Pimobendan Inhibits HBV Transcription and Replication by Suppressing HBV Promoters Activity

作者全名："Yuan, Si-Yu; Yu, Hai-Bo; Yang, Zhen; Qin, Yi-Ping; Ren, Ji-Hua; Cheng, Sheng-Tao; Ren, Fang; Law, Betty Yuen Kwan; Wong, Vincent Kam Wai; Ng, Jerome P. L.; Zhou, Yu-Jiao; He, Xin; Tan, Ming; Zhang, Zhen-Zhen; Chen, Juan"

作者地址："[Yuan, Si-Yu; Yu, Hai-Bo; Yang, Zhen; Qin, Yi-Ping; Ren, Ji-Hua; Cheng, Sheng-Tao; Ren, Fang; Zhou, Yu-Jiao; He, Xin; Tan, Ming; Chen, Juan] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Designated Chinese Minist Educ, Chongqing, Peoples R China; [Law, Betty Yuen Kwan; Wong, Vincent Kam Wai; Ng, Jerome P. L.] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau, Peoples R China; [Zhang, Zhen-Zhen] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Infect Dis,Minist Educ,Key Lab Child Dev & Di, Chongqing Key Lab Child Infect & Immun,Childrens H, Chongqing, Peoples R China"

通信作者："Chen, J (通讯作者)，Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Designated Chinese Minist Educ, Chongqing, Peoples R China.; Zhang, ZZ (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Infect Dis,Minist Educ,Key Lab Child Dev & Di, Chongqing Key Lab Child Infect & Immun,Childrens H, Chongqing, Peoples R China."

来源：FRONTIERS IN PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000812732800001

JCR分区：Q1

影响因子：5.6

年份：2022

卷号：13

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：hepatitis B virus; HBsAg; pimobendan; anti-HBV agents; drug repurposing

摘要："Current anti-HBV therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure, inducing hepatitis B surface antigen (HBsAg) loss in very few patients. Notably, the level of HBsAg has been established as an accurate indicator to evaluate the drug efficacy and predict the disease prognosis, thus exploring a novel drug targeting HBsAg will be of great significance. Herein, by screening 978 compounds from an FDA-approved drug library and determining the inhibitory function of each drug on HBsAg level in HepG2.2.15 cells supernatant, we identified that pimobendan (Pim) has a powerful antiviral activity with relatively low cytotoxicity. The inhibitory effect of Pim on HBsAg as well as other HBV markers was validated in HBV-infected cell models and HBV-transgenic mice. Mechanistically, real-time PCR and dual-luciferase reporter assay were applied to identify the partial correlation of transcription factor CAAT enhancer-binding protein alpha (C/EBP alpha) with the cccDNA transcription regulated by Pim. This indicates Pim is an inhibitor of HBV transcription through suppressing HBV promoters to reduce HBV RNAs levels and HBsAg production. In conclusion, Pim was identified to be a transcription inhibitor of cccDNA, thereby inhibiting HBsAg and other HBV replicative intermediates both in vitro and in vivo. This report may provide a promising lead for the development of new anti-HBV agent."

基金机构："National Natural Science Foundation of China [81861168035, 81922011, 81871656]; Creative Research Group of CQ University [CXQT19016]; Chongqing Natural Science Foundation [cstc2018jcyjAX0114, cstc2021jcyj-msxmX0139]"

基金资助正文："Funding This work was supported by the National Natural Science Foundation of China (Grant No. 81861168035, 81922011 and 81871656 to JC), Creative Research Group of CQ University (CXQT19016 to JC), and Chongqing Natural Science Foundation (cstc2018jcyjAX0114 to JC and cstc2021jcyj-msxmX0139 to Z-ZZ)."