Identification of hydrolyzable tannins (punicalagin, punicalin and geraniin) as novel inhibitors of hepatitis B virus covalently closed circular DNA.
Identification of hydrolyzable tannins (punicalagin, punicalin and geraniin) as novel inhibitors of hepatitis B virus covalently closed circular DNA.
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DOI：
10.1016/j.antiviral.2016.08.026
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发表时间：
2016-10
影响因子：
7.6
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Liu C;Cai D;Zhang L;Tang W;Yan R;Guo H;Chen X
由于目前治疗B型肝炎可用药物的局限性，迫切需要开发靶向HBV cccDNA的新药物。通过使用基于细胞的测定，其中HBeAg的产生是以cccDNA依赖的方式，我们筛选了来自中草药的化合物库，用于抑制HBV cccDNA。三种可水解的单宁，特别是安石榴苷，安石榴苷和天竺葵素，成为新的抗HBV药物。在我们的试验中，这些化合物以剂量依赖性方式显著降低了分泌型HBeAg和cccDNA的产生，而没有显著改变病毒DNA复制。此外，安石榴苷不影响前核心/核心启动子活性、pgRNA转录、核心蛋白表达或HBsAg分泌。通过采用基于细胞的cccDNA积累和稳定性测定，我们发现这些单宁显著抑制cccDNA的建立，并适度促进预先存在的cccDNA的降解。总的来说，我们的研究结果表明，可水解单宁通过双重机制抑制HBV cccDNA的产生，通过防止cccDNA的形成和促进cccDNA衰变，尽管后者的作用相当小。这些可水解的单宁可作为开发治疗HBV感染的新药物的先导化合物。
The development of new agents to target HBV cccDNA is urgently needed because of the limitations of current available drugs for treatment of hepatitis B. By using a cell-based assay in which the production of HBeAg is in a cccDNA-dependent manner, we screened a compound library derived from Chinese herbal remedies for inhibitors against HBV cccDNA. Three hydrolyzable tannins, specifically punicalagin, punicalin and geraniin, emerged as novel anti-HBV agents. These compounds significantly reduced the production of secreted HBeAg and cccDNA in a dose-dependent manner in our assay, without dramatic alteration of viral DNA replication. Furthermore, punicalagin did not affect precore/core promoter activity, pgRNA transcription, core protein expression, or HBsAg secretion. By employing the cell-based cccDNA accumulation and stability assay, we found that these tannins significantly inhibited the establishment of cccDNA and modestly facilitated the degradation of preexisting cccDNA. Collectively, our results suggest that hydrolyzable tannins inhibit HBV cccDNA production via a dual mechanism through preventing the formation of cccDNA and promoting cccDNA decay, although the latter effect is rather minor. These hydrolyzable tannins may serve as lead compounds for the development of new agents to cure HBV infection.
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DOI：
10.1007/978-1-62703-484-5_13
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Cai, Dawei;Nie, Hui;Yan, Ran;Guo, Ju-Tao;Block, Timothy M;Guo, Haitao
通讯作者：
Guo, Haitao
影响因子：
56.9
作者：
Deres, K;Schröder, CH;Rübsamen-Waigmann, H
通讯作者：
Rübsamen-Waigmann, H
影响因子：
5.4
作者：
Moraleda, G;Saputelli, J;Mason, WS
通讯作者：
Mason, WS
影响因子：
7.6
作者：
Guo JT;Guo H
通讯作者：
Guo H
影响因子：
46.9
作者：
Petersen, Joerg;Dandri, Maura;Urban, Stephan
通讯作者：
Urban, Stephan