ABSTRACT
Chlorogenic acid and its related compounds are abundant plant polyphenols that have a diverse antiviral activity. In this study, HepG2.2.15 cells and duck hepatitis B virus infection model were used as in vitro and in vivo models to evaluate their anti-HBV activity. In the cell model, all the three compounds inhibited HBV-DNA replication as well as HBsAg production. Chlorogenic acid and caffeic acid also reduced serum DHBV level in DHBV-infected duckling model. Moreover, the anti-HBV activity of crude extracts of coffee beans, which have a high content of chlorogenic acid, was studied. Both the extracts of regular coffee and that of decaffeinated coffee showed inhibitory effect on HBV replication.
Subject(s)
Antiviral Agents/therapeutic use , Caffeic Acids/pharmacology , Chlorogenic Acid/therapeutic use , Hepadnaviridae Infections/drug therapy , Hepatitis B Virus, Duck/drug effects , Hepatitis, Viral, Animal/drug therapy , Quinic Acid/therapeutic use , Animals , Antiviral Agents/pharmacology , Caffeic Acids/therapeutic use , Cell Line , Chlorogenic Acid/pharmacology , Ducks , Hepatocytes/virology , Humans , Inhibitory Concentration 50 , Quinic Acid/pharmacology , Serum/virology , Virus Replication/drug effectsSubject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Design , Hepatitis B virus/drug effects , Antiviral Agents/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Microbial Sensitivity Tests , Molecular Structure , Small Molecule Libraries , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacology , Viral Nonstructural Proteins/drug effects , Virus Replication/drug effectsABSTRACT
We have recently reported that the naturally occurring spliced variant of Hepatitis B virus protein, HBSP, displayed proapoptotic activity through its BH3 domain. To investigate whether the BH3 domain in HBSP interacted with Bcl-2 family of proteins, HBSP and Bcl-2 family of proteins were cloned and expressed in our mammalian two-hybrid system. Interaction assays were carried out in HepG2 cells and measured by the activity of the reporter gene product luciferase. Our results indicated that HBSP interacted with Bcl-2/Bcl-xl in vitro and induced apoptosis in HepG2 cells.
Subject(s)
Apoptosis/physiology , Hepatitis B virus/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Viral Proteins/metabolism , bcl-X Protein/metabolism , Alternative Splicing , Cell Line , Humans , Protein Isoforms/genetics , Protein Isoforms/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Viral Proteins/genetics , bcl-X Protein/geneticsABSTRACT
A series of 1-isopropylsulfonyl-2-amine benzimidazole derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in the HepG2.2.15 cell line. In general, these derivatives are potent HBV inhibitors (IC(50)<4 microM) with high selectivity indices (SIs>40). Compounds 5b-e, g, j, and 9a were among the most prominent compounds, with IC(50)s of 0.70-2.0 microM and SIs of 41-274. The potent anti-HBV activity and safety profiles of the most promising compounds 5d and j (IC(50)s=0.70 microM, SIs>120) demonstrate the potential of this series of benzimidazoles for the development of new anti-HBV drugs.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Hepatitis B virus/drug effects , Animals , Benzimidazoles/chemistry , Benzimidazoles/toxicity , Cattle , Cell Death/drug effects , Cell Line, Tumor , DNA, Viral/biosynthesis , Hepatitis B virus/physiology , Humans , Inhibitory Concentration 50ABSTRACT
A series of novel benzimidazole derivatives was synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in vitro. Strong activity against HBV replication and low cytotoxicity were generally observed in these benzimidazoles. The most promising compounds were 12a and 12b, with similar high antiviral potency (IC50 = 0.9 and 0.7 microM, respectively) and remarkable selectivity indices (>1111 and 714, respectively). They were selected for further evaluation as novel HBV inhibitors.
