title: Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity.
abstract: Hepatitis B virus (HBV) remains a major human pathogen despite the development of both antiviral drugs and a vaccine, in part because the current therapies do not suppress HBV replication far enough to eradicate the virus. Here, we screened 51 troponoid compounds for their ability to suppress HBV RNaseH activity and HBV replication based on the activities of α-hydroxytropolones against HIV RNaseH, with the goal of determining whether the tropolone pharmacophore may be a promising scaffold for anti-HBV drug development. Thirteen compounds inhibited HBV RNaseH, with the best 50% inhibitory concentration (IC50) being 2.3 μM. Similar inhibition patterns were observed against HBV genotype D and C RNaseHs, implying limited genotype specificity. Six of 10 compounds tested against HBV replication in culture suppressed replication via blocking of viral RNaseH activity, with the best 50% effective concentration (EC50) being 0.34 μM. Eighteen compounds inhibited recombinant human RNaseH1, and moderate cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50]=25 to 79 μM). Therapeutic indexes ranged from 3.8 to 94. Efficient inhibition required an intact α-hydroxytropolone moiety plus one or more short appendages on the tropolone ring, but a wide variety of constituents were permissible. These data indicate that troponoids and specifically α-hydroxytropolones are promising lead candidates for development as anti-HBV drugs, providing that toxicity can be minimized. Potential anti-RNaseH drugs are envisioned to be employed in combination with the existing nucleos(t)ide analogs to suppress HBV replication far enough to block genomic maintenance, with the goal of eradicating infection.
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA Saint Louis University Liver Center, Saint Louis University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Lomonosova
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Eileen A
authors.initials: EA
authors.lastname: Moran
authors.affiliation: Center for World Health and Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Meyers
authors.affiliation: Basic Research Laboratory, National Cancer Institute, Frederick, Maryland, USA.
authors.forename: Stuart F J
authors.initials: SF
authors.lastname: Le Grice
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jian-kang
authors.initials: JK
authors.lastname: Jiang
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA Department of Chemistry, The Graduate Center, The City University of New York, New York, New York, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Meck
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA Department of Chemistry, The Graduate Center, The City University of New York, New York, New York, USA.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Hirsch
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA Department of Chemistry, The Graduate Center, The City University of New York, New York, New York, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: D'Erasmo
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA.
authors.forename: Duygu M
authors.initials: DM
authors.lastname: Suyabatmaz
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA Department of Chemistry, The Graduate Center, The City University of New York, New York, New York, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Murelli
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA Saint Louis University Liver Center, Saint Louis University School of Medicine, Saint Louis, Missouri, USA tavisje@slu.edu.
authors.forename: John E
authors.initials: JE
authors.lastname: Tavis
mesh_terms: D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D016914:Ribonuclease H / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014334:Tropolone / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D014334:Tropolone; D016914:Ribonuclease H