Dysregulation of Retinoic Acid Receptor Diminishes Hepatocyte Permissiveness to Hepatitis B Virus Infection through Modulation of Sodium Taurocholate Cotransporting Polypeptide (NTCP) Expression

Tsukuda, Senko; Watashi, Koichi; Iwamoto, Masashi; Suzuki, Ritsuro; Aizaki, Hideki; Okada, M.; Sugiyama, Masaya; Kojima, Soichi; Tanaka, Yasuhito; Mizokami, Masashi; Li, Jisu; Tong, Shuping; Wakita, Takaji

doi:10.1074/jbc.m114.602540

Cited by 58 publications

(57 citation statements)

References 58 publications

(62 reference statements)

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“…After incubation for 72 h, the cells were lysed and their luciferase activity was measured with a Luciferase Assay System according to the manufacturer's protocol (Promega) (12). Simultaneously, cell viability was measured at 72 h posttreatment with a Cell Proliferation Kit II (XTT), as recommended by the manufacturer (Roche) (37). This replicon's advantage for high-throughput assays enables one to produce the large scale of data that is required for quantifying the antiviral activity of drugs and drug combinations.…”

Section: Methodsmentioning

confidence: 99%

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Koizumi

Ohashi

Nakajima

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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With the introduction of direct-acting antivirals (DAAs), treatment against hepatitis C virus (HCV) has significantly improved. To manage and control this worldwide infectious disease better, the “best” multidrug treatment is demanded based on scientific evidence. However, there is no method available that systematically quantifies and compares the antiviral efficacy and drug-resistance profiles of drug combinations. Based on experimental anti-HCV profiles in a cell culture system, we quantified the instantaneous inhibitory potential (IIP), which is the logarithm of the reduction in viral replication events, for both single drugs and multiple-drug combinations. From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-α, IFN-λ1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. We also compared intrinsic antiviral activities of a panel of drug combinations. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials.

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Section: Methodsmentioning

confidence: 99%

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Koizumi

Ohashi

Nakajima

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Although already known NTCP inhibitors have been reported to inhibit viral infection, there is no report identifying novel compounds that target NTCP and inhibit HBV infection. (Ϫ)-Epigallocatechin-3-gallate (EGCG) and Ro41-5253 decreased cell surface NTCP expression and reduced HBV infection (19,50). Vanitaracin A was shown to have a greater potential to inhibit HBV infection (IC 50 of Ͻ1 M) than these compounds (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…To examine binding between a pre-S1 peptide and host cells, we treated HepG2-hNTCP-C4 cells with 40 nM 6-carboxytetramethylrhodamine (TAMRA)-labeled pre-S1 peptide (pre-S1-TAMRA) for 30 min and then washed out free peptide, fixed the cells with paraformaldehyde, and finally stained the samples with 4=,6-diamidino-2-phenylindole (DAPI), as described previously (19).…”

Section: Methodsmentioning

confidence: 99%

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A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide

Kaneko

Watashi

Kamisuki

et al. 2015

J Virol

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Anti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. A challenge of drug development is the identification of small molecules thatC hronic hepatitis B virus (HBV) infection, constituting a public health problem, with an estimated 240 million carriers worldwide (1), elevates the risk of development of liver cirrhosis and hepatocellular carcinoma (2). Antiviral agents against HBV include nucleos(t)ide analogs (NAs) and interferons (IFNs), which can achieve significant reductions in HBV loads (3). Although IFN-␣ and its pegylated form (peg-IFN-␣) modulate host immune responses to HBV infection or directly inhibit HBV replication in hepatocytes, these regimens show low tolerability because of serious adverse effects (3, 4). NAs, including lamivudine (LMV), adefovir, entecavir (ETV), tenofovir, and telbivudine, inhibit reverse transcription to suppress HBV replication, but longterm treatment with some of these NAs often results in selection for a significant number of drug-resistant viruses, which decreases treatment efficacy; i.e., the introduction of two substitutions, L180M and M204V, in the polymerase region leads to resistance to LMV, and an additional mutation of either T184, S202, or M250 with the L180M/M204V mutations confers further ETV resistance (5). More notably, it is difficult for the above-mentioned anti-HBV drugs to completely eliminate HBV from infected cells. Future antiviral strategies include multidrug treatment with an existing drug and a new anti-HBV agent. Consequently, there is a

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“…Iwamoto et al [120] , Watashi et al [121] and Tsukuda et al [122] reported that cyclosporine A and its analogs blocked HBV entry through inhibiting the interaction between NTCP and the HBV large surface protein. HBV entry inhibitors might also be useful for controlling HBV infection in the near future.…”

Section: Sodium Taurocholate Cotransporting Polypeptidementioning

confidence: 99%

Current and future directions for treating hepatitis B virus infection

Tawada

Yokosuka

2015

WJH

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Hepatitis B virus (HBV) persistently infects approximately 350 million people, and approximately 600000 liverrelated deaths are observed per year worldwide. HBV infection is also one of the major risk factors for hepatocellular carcinoma (HCC). The persistence of serum hepatitis B e antigen (HBeAg) and high level of serum HBV DNA are thought to reflect a high HBV replication status in hepatocytes, causing cirrhosis, HCC and liver-related deaths. It has been reported that antiviral therapy, such as peginterferon and nucleos(t)ide analogues (NUCs), could suppress liver-related death by inhibiting the HBV DNA levels and inducing seroconversion from HBeAg to antibody to HBe antigen. Currently, peginterferon is widely used, but there are also several disadvantages in the use of peginterferon, such as various adverse events, the administration route and duration. It is difficult to predict the effects of treatment and interferon is contraindicated for the patients with advanced fibrosis of the liver and cirrhosis. With respect to NUCs, entecavir and tenofovir disoproxil fumarate are current the first-choice drugs. NUCs can be administered orally, and their anti-viral effects are stronger than that of peginterferon. However, because cessation of NUC administration leads to high levels of viral replication and causes severe hepatitis, they must be administered for a long time. On the other hand, the use of both interferon and NUCs cannot eliminate covalently closed circular DNA of HBV. In this review, we evaluate the natural course of chronic HBV infection and then provide an outline of these representative drugs, such as peginterferon, entecavir and tenofovir disoproxil fumarate.

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Dysregulation of Retinoic Acid Receptor Diminishes Hepatocyte Permissiveness to Hepatitis B Virus Infection through Modulation of Sodium Taurocholate Cotransporting Polypeptide (NTCP) Expression

Cited by 58 publications

References 58 publications

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide

Current and future directions for treating hepatitis B virus infection

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