title: Synergistic Interactions between Hepatitis B Virus RNase H Antagonists and Other Inhibitors.
abstract: Combination therapies are standard for management of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections; however, no such therapies are established for human hepatitis B virus (HBV). Recently, we identified several promising inhibitors of HBV RNase H (here simply RNase H) activity that have significant activity against viral replicationin vitroHere, we investigated thein vitroantiviral efficacy of combinations of two RNase H inhibitors with the current anti-HBV drug nucleoside analog lamivudine, with HAP12, an experimental core protein allosteric modulator, and with each other. Anti-HBV activities of the compounds were tested in a HepG2-derived cell line by monitoring intracellular core particle DNA levels, and cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. The antiviral efficiencies of the drug combinations were evaluated using the median-effect equation derived from the mass-action law principle and combination index theorem of Chou and Talalay. We found that combinations of two RNase H inhibitors from different chemical classes were synergistic with lamivudine against HBV DNA synthesis. Significant synergism was also observed for the combination of the two RNase H inhibitors. Combinations of RNase H inhibitors with HAP12 had additive antiviral effects. Enhanced cytotoxicity was not observed in the combination experiments. Because of these synergistic and additive effects, the antiviral activity of combinations of RNase H inhibitors with drugs that act by two different mechanisms and with each other can be achieved by administering the compounds in combination at doses below the respective single drug doses.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University, and Saint Louis University Liver Center, St. Louis, Missouri, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Lomonosova
authors.affiliation: Molecular and Cellular Biology Department, Indiana University, Bloomington, Indiana, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Zlotnick
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University, and Saint Louis University Liver Center, St. Louis, Missouri, USA tavisje@slu.edu.
authors.forename: John E
authors.initials: JE
authors.lastname: Tavis
mesh_terms: D000494:Allosteric Regulation; D000998:Antiviral Agents / Q000494:pharmacology*; D003841:Deoxycytidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D015870:Gene Expression; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D019259:Lamivudine / Q000494:pharmacology*; D016914:Ribonuclease H / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D014334:Tropolone / Q000031:analogs & derivatives / Q000494:pharmacology; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: C558516:2-hydroxyisoquinoline-1,3(2H,4H)-dione; D000998:Antiviral Agents; D004338:Drug Combinations; D007546:Isoquinolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D014764:Viral Proteins; C497842:beta-thujaplicinol; D003841:Deoxycytidine; C070380:3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; D019259:Lamivudine; D014334:Tropolone; D016914:Ribonuclease H
keywords: RNase H; antiviral combination; hepatitis B virus; synergy; viral replication