Pimobendan Inhibits HBV Transcription and Replication by Suppressing HBV Promoters Activity
Si-Yu Yuan 1 , Hai-Bo Yu 1 , Zhen Yang 1 , Yi-Ping Qin 1 , Ji-Hua Ren 1 , Sheng-Tao Cheng 1 , Fang Ren 1 , Betty Yuen Kwan Law 2 , Vincent Kam Wai Wong 2 , Jerome P L Ng 2 , Yu-Jiao Zhou 1 , Xin He 1 , Ming Tan 1 , Zhen-Zhen Zhang 3 , Juan Chen 1
Affiliations
Affiliations
1
The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
2
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China.
3
Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Department of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing, China.
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 α (C/EBPα) 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.
Keywords: HBsAg; anti-HBV agents; drug repurposing; hepatitis B virus; pimobendan.