Sphondin efficiently blocks HBsAg production and cccDNA transcription through promoting HBx degradation

作者全名："Ren, Fang; Hu, Junchi; Dang, Yongjun; Deng, Haijun; Ren, Jihua; Cheng, Shengtao; Tan, Ming; Zhang, Hui; He, Xin; Yu, Haibo; Zhang, Juan; Zhang, Zhenzhen; Chen, Weixian; Hu, Jieli; Cai, Xuefei; Hu, Yuan; Huang, Ailong; Chen, Juan"

作者地址："[Ren, Fang; Deng, Haijun; Ren, Jihua; Cheng, Shengtao; Tan, Ming; Zhang, Hui; He, Xin; Yu, Haibo; Hu, Jieli; Cai, Xuefei; Hu, Yuan; Huang, Ailong; Chen, Juan] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis Design, Chongqing, Peoples R China; [Ren, Fang; Zhang, Juan] Chongqing Hosp Tradit Chinese Med, Chongqing Key Lab Sichuan Chongqing Coconstruct Di, Chongqing, Peoples R China; [Dang, Yongjun] Chongqing Med Univ, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing, Peoples R China; [Zhang, Zhenzhen] Chongqing Med Univ, Dept Infect Dis, Childrens Hosp, Chongqing, Peoples R China; [Chen, Weixian] Chongqing Med Univ, Dept Clin Lab, Affiliated Hosp 2, Chongqing, Peoples R China; [Chen, Juan] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing, Peoples R China; [Chen, Juan] Room 617,Coll Life Sci Bldg,1 YiXueYuan Rd, Chongqing 400016, Peoples R China"

通信作者："Chen, J (通讯作者)，Room 617,Coll Life Sci Bldg,1 YiXueYuan Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF MEDICAL VIROLOGY

ESI学科分类：MICROBIOLOGY

WOS号：WOS:000960340500010

JCR分区：Q1

影响因子：6.8

年份：2023

卷号：95

期号：3

开始页：　

结束页：　

文献类型：Article

关键词：HBx; hepatitis B surface antigen; hepatitis B virus; natural compounds; sphondin

摘要："Hepatitis B surface antigen (HBsAg) loss and seroconversion, which is considered as functional cure of chronic Hepatitis B virus (HBV) infection, is rarely achieved even after long-term antiviral treatments. Therefore, new antiviral strategies interfering with other HBV replication steps are required, especially those that could efficiently inhibit HBsAg production. Here, we identified novel anti-HBV compounds that could potently block HBsAg expression from cccDNA by screening a natural compound library derived from Chinese traditional medical plants by a novel screening strategy. The combination of ELISA assay detecting the HBsAg and real-time PCR detecting HBV RNAs as indicator for cccDNA transcriptional activity were used. The antiviral activity of a candidate compound and underlying mechanism were evaluated in HBV-infected cells and a humanized liver mouse model. Herein, we selected a highly effective low-cytotoxic compound sphondin, which could effectively inhibit both intracellular HBsAg production and HBV RNAs levels. Moreover, we found that sphondin markedly inhibited cccDNA transcriptional activity without affecting cccDNA level. Mechanistic study found sphondin preferentially bound to HBx protein by residue Arg72, which led to increased 26S proteasome-mediated degradation of HBx. Sphondin treatment significantly reduced the recruitment of HBx to cccDNA, which subsequently led to inhibition of cccDNA transcription and HBsAg expression. The absence of HBx or R72A mutation potently abrogated the antiviral effect induced by sphondin in HBV-infected cells. Collectively, sphondin may be considered as a novel and natural antiviral agent directly targeting HBx protein, which effectively inhibited cccDNA transcription and HBsAg expression."

基金机构："National Natural Science Foundation of China [81861168035, 81922011, 81871656]; National key research and development program [2022YFA1303600]; Creative Research Group of CQ University [CXQT19016]; Chongqing Natural Science Foundation [CSTB2022NSCQ-MSX1560]; Natural Science Foundation Project of Chongqing [cstc2019jscx-dxwtBX0020]; China Postdoctoral Science Foundation [2021MD703920]"

基金资助正文："ACKNOWLEDGMENTS This work was supported by National Natural Science Foundation of China (Grant No. 81861168035, 81922011 and 81871656 to J. C.); National key research and development program (2022YFA1303600 to A. L. H.); Creative Research Group of CQ University (CXQT19016 to J. C.); Chongqing Natural Science Foundation (cstc2018jcyjAX0114 to J. C.); Natural Science Foundation Project of Chongqing (cstc2019jscx-dxwtBX0020 to J. C.); Chongqing Natural Science Foundation (CSTB2022NSCQ-MSX1560 to F. R.); China Postdoctoral Science Foundation (2021MD703920 to F. R.)."