Inhibitory effect of fasiglifam on hepatitis B virus infections through suppression of the sodium taurocholate cotransporting polypeptide

Nio, Yasunori; Akahori, Yuichi; Okamura, Hitomi; Watashi, Koichi; Wakita, Takaji; Hijikata, Makoto

doi:10.1016/j.bbrc.2018.04.199

Cited by 12 publications

(5 citation statements)

References 27 publications

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“…This class of drugs includes cyclosporin A, ezetimibe, irbesartan, proscillaridin A, rapamycin, fasiglifam, and zafirlukast. 144,147–155 Small molecules that interact with NTCP have been identified from natural products or other sources using NTCP-reconstituted cell lines. This class includes vanitaracin A (a tricyclic polyketide), NTI-007 (an imidazopyridine derivative), NPD8716 (a coumarin derivative), SCY995 (a cyclosporin derivative), and WD1 (a macrocyclic peptide).…”

Section: Application For Drug Developmentmentioning

confidence: 99%

Cell and Animal Models for Studying Hepatitis B Virus Infection and Drug Development

Lin

Chen

et al. 2019

Gastroenterology

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Many cell culture and animal models have been used to study hepatitis B virus (HBV) replication and its effects in the liver; these have facilitated development of strategies to control and clear chronic HBV infection. We discuss the advantages and limitations of systems for studying HBV and developing antiviral agents, along with recent advances. New and improved model systems are needed. Cell culture systems should be convenient, support efficient HBV infection, and reproduce responses of hepatocytes in the human body. We also need animals that are fully permissive to HBV infection, convenient for study, and recapitulate human immune responses to HBV and effects in the liver. High-throughput screening technologies could facilitate drug development based on findings from cell and animal models.

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Section: Application For Drug Developmentmentioning

confidence: 99%

Cell and Animal Models for Studying Hepatitis B Virus Infection and Drug Development

Lin

Chen

et al. 2019

Gastroenterology

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“…The IC 50 was estimated to be approximately 10 μM. Fasiglifam (Figure , 35 ), a drug developed for the treatment of type 2 diabetes, was terminated in clinical trials because of drug-induced liver injury, which is probably related to its inhibitory effect on NTCP. , In HepG2-NTCP cells, treatment with 35 significantly decreased the HBV DNA level with an IC 50 of nearly 30 μM . As an NTCP inhibitor, benzamide compound N4 (Figure , 36 ) was identified to be active in in vitro experiments using HepG2.2.15 cells .…”

Section: Small Molecule Inhibitors Of Ntcpmentioning

confidence: 99%

“…81,82 In HepG2-NTCP cells, treatment with 35 significantly decreased the HBV DNA level with an IC 50 of nearly 30 μM. 83 As an NTCP inhibitor, benzamide compound N4 (Figure 11, 36) was identified to be active in in vitro experiments using HepG2.2.15 cells. 84 Administration of 36 reduced the HBsAg and HBeAg levels with IC 50 values of 7.5 μM and 3.7 μM.…”

Section: Other Active Small Molecule Inhibitorsmentioning

confidence: 99%

Inhibiting Sodium Taurocholate Cotransporting Polypeptide in HBV-Related Diseases: From Biological Function to Therapeutic Potential

et al. 2022

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Hepatitis B virus (HBV) infection is a worldwide health problem, and chronic infection can cause many diseases ranging from liver fibrosis to hepatocellular carcinoma (HCC) by complicated mechanisms. Currently, the treatment of HBV infection mainly depends on interferons (IFNs) and nucleotide analogues (NAs); however, both have some limitations. In 2012, sodium taurocholate cotransporting polypeptide (NTCP) was identified as the entry receptor of HBV. Based upon this groundbreaking discovery, a series of molecules have been gradually developed and evaluated to discover novel entry inhibitors targeting NTCP. However, only two macromolecules have been used for potential clinical applications so far. In this Perspective, we focus on summarizing the structural features that convey the biological functions of NTCP, as well as further discuss the anti-HBV activity and selectivity of inhibitors in HBV-related diseases, which should provide clues in the future for the discovery of drug candidates targeting NTCP.

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“…The other discovered NTCP inhibitors include FDA approved drugs (ie, CsA, 123 ezetimibe, and ritonavir, 124 etc), fasiglifam, 125 oxysterol, 126 vanitaracin A, 127 NTI007, 128 and among others. 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.…”

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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Inhibitory effect of fasiglifam on hepatitis B virus infections through suppression of the sodium taurocholate cotransporting polypeptide

Cited by 12 publications

References 27 publications

Cell and Animal Models for Studying Hepatitis B Virus Infection and Drug Development

Cell and Animal Models for Studying Hepatitis B Virus Infection and Drug Development

Inhibiting Sodium Taurocholate Cotransporting Polypeptide in HBV-Related Diseases: From Biological Function to Therapeutic Potential

Medicinal chemistry strategies toward host targeting antiviral agents

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