Identification of a novel long-acting 4'-modified nucleoside reverse transcriptase inhibitor against HBV.

Autor: Higashi-Kuwata N; Department of Refractory Viral Infections, National Center for Global Health & Medicine Research Institute, Tokyo, Japan., Hayashi S; Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan., Kumamoto H; Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama, Japan., Ogata-Aoki H; Department of Refractory Viral Infections, National Center for Global Health & Medicine Research Institute, Tokyo, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Das D; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Venzon D; Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Hattori SI; Department of Refractory Viral Infections, National Center for Global Health & Medicine Research Institute, Tokyo, Japan., Bulut H; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Hashimoto M; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan., Otagiri M; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan., Takamune N; Kumamoto Innovative Development Organization, Kumamoto University, Kumamoto, Japan., Kishimoto N; Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan., Davis DA; Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Misumi S; Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan., Kakuni M; PhoenixBio Co., Ltd., Higashi-hiroshima, Hiroshima, Japan., Tanaka Y; Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan., Mitsuya H; Department of Refractory Viral Infections, National Center for Global Health & Medicine Research Institute, Tokyo, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Department of Clinical Sciences, Kumamoto University Hospital, Kumamoto, Japan. Electronic address: hmitsuya@hosp.ncgm.go.jp.
Jazyk: angličtina
Zdroj: Journal of hepatology [J Hepatol] 2021 May; Vol. 74 (5), pp. 1075-1086. Date of Electronic Publication: 2020 Dec 15.
DOI: 10.1016/j.jhep.2020.12.006
Abstrakt: Background & Aims: While certain nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are efficacious in treating HBV infection, their effects are yet to be optimized and the emergence of NRTI-resistant HBV variants is an issue because of the requirement for lifelong treatment. The development of agents that more profoundly suppress wild-type and drug-resistant HBVs, and that have a long-acting effect, are crucial to improve patient outcomes.
Methods: Herein, we synthesized a novel long-acting 4'-modified NRTI termed E-CFCP. We tested its anti-HBV activity in vitro, before evaluating its anti-HBV activity in HBV-infected human-liver-chimeric mice (PXB-mice). E-CFCP's long-acting features and E-CFCP-triphosphate's interactions with the HBV reverse transcriptase (HBV-RT) were examined.
Results: E-CFCP potently blocked HBV WT D1 production (IC 50 qPCR_cell = 1.8 nM) in HepG2.2.15 cells and HBV WT C2 (IC 50 SB_cell =0.7 nM), entecavir (ETV)-resistant HBV ETV-R L180M/S202G/M204V (IC 50 SB_cell =77.5 nM), and adefovir-resistant HBV ADV-R A181T/N236T production (IC 50 SB_cell =14.1 nM) in Huh7 cells. E-CFCP profoundly inhibited intracellular HBV DNA production to below the detection limit, but ETV and tenofovir alafenamide (TAF) failed to do so. E-CFCP also showed less toxicity than ETV and TAF. E-CFCP better penetrated hepatocytes and was better tri-phosphorylated; E-CFCP-triphosphate persisted intracellularly for longer than ETV-triphosphate. Once-daily peroral E-CFCP administration over 2 weeks (0.02~0.2 mg/kg/day) reduced HBV WT C2 -viremia by 2-3 logs in PXB-mice without significant toxicities and the reduction persisted over 1-3 weeks following treatment cessation, suggesting once-weekly dosing capabilities. E-CFCP also reduced HBV ETV-R L180M/S202G/M204V -viremia by 2 logs over 2 weeks, while ETV completely failed to reduce HBV ETV-R L180M/S202G/M204V -viremia. E-CFCP's 4'-cyano and fluorine interact with both HBV WT -RT and HBV ETV-R L180M/S202G-M204 -RT via Van der Waals and polar forces, being important for E-CFCP-triphosphate's interactions and anti-HBV potency.
Conclusion: E-CFCP represents the first reported potential long-acting NRTI with potent activity against wild-type and treatment-resistant HBV.
Lay Summary: Although there are currently effective treatment options for HBV, treatment-resistant variants and the need for lifelong therapy pose a significant challenge. Therefore, the development of new treatment options is crucial to improve outcomes and quality of life. Herein, we report preclinical evidence showing that the anti-HBV agent, E-CFCP, has potent activity against wild-type and treatment-resistant variants. In addition, once-weekly oral dosing may be possible, which is preferrable to the current daily dosing regimens.
Competing Interests: Conflict of interest Yasuhito Tanaka has received personal fees from Fujirebio Inc. Except for Yasuhito Tanaka, none of the co-authors has issues to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.
(Published by Elsevier B.V.)
Databáze: MEDLINE
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