, Feifei Liu, Xiankun Tong, Fenghua Zhu, Xiaoqian Yang, Li Yang, Jianping Zuo. Psoralen inhibits hepatitis B viral replication by down-regulating the host transcriptional machinery of viral promoters .VIROLOGICA SINICA, 2022, 37(2) : 256-265. http://dx.doi.org/10.1016/j.virs.2022.01.027

补骨脂素通过下调病毒转录因子表达抑制乙型肝炎病毒复制

马鑫娜 ^a,b ,
李恒 ^b,c ,
巩颖 ^b,c ,
刘菲菲 ^b ,
童贤崑 ^b ,
朱峰华 ^b ,
杨晓倩 ^b ,
杨莉 ^b,, ,
左建平 ^a,b,c,,

中国科学院上海药物研究所

通讯作者： 杨莉, yangli@simm.ac.cn; 左建平, jpzuo@simm.ac.cn
收稿日期： 2021-05-30
录用日期： 2021-10-18

摘要

乙型肝炎病毒（HBV）具有高度传染性，是一个全球性的公共卫生问题。据估计，每年约有2.5亿人患有慢性乙型肝炎病毒感染。尽管核苷类似物能显著降低乙型肝炎发展为更严重肝病的风险，但它们不能完全根除病毒，因此迫切需要针对乙型肝炎的新的治疗方案和药物。补骨脂素是一种具有抑制病毒复制和灭活病毒作用的中药单体。qPCR和southern blot实验显示补骨脂素可以浓度依赖性地抑制HepG2.2.15细胞中的HBV DNA复制。此外，补骨脂素对3TC/ETV双重耐药HBV突变体也具有抑制活性。进一步研究表明补骨脂素能够抑制HBV RNA转录和核心蛋白表达。Co-IP实验显示补骨脂素抑制FOXO1的表达，从而降低FOXO1-PGC1α共激活因子与HBV启动子的结合。FOXO1是已知的PGC1α共激活靶点，与HBV前核心/核心启动子增强子II区域结合并激活HBV RNA转录。我们的研究表明补骨脂素通过下调FOXO1的表达抑制HBV RNA转录，最终导致HBV复制下降。
- 补骨脂素
- , 乙型肝炎病毒(HBV)
- , 叉头盒转录因子-O1(FOXO1)
- , PPARγ辅助活化因子1α(PGC1α)
- , 转录

Psoralen inhibits hepatitis B viral replication by down-regulating the host transcriptional machinery of viral promoters

Xinna Ma ^a,b ,
Heng Li ^b,c ,
Ying Gong ^b,c ,
Feifei Liu ^b ,
Xiankun Tong ^b ,
Fenghua Zhu ^b ,
Xiaoqian Yang ^b ,
Li Yang ^b,, ,
Jianping Zuo ^a,b,c,,

a Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

Corresponding author: Li Yang, yangli@simm.ac.cn Jianping Zuo, jpzuo@simm.ac.cn
Received Date: 30 May 2021
Accepted Date: 18 October 2021

Abstract

The hepatitis B virus (HBV) is a global public health challenge due to its highly contagious nature. It is estimated that almost 300 million people live with chronic HBV infection annually. Although nucleoside analogs markedly reduce the risk of liver disease progression, the analogs do not fully eradicate the virus. As such, new treatment options and drugs are urgently needed. Psoralen is a nourishing monomer of Chinese herb and is known to inhibit virus replication and inactivate viruses. In this study, we evaluated the potential of psoralen as an anti-HBV agent. Quantitative PCR and Southern blot analysis revealed that psoralen inhibited HBV replication in HepG2.2.15 cells in a concentration-dependent manner. Moreover, psoralen was also active against the 3TC/ETV-dual-resistant HBV mutant. Further investigations revealed that psoralen suppressed both HBV RNA transcription and core protein expression. The transcription factor FOXO1, a known target for PGC1α co-activation, binds to HBV pre-core/core promoter enhancer II region and activates HBV RNA transcription. Co-immunoprecipitation showed that psoralen suppressed the expression of FOXO1, thereby decreasing the binding of FOXO1 co-activator PGC1α to the HBV promoter. Overall, our results demonstrate that psoralen suppresses HBV RNA transcription by down-regulating the expression of FOXO1 resulting in a reduction of HBV replication.
- Psoralen
- , Hepatitis B virus (HBV)
- , Forkhead box-O 1 (FOXO1)
- , PPARγ co-activator 1α (PGC1α)
- , Transcription

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Electronic Supplementary Material

10.1016j.virs.2022.01.027-ESM.docx