scholarly journals Tyrphostin AG1478 Inhibits Encephalomyocarditis Virus and Hepatitis C Virus by Targeting Phosphatidylinositol 4-Kinase IIIα

2016 ◽  
Vol 60 (10) ◽  
pp. 6402-6406 ◽  
Author(s):  
Cristina M. Dorobantu ◽  
Christian Harak ◽  
Rahel Klein ◽  
Lonneke van der Linden ◽  
Jeroen R. P. M. Strating ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Growth Factor Receptor ◽  
Encephalomyocarditis Virus ◽  
Genome Replication ◽  
Chemotherapy Agent ◽  
Epidermal Growth ◽  
Phosphatidylinositol 4 ◽  
Tyrphostin Ag1478

ABSTRACTEncephalomyocarditis virus (EMCV), like hepatitis C virus (HCV), requires phosphatidylinositol 4-kinase IIIα (PI4KA) for genome replication. Here, we demonstrate that tyrphostin AG1478, a known epidermal growth factor receptor (EGFR) inhibitor, also inhibits PI4KA activity, bothin vitroand in cells. AG1478 impaired replication of EMCV and HCV but not that of an EMCV mutant previously shown to escape PI4KA inhibition. This work uncovers novel cellular and antiviral properties of AG1478, a compound previously regarded only as a cancer chemotherapy agent.

scholarly journals Involvement of Creatine Kinase B in Hepatitis C Virus Genome Replication through Interaction with the Viral NS4A Protein

2009 ◽  
Vol 83 (10) ◽  
pp. 5137-5147 ◽  
Author(s):  
Hiromichi Hara ◽  
Hideki Aizaki ◽  
Mami Matsuda ◽  
Fumiko Shinkai-Ouchi ◽  
Yasushi Inoue ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Genome ◽  
Proteome Analysis ◽  
Virus Genome ◽  
Genome Replication ◽  
Creatine Kinase B ◽  
Efficient Replication

ABSTRACT Persistent infection with hepatitis C virus (HCV) is a major cause of chronic liver diseases. The aim of this study was to identify host cell factor(s) participating in the HCV replication complex (RC) and to clarify the regulatory mechanisms of viral genome replication dependent on the host-derived factor(s) identified. By comparative proteome analysis of RC-rich membrane fractions and subsequent gene silencing mediated by RNA interference, we identified several candidates for RC components involved in HCV replication. We found that one of these candidates, creatine kinase B (CKB), a key ATP-generating enzyme that regulates ATP in subcellular compartments of nonmuscle cells, is important for efficient replication of the HCV genome and propagation of infectious virus. CKB interacts with HCV NS4A protein and forms a complex with NS3-4A, which possesses multiple enzyme activities. CKB upregulates both NS3-4A-mediated unwinding of RNA and DNA in vitro and replicase activity in permeabilized HCV replicating cells. Our results support a model in which recruitment of CKB to the HCV RC compartment, which has high and fluctuating energy demands, through its interaction with NS4A is important for efficient replication of the viral genome. The CKB-NS4A association is a potential target for the development of a new type of antiviral therapeutic strategy.

scholarly journals Epidermal Growth Factor Receptor-Dependent Mutual Amplification between Netrin-1 and the Hepatitis C Virus

PLoS Biology ◽  
2016 ◽  
Vol 14 (3) ◽  
pp. e1002421 ◽  
Author(s):  
Marie-Laure Plissonnier ◽  
Thomas Lahlali ◽  
Maud Michelet ◽  
Fanny Lebossé ◽  
Jessica Cottarel ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Epidermal Growth

scholarly journals All Three Domains of the Hepatitis C Virus Nonstructural NS5A Protein Contribute to RNA Binding

2010 ◽  
Vol 84 (18) ◽  
pp. 9267-9277 ◽  
Author(s):  
Toshana L. Foster ◽  
Tamara Belyaeva ◽  
Nicola J. Stonehouse ◽  
Arwen R. Pearson ◽  
Mark Harris
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Binding ◽  
Nonstructural Protein ◽  
Binding Capacity ◽  
Specific Interaction ◽  
Genome Replication ◽  
Mobility Shift ◽  
Positive Strand Rna

ABSTRACT The hepatitis C virus (HCV) nonstructural protein NS5A is critical for viral genome replication and is thought to interact directly with both the RNA-dependent RNA polymerase, NS5B, and viral RNA. NS5A consists of three domains which have, as yet, undefined roles in viral replication and assembly. In order to define the regions that mediate the interaction with RNA, specifically the HCV 3′ untranslated region (UTR) positive-strand RNA, constructs of different domain combinations were cloned, bacterially expressed, and purified to homogeneity. Each of these purified proteins was probed for its ability to interact with the 3′ UTR RNA using filter binding and gel electrophoretic mobility shift assays, revealing differences in their RNA binding efficiencies and affinities. A specific interaction between domains I and II of NS5A and the 3′ UTR RNA was identified, suggesting that these are the RNA binding domains of NS5A. Domain III showed low in vitro RNA binding capacity. Filter binding and competition analyses identified differences between NS5A and NS5B in their specificities for defined regions of the 3′ UTR. The preference of NS5A, in contrast to NS5B, for the polypyrimidine tract highlights an aspect of 3′ UTR RNA recognition by NS5A which may play a role in the control or enhancement of HCV genome replication.

scholarly journals The Clinical Role of Serum Epidermal Growth Factor Receptor 3 in Hepatitis C Virus-Infected Patients with Early Hepatocellular Carcinoma

Biology ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 215
Author(s):  
Gian Paolo Caviglia ◽  
Maria Lorena Abate ◽  
Emanuela Rolle ◽  
Patrizia Carucci ◽  
Angelo Armandi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epidermal Growth Factor Receptor ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Early Hepatocellular Carcinoma ◽  
Early Hcc ◽  
Epidermal Growth

Epidermal growth factor receptor 3 (ERBB3) is a surface tyrosine kinase receptor belonging to the EGFR/ERBB family, involved in tumor development and progression. We evaluated the diagnostic and prognostic value of serum ERBB3 measurement in hepatitis C virus (HCV)-infected patients with early hepatocellular carcinoma (HCC). A total of 164 HCV-infected patients (82 with cirrhosis and 82 with early HCC) were included in the study. HCC was classified according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Among patients with HCC, 23 (28%) had a diagnosis of very early tumor (BCLC = 0), while 59 (62%) had a diagnosis of early HCC (BCLC = A). Median overall survival (OS) in patients with HCC was 79.2 (95% CI 51.6–124.8) months. While ERBB3 serum values were similar between patients with cirrhosis and those with HCC (p = 0.993), in the latter, serum ERBB3 ≥ 2860 RU resulted significantly and independently associated with OS (Hazard Ratio = 2.24, 95% CI 1.16–4.35, p = 0.017). Consistently, the 1-, 3-, and 5-year OS rates in patients with serum ERBB3 ≥ 2860 RU were 90% (36/40), 53% (19/36), and 28% (8/29) in comparison to patients with serum ERBB3 < 2860 RU, which were 98% (40/41), 80% (32/40), and 74% (26/35) (Log-rank test; p = 0.014). In conclusion, serum ERBB3 values resulted an independent prognostic factor of patients with early HCC and might be useful to tailor more personalized treatment strategies.

scholarly journals Anti-Hepatitis C Virus Activity and Toxicity of Type III Phosphatidylinositol-4-Kinase Beta Inhibitors

2012 ◽  
Vol 56 (10) ◽  
pp. 5149-5156 ◽  
Author(s):  
M. J. LaMarche ◽  
J. Borawski ◽  
A. Bose ◽  
C. Capacci-Daniel ◽  
R. Colvin ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cellular Targets ◽  
Type Iii ◽  
Genotype 1A ◽  
Cellular Target ◽  
Phosphatidylinositol 4 ◽  
Interfering Rna

ABSTRACTType III phosphatidylinositol-4-kinase beta (PI4KIIIβ) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIβ inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virusin vitro. Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensivein vitroprofiling of the compounds revealed a role of PI4KIIIβ in lymphocyte proliferation. Previously proposed functions of PI4KIIIβ in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIβ inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.

scholarly journals Nuclear receptor 4 group A member 1 determines hepatitis C virus entry efficiency through the regulation of cellular receptor and apolipoprotein E expression

2014 ◽  
Vol 95 (7) ◽  
pp. 1510-1521 ◽  
Author(s):  
Wandi Zhu ◽  
Rongjuan Pei ◽  
Rui Jin ◽  
Xue Hu ◽  
Yuan Zhou ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Apolipoprotein E ◽  
Nuclear Receptor ◽  
Virus Entry ◽  
Scavenger Receptor ◽  
Growth Factor Receptor ◽  
Genome Replication ◽  
Orphan Nuclear Receptor ◽  
Group A

Orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) is a transcription factor stimulated by many factors and plays pivotal roles in metabolism, proliferation and apoptosis. In this study, the expression of NR4A1 in Huh7.5.1 cells was significantly upregulated by hepatitis C virus (HCV) infection. The silencing of NR4A1 inhibited the entry of HCV and reduced the specific infectivity of secreted HCV particles but had only minor or no effect on the genome replication and translation, virion assembly and virus release steps of the virus life cycle. Further experiments demonstrated that the silencing of NR4A1 affected virus entry through pan-downregulation of the expression of HCV receptors scavenger receptor BI, occludin, claudin-1 and epidermal growth factor receptor but not CD81. The reduced specific infectivity of HCV in the knockdown cells was due to decreased apolipoprotein E (ApoE) expression. These results explain the delayed spread of HCV in NR4A1 knockdown Huh7.5.1 cells. Thus, NR4A1 plays a role in HCV replication through regulating the expression of HCV receptors and ApoE, and facilitates HCV entry and spread.

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