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Antiviral Res. 2018 Jan;149:41-47. doi: 10.1016/j.antiviral.2017.11.008. Epub 2017 Nov 10.

Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice.

Author information

1
Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: klong@7thwavelabs.com.
2
Department 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: elena.lomonosova@health.slu.edu.
3
Department 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: qilan.li@health.slu.edu.
4
Department 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: nathan.ponzar@slu.edu.
5
Department 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: juan.villatorrecilla@health.slu.edu.
6
Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: etouchette@7thwavelabs.com.
7
Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: srapp@7thwavelabs.com.
8
Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: mliley@7thwavelabs.com.
9
Brookyln College & PhD Program in Chemistry at the Graduate Center of the City University of New York, NY 11210, USA. Electronic address: rpmurelli@brooklyn.cuny.edu.
10
Brookyln College & PhD Program in Chemistry at the Graduate Center of the City University of New York, NY 11210, USA. Electronic address: alexgrigoryan@gmail.com.
11
Department 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.
12
Yecuris Corporation, P.O. Box 4645, Tualatin, OR 97062, USA. Electronic address: lisawilson@yecuris.com.
13
Yecuris Corporation, P.O. Box 4645, Tualatin, OR 97062, USA. Electronic address: johnbial@yecuris.com.
14
Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: jsagartz@7thwavelabs.com.
15
Department 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: john.tavis@health.slu.edu.

Abstract

Chronic 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.

KEYWORDS:

Antivirals; Chimeric mice; FRG; HBV; RNaseH

PMID:
29129708
PMCID:
PMC5743599
DOI:
10.1016/j.antiviral.2017.11.008
[Indexed for MEDLINE]
Free PMC Article

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