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Rapamycin inhibits hepatitis B virus covalently closed circular DNA transcription by enhancing the ubiquitination of HBx
Yuan Zhang 1 2 3 4 , Liang Li 5 , Sheng-Tao Cheng 1 , Yi-Ping Qin 1 , Xin He 1 , Fan Li 6 , Dai-Qing Wu 1 , Fang Ren 7 8 , Hai-Bo Yu 1 , Jing Liu 1 , Juan Chen 1 , Ji-Hua Ren 1 , Zhen-Zhen Zhang 2 3 4
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
Department of Infectious Disease, Children's Hospital of Chongqing Medical University, Chongqing, China.
3
National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.
4
Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China.
5
Department of Gastroenterology, Chongqing University Three Gorges Hospital, Chongqing, China.
6
Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
7
Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chongqing, China.
8
Department of Laboratory Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China.
PMID: 36033851 PMCID: PMC9403416 DOI: 10.3389/fmicb.2022.850087
Abstract
Hepatitis B virus (HBV) infection is still a serious public health problem worldwide. Antiviral therapies such as interferon and nucleos(t)ide analogs efficiently control HBV replication, but they cannot eradicate chronic hepatitis B (CHB) because of their incapacity to eliminate endocellular covalently closed circular DNA (cccDNA). Thus, there is a necessity to develop new strategies for targeting cccDNA. As cccDNA is difficult to clear, transcriptional silencing of cccDNA is a possible effective strategy. HBx plays a vitally important role in maintaining the transcriptional activity of cccDNA and it could be a target for blocking the transcription of cccDNA. To screen new drugs that may contribute to antiviral therapy, the ability of 2,000 small-molecule compounds to inhibit HBx was examined by the HiBiT lytic detection system. We found that the macrolide compound rapamycin, which is clinically used to prevent acute rejection after organ transplantation, could significantly reduce HBx protein expression. Mechanistic studies demonstrated that rapamycin decreased the stability of the HBx protein by promoting its degradation via the ubiquitin-proteasome system. Moreover, rapamycin inhibited HBV RNA, HBV DNA, and cccDNA transcription levels in HBV-infected cells. In addition, HBx deficiency abrogated the inhibition of cccDNA transcription induced by rapamycin. Similar results were also confirmed in a recombinant cccDNA mouse model. In summary, we report a new small-molecule, rapamycin, which targets HBx to block HBV cccDNA transcription and inhibit HBV replication. This approach can identify new strategies to cure CHB.
Keywords: HBx; covalently closed circular DNA; hepatitis B virus; rapamycin; transcription.
Copyright © 2022 Zhang, Li, Cheng, Qin, He, Li, Wu, Ren, Yu, Liu, Chen, Ren and Zhang. |
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