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Antiviral Res. 2017 Nov 9. pii: S0166-3542(17)30532-6. doi: 10.1016/j.antiviral.2017.11.008. [Epub ahead of print]
Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice.Long KR1, Lomonosova E2, Li Q3, Ponzar NL4, Villa JA5, Touchette E6, Rapp S7, Liley RM8, Murelli RP9, Grigoryan A10, Buller RM11, Wilson L12, Bial J13, Sagartz JE14, Tavis JE15.
Author information
1Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].2Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].3Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].4Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].5Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].6Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].7Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].8Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].9Brookyln College, City University of New York, NY 11210, USA. Electronic address: [email protected].10Brookyln College, City University of New York, NY 11210, USA. Electronic address: [email protected].11Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].12Yecuris Corporation, P.O. Box 4645, Tualatin, OR 97062, USA. Electronic address: [email protected].13Yecuris Corporation, P.O. Box 4645, Tualatin, OR 97062, USA. Electronic address: [email protected].14Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: [email protected].15Department of Molecular Microbiology and Immunology & the Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: [email protected].
AbstractChronic hepatitis B virus infection cannot be cured by current therapies, so new treatments are urgently needed. We recently identified novel inhibitors of the hepatitis B virus ribonuclease H that suppress viral replication in cell culture. Here, we employed immunodeficient FRG KO mice whose livers had been engrafted with primary human hepatocytes to ask whether ribonuclease H inhibitors can suppress hepatitis B virus replication in vivo. Humanized FRG KO mice infected with hepatitis B virus were treated for two weeks with the ribonuclease H inhibitors #110, an α-hydroxytropolone, and #208, an N-hydroxypyridinedione. Hepatitis B virus viral titers and S and e antigen plasma levels were measured. Treatment with #110 and #208 caused significant reductions in plasma viremia without affecting hepatitis B virus S or e antigen levels, and viral titers rebounded following treatment cessation. This is the expected pattern for inhibitors of viral DNA synthesis. Compound #208 suppressed viral titers of both hepatitis B virus genotype A and C isolates. These data indicate that Hepatitis B virus replication can be suppressed during infection in an animal by inhibiting the viral ribonuclease H, validating the ribonuclease H as a novel target for antiviral drug development.
Copyright © 2017. Published by Elsevier B.V.
KEYWORDS: Antivirals; Chimeric mice; FRG; HBV; RNaseH
PMID:29129708DOI:10.1016/j.antiviral.2017.11.008
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