Diverse Effects of Cyclosporine on Hepatitis C Virus Strain Replication

Ishii, Naoto; Watashi, Koichi; Hishiki, Takayuki; Goto, Kaku; Inoue, Daisuke; Hijikata, Makoto; Wakita, Takaji; Kato, Naoya; Shimotohno, Kunitada

doi:10.1128/jvi.80.9.4510-4520.2006

Cited by 135 publications

(136 citation statements)

References 34 publications

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“…To further confirm the aberrant upregulation of AID by HCV infection, we analysed the expression levels of endogenous AID in the full-genome HCV replicon cells producing whole HCV RNA and proteins (NNC#2 cells) (Ishii et al, 2006). Consistent with a previous report, the expression of the HCV core in the replicon cells was confirmed by RT-PCR (Figure 4d).…”

Section: Hcv Core Protein Triggers Aid Expression Via Nf-kbsupporting

confidence: 82%

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Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling

et al. 2007

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Activation-induced cytidine deaminase (AID) is involved in somatic DNA alterations of the immunoglobulin gene for amplification of immune diversity. The fact that constitutive expression of AID in mice causes tumors in various organs, including lymphoid tissues and lungs, suggests the important role of the aberrant editing activity of AID on various tumor-related genes for carcinogenesis. AID expression, however, is restricted to activated B cells under physiological conditions. We demonstrate here that ectopic AID expression is induced in response to tumor necrosis factor-a stimulation in cultured human hepatocytes. The proinflammatory cytokine-mediated expression of AID is achieved by IjB kinase-dependent nuclear factor (NF)-jB signaling pathways. Hepatitis C virus, one of the leading causes of hepatocellular carcinoma (HCC), enhanced AID expression via NF-jB activation through expression of viral core protein. The aberrant expression of AID in hepatoma-derived cells resulted in accumulation of genetic alterations in the c-myc and pim1 genes, suggesting that inappropriate expression of AID acts as a DNA mutator that enhances the genetic susceptibility to mutagenesis in human hepatocytes. Our current findings indicate that the inappropriate expression of AID is induced by proinflammatory cytokine stimulation and may provide the link between hepatic inflammation and the development of HCC.

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Section: Hcv Core Protein Triggers Aid Expression Via Nf-kbsupporting

confidence: 82%

“…A full genome HCV replicon system was established by transfecting to the cells with the NN strain (genotype 1b) (Ishii et al, 2006).…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling

et al. 2007

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“…One of the potential compounds (25) was further confirmed by single crystal Xray diffraction analysis. Figure 3 represents an ellipsoidal plot of 25 as an ORTEP diagram with 30% probability level.…”

mentioning

confidence: 87%

Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

Konreddy

Toyama

Ito

et al. 2013

ACS Med. Chem. Lett.

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High genetic variability in hepatitis C virus (HCV), emergence of drug resistant viruses and side effects demand the requirement for development of new scaffolds to show an alternate mechanism. Herein, we report discovery of new scaffold I based on 4-hydroxyamino α-pyranone carboxamide as promising anti-HCV agents. A comprehensive structure−activity relationship (SAR) was explored with several newly synthesized compounds. In all promising compounds (17−19, 21−22, 24− 25, and 49) with EC 50 ranging 0.15 to 0.40 μM, the aryl group at C-6 position of α-pyranone were unsubstituted. In particular, 25 demonstrated potential anti-HCV activity with EC 50 of 0.18 μM in cell based HCV replicon system with lower cytotoxicity (CC 50 > 20 μM) and provided a new scaffold for anti-HCV drug development. Further investigations, including biochemical characterization, are yet to be performed to elucidate its possible mode of action. KEYWORDS: Hepatitis C virus, non-nucleoside inhibitor, α-pyranone carboxamide H epatitis C virus (HCV) is a single stranded 9.6 kb RNA virus of the Flaviviridae family predominantly infecting hepatocytes. HCV infection is silent and in long-term may lead to serious liver disease, including fibrosis and cirrhosis followed by hepatocellular carcinoma. 1,2 The prophylactic treatment has been of very limited success, 3 and so far no vaccine is available. 4 A serious health threat has been realized, and a series of investigations are underway to discover direct acting antivirals (DAAs) as promising anti-HCV agents. 5 The potential molecules 1−4 (Figure 1) belonging to DAAs target mainly three viral enzymes: (i) protease NS3/4A, (ii) replicase factor NS5A, and (iii) HCV RNA-dependent RNA polymerase (HCV RdRp) NS5B. 6 The medicinal chemistry approaches with breakthrough exploration in HCV biology 7 were translated recently into first generation DAAs, boceprevir 8 and telaprevir 9 (protease inhibitors) approved by US FDA. Several new generation protease inhibitors are under serious investigations to combat the challenges associated with anti-HCV therapy. 10,11 The current standard of care (SoC) for HCV treatment includes one of the approved protease inhibitors combined with pegylated interferon-α (PegIFN) and ribavirin (RBV).The new regimen improves sustained viral response (SVR) rates to ∼75%; 8,9 however, it also adds side effect burden to patients. The use of PegIFN/RBV is associated with severe side effects followed by treatment discontinuation and contraindication. 12 Overall, drug-resistance, drug−drug interactions, and side effects are major concerns, 13 which demand effective PegIFN/RBV free regimen. In addition to recent success in protease inhibitors, 10,11 parallel research efforts are in progress to discover nucleoside inhibitors (NIs) to find novel DAAs to target HCV RdRp. 14,15 Similarly, several non-nucleoside allosteric inhibitors are in development phase, which may provide a choice of combination with other DAAs to discover

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“…The JFH-1 2a replicon has been demonstrated to have lower CsA susceptibility compared to a genotype 1b replicon. 8 This, together with clinical data, suggests that different HCV genotypes may have a variable response to immunosuppressants. Thus, treatment of HCV liver transplant patients may need to be tailored based on sequence diversity.…”

Section: H Epatitis C Virus (Hcv) Chronically Infects Ap-mentioning

confidence: 99%

“…[6][7][8][9] CsA binds molecular chaperones called cyclophilins (CyPs) in cells and inhibits their peptidylproline isomerase activity. 10 The CsA-CyP complex also binds calcineurin and inhibits its activation of T cells.…”

Section: H Epatitis C Virus (Hcv) Chronically Infects Ap-mentioning

confidence: 99%

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

et al. 2007

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HCV reoccurs after liver transplantation and increases mortality. Cyclosporine, but not tacrolimus, has potent antiviral effects against HCV replication in cell culture. To determine the conditions, if any, under which HCV is susceptible to cyclosporine in vivo, we selected for cyclosporine-resistant mutant HCV in vitro. The resulting mutations were mapped to x-ray crystallographic structures and sequence databases. Mutations selected by cyclosporine were clustered in the nonstructural (NS) proteins NS5A and NS5B. Different sets of mutations in NS5A, paired with the same 2 NS5B mutations, conferred different levels of cyclosporine resistance when engineered back into the HCV replicon. Mutations in NS5B are structurally consistent with a proposed model of regulation of RNA binding by cyclophilin B (CyPB). These mutations also highlight a natural polymorphism between different HCV genotypes that correlates with the variation in response to cyclosporine A (CsA) noted in some clinical trials. Replicons engineered to have mutations in only NS5A (P < 0.0001) or only NS5B (P ‫؍‬ 0.002) suggest that while both NS5A or NS5B variants alter cyclosporine susceptibility, NS5A has the largest effect. Conclusion: Preexisting sequence variation could alter the effect of cyclosporine on HCV in vivo. (HEPATOLOGY

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Diverse Effects of Cyclosporine on Hepatitis C Virus Strain Replication

Cited by 135 publications

References 34 publications

Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling

Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling

Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

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