| Autor: |
Li Wang, Qihui Zhu, Jitao David Zhang, Yaling Zhang, Xiaoju Ni, Kunlun Xiang, Jiaxi Jiang, Baocun Li, Youjun Yu, Hui Hu, Meifang Zhang, Waikwong Wu, Jing Zeng, Zhipeng Yan, Jieyu Dai, Kai Sun, Xin Zhang, Dongdong Chen, Song Feng, Lisa Sach-Peltason, John A.T. Young, Lu Gao |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Journal of Hepatology. 78:742-753 |
| ISSN: |
0168-8278 |
| DOI: |
10.1016/j.jhep.2022.12.014 |
| Popis: |
The persistence of covalently closed circular DNA (cccDNA) in infected hepatocytes is the major barrier preventing viral eradication with existing therapies in patients with chronic hepatitis B (CHB). Therapeutic agents that can eliminate cccDNA are urgently needed to achieve virus eradication and thus HBV cure.A phenotypic assay with HBV-infected primary human hepatocytes (PHHs) was employed to screen for novel cccDNA inhibitors. A HBVcircle mouse model and a urokinase-type plasminogen activator-severe combined immunodeficiency (uPA-SCID) humanized liver mouse model were used to evaluate the anti-HBV efficacy of the discovered cccDNA inhibitors.Potent and dose-dependent reductions in extracellular HBV DNA, HBsAg, and HBeAg levels were achieved upon the initiation of ccc_R08 treatment two days after the HBV infection of PHHs. More importantly, the level of cccDNA was specifically reduced by ccc_R08, while it did not obviously affect mitochondrial DNA. Additionally, ccc_R08 showed no significant cytotoxicity in PHHs or in multiple proliferating cell lines. The twice daily oral administration of ccc_R08 to HBVcircle model mice, which contained surrogate cccDNA molecules, significantly decreased the serum levels of HBV DNA and antigens, and these effects were sustained during the off-treatment follow-up period. Moreover, at the end of the follow-up, the levels of surrogate cccDNA molecules in the livers of ccc_R08-treated HBVcircle mice were reduced to below the lower limit of quantification (LLOQ).We have discovered a small molecule cccDNA inhibitor that reduces HBV cccDNA levels. cccDNA inhibitors potentially represent a new approach to completely cure patients chronically infected with HBV. IMPACT AND IMPLICATIONS: cccDNA persistence in HBV-infected hepatocytes is the root cause of chronic hepatitis B. We discovered a novel small molecule cccDNA inhibitor that can specifically reduce cccDNA levels in HBV infected hepatocytes. This type of molecule offers a new approach to completely cure patients chronically infected with HBV. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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