title: Identification of hydrolyzable tannins (punicalagin, punicalin and geraniin) as novel inhibitors of hepatitis B virus covalently closed circular DNA.
abstract: 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.
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 43001, Hubei, China.
authors: Chunlan
authors: C
authors: Liu
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors: Dawei
authors: D
authors: Cai
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 43001, Hubei, China.
authors: Lin
authors: L
authors: Zhang
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 43001, Hubei, China.
authors: Wei
authors: W
authors: Tang
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors: Ran
authors: R
authors: Yan
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA. Electronic address: haitguo@iupui.edu.
authors: Haitao
authors: H
authors: Guo
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 43001, Hubei, China. Electronic address: chenxl@wh.iov.cn.
authors: Xulin
authors: X
authors: Chen
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D004270:DNA, Circular / Q000037:antagonists & inhibitors* / Q000187:drug effects; D004279:DNA, Viral / Q000037:antagonists & inhibitors* / Q000187:drug effects; D055808:Drug Discovery; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005960:Glucosides / Q000494:pharmacology*; D006509:Hepatitis B / Q000188:drug therapy; D006513:Hepatitis B e Antigens / Q000187:drug effects / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects*; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D054852:Small Molecule Libraries; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004270:DNA, Circular; D004279:DNA, Viral; D004365:Drugs, Chinese Herbal; D005960:Glucosides; D006513:Hepatitis B e Antigens; D047348:Hydrolyzable Tannins; D054852:Small Molecule Libraries; C024603:Geraniin; C115642:punicalagin; C115643:punicalin
keywords: Antiviral; HBV; Hydrolyzable tannins; cccDNA