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

Autor: Long KR; Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: klong@7thwavelabs.com., Lomonosova E; 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., Li Q; 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., Ponzar NL; 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., Villa JA; 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., Touchette E; Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: etouchette@7thwavelabs.com., Rapp S; Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: srapp@7thwavelabs.com., Liley RM; Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: mliley@7thwavelabs.com., Murelli RP; 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., Grigoryan A; 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., Buller RM; 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., Wilson L; Yecuris Corporation, P.O. Box 4645, Tualatin, OR 97062, USA. Electronic address: lisawilson@yecuris.com., Bial J; Yecuris Corporation, P.O. Box 4645, Tualatin, OR 97062, USA. Electronic address: johnbial@yecuris.com., Sagartz JE; Seventh Wave Laboratories LLC, 19 Worthington Access Drive, Maryland Heights, MO 63043, USA. Electronic address: jsagartz@7thwavelabs.com., Tavis JE; 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.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2018 Jan; Vol. 149, pp. 41-47. Date of Electronic Publication: 2017 Nov 10.
DOI: 10.1016/j.antiviral.2017.11.008
Abstrakt: 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.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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