Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity

Shimura, Satomi; Watashi, Koichi; Fukano, Kento; Peel, Michael R.; Sluder, Ann E.; Kawai, Fumihiro; Iwamoto, Masashi; Tsukuda, Senko; Takeuchi, Junko; Miyake, Takeshi; Sugiyama, Masaya; Ogasawara, Yuki; Park, Sam Yong; Tanaka, Yasuhito; Kusuhara, Hiroyuki; Mizokami, Masashi; Sureau, Camille; Wakita, Takaji

doi:10.1016/j.jhep.2016.11.009

Cited by 101 publications

(89 citation statements)

References 51 publications

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“…Other drugs already in use that block the in vitro interactions of HBV with NTCP include the immunomodulatory agent CyclosporinA, anti-retroviral ritonavir, ezetimibe (cholesterol lowering) and irbesarten (anti-hypertensive angiotensin II receptor antagonist) [178] . Recent studies have identified new small molecules (derivatives of CyclosporinA) which are able to inhibit HBV viral attachment, without impairing the NTCP-dependent uptake of bile acids, suggesting that these functions may be separated [179] .…”

Section: Treatmentmentioning

confidence: 99%

HIV-hepatitis B virus coinfection

Singh¹,

Crane

Audsley

et al. 2017

Aids

175

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HIV infection has a significant impact on the natural history of chronic HBV infection, with increased levels of HBV DNA, accelerated progression of liver disease and increased liver-associated mortality compared to HBV mono-infection. Widespread uptake and early initiation of HBV-active antiretroviral therapy (ART) has substantially improved the natural history of HIV-HBV co-infection but the prevalence of liver disease remains elevated in this population. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease and seroconversion in HIV-HBV co-infection in the era of HBV-active ART and the effects of HIV directly on liver disease. We also review novel therapeutics for the management of HBV with a particular emphasis on clinical strategies being developed for an HBV cure and an HIV cure and their impact on HIV-HBV co-infected individuals.

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Section: Treatmentmentioning

confidence: 99%

HIV-hepatitis B virus coinfection

Singh¹,

Crane

Audsley

et al. 2017

Aids

175

View full text Add to dashboard Cite

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“…Currently, primary human hepatocytes (PHHs) (Lempp et al, 2017;Ni and Urban, 2017;Shimura et al, 2017), HepaRG cells (Gripon et al, 2002;Schulze et al, 2012), and primary tupia hepatocytes (PTHs) (Kock et al, 2001;Ren and Nassal, 2001) are the main cell models used to study the early steps of HBV infection. PHHs, the natural host of HBV, are regarded as the ideal cellular model for HBV infection.…”

Section: Introductionmentioning

confidence: 99%

Productive HBV infection of well-differentiated, hNTCP-expressing human hepatoma-derived (Huh7) cells

et al. 2017

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Feasible and effective cell models for hepatitis B virus (HBV) infection are required for investigating the complete lifecycle of this virus, including the early steps of viral entry. Resistance to dimethyl sulfoxide/polyethylene glycol (DMSO/PEG), hNTCP expression, and a differentiated state are the limiting factors for successful HBV infection models. In the present study, we used a hepatoma cell line (Huh7D hNTCP ) to overcome these limiting factors so that it exhibits excellent susceptibility to HBV infection. To achieve this goal, different hepatoma cell lines were tested with 2.5% DMSO / 4% PEG8000, and one resistant cell line (Huh7D) was used to construct a stable hNTCP-expressing cell line (Huh7D hNTCP ) using a recombinant lentivirus system. Then, the morphological characteristics and differentiation molecular markers of Huh7D hNTCP cells with or without DMSO treatment were characterized. Finally, the susceptibility of Huh7D hNTCP cells to HBV infection was assessed. Our results showed that Huh7D cells were resistant to 2.5% DMSO / 4% PEG8000, whereas the others were not. Huh7D hNTCP cells were established to express a high level of hNTCP compared to liver extracts, and Huh7D hNTCP cells rapidly transformed into a non-dividing, well-differentiated polarized phenotype under DMSO treatment. Huh7D hNTCP cells fully supported the entire lifecycle of HBV infection. This cell culture system will be useful for the analysis of host-virus interactions, which should facilitate the discovery of antiviral drugs and vaccines.

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“…129 The inhibition of NTCP by these inhibitors normally will result in the loss of transporter function of NTCP, leading to the inhibition of bile acid uptake, which might cause unwanted adverse effects. Interestingly, Shimura et al 130 derivatives with anti-HBV activity in vitro via direct interaction with NTCP to inhibit viral attachment. These compounds inhibited multiple HBV genotypes including one clinically relevant nucleoside analog-resistant HBV isolate.…”

Section: Sodium Taurocholate Cotransporting Polypeptidementioning

confidence: 99%

Medicinal chemistry strategies toward host targeting antiviral agents

2020

Medicinal Research Reviews

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Direct-acting antiviral agents (DAAs) represent a class of drugs targeting viral proteins and have been demonstrated to be very successful in combating viral infections in clinic. However, DAAs suffer from several inherent limitations, including narrow-spectrum antiviral profiles and liability to drug resistance, and hence there are still unmet needs in the treatment of viral infections. In comparison, host targeting antivirals (HTAs) target host factors for antiviral treatment. Since host proteins are probably broadly required for various viral infections, HTAs are not only perceived, but also demonstrated to exhibit broad-spectrum antiviral activities. In addition, host proteins are not under the genetic control of viral genome, and hence HTAs possess much higher genetic barrier to drug resistance as compared with DAAs. In recent years, much progress has been made to the development of HTAs with the approval of chemokine receptor type 5 antagonist maraviroc for human immunodeficiency virus treatment and more in the pipeline for other viral infections. In this review, we summarize various host proteins as antiviral targets from a medicinal chemistry prospective. Challenges and issues associated with HTAs are also discussed. K E Y W O R D S broad-spectrum antivirals, direct-acting antiviral agents, drug resistance, host targeting antiviral agents

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Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity

Abstract: In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects.

Cited by 101 publications

References 51 publications

HIV-hepatitis B virus coinfection

HIV-hepatitis B virus coinfection

Productive HBV infection of well-differentiated, hNTCP-expressing human hepatoma-derived (Huh7) cells

Medicinal chemistry strategies toward host targeting antiviral agents

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