Hepatitis C--new developments in the studies of the viral life cycle.

Rychłowska, Małgorzata; Bieńkowska-Szewczyk, Krystyna

doi:10.18388/abp.2007_3138

Cited by 8 publications

(5 citation statements)

References 125 publications

(136 reference statements)

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“…The NS3 region of the HCV genome contains a serine protease that possesses NTPase and helicase activity. Together, the coupled NTPase and helicase function to unwind duplex RNA, and is an essential mechanism in the viral replication cycle (Reviewed in [25,26]). Identification of critical steps in the viral replication cycle provides a unique opportunity to design compounds targeting one or more of these mechanisms.…”

Section: Helicase Inhibitorsmentioning

confidence: 99%

HCV drug discovery aimed at viral eradication

Schinazi

Bassit

Gavegnano

2010

Journal of Viral Hepatitis

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SUMMARY Hepatitis C virus (HCV) causes significant morbidity and mortality worldwide with nearly 3% of the world population infected by this virus. Fortunately, this virus does not establish latency, and hence it may be possible to eradicate it. HCV is strongly associated with liver cirrhosis and hepatocellular carcinoma and is currently treated with pegylated interferon-α (peg-IFN-α) and ribavirin. Unfortunately, these limited treatment options often produce significant side effects, and currently, complete eradication of virus with combined drug modalities has not yet been achieved for the majority of chronically HCV-infected individuals. Restricted treatment options, lack of a universal cure for HCV and the link between chronic infection, liver cirrhosis and hepatocellular carcinoma necessitate design of novel drugs and treatment options. Understanding the relationship between the immune response, viral clearance and inhibition of viral replication with pharmacology-based design can ultimately allow for complete eradication of HCV. This review focuses upon significant novel preclinical and clinical specifically targeted antiviral therapy (STAT-C) drugs under development, highlights their mechanism of action, and discusses their impact on systemic viral loads and permanent clearance of infection.

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Section: Helicase Inhibitorsmentioning

confidence: 99%

HCV drug discovery aimed at viral eradication

Schinazi

Bassit

Gavegnano

2010

Journal of Viral Hepatitis

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“…In order to test the competence of the zymoxins in eradicating HCV infected liver cells, we utilized one of the currently used models to study hepatitis C virus in which recombinant infectious HCV particles are produced in cell culture (HCVcc) based on Huh7.5 hepatoma cell line [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [56] . First, we have verified that NS3 expression sensitizes Huh7.5 liver cells to zymoxin intoxication as was observed following inducible NS3 expression in HEK293 cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…HCVcc systems render all steps of the HCV life cycle, including entry and release of viral particles, amenable to systematic analysis. [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] .…”

Section: Introductionmentioning

confidence: 99%

Engineered Toxins “Zymoxins” Are Activated by the HCV NS3 Protease by Removal of an Inhibitory Protein Domain

et al. 2011

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The synthesis of inactive enzyme precursors, also known as “zymogens,” serves as a mechanism for regulating the execution of selected catalytic activities in a desirable time and/or site. Zymogens are usually activated by proteolytic cleavage. Many viruses encode proteases that execute key proteolytic steps of the viral life cycle. Here, we describe a proof of concept for a therapeutic approach to fighting viral infections through eradication of virally infected cells exclusively, thus limiting virus production and spread. Using the hepatitis C virus (HCV) as a model, we designed two HCV NS3 protease-activated “zymogenized” chimeric toxins (which we denote “zymoxins”). In these recombinant constructs, the bacterial and plant toxins diphtheria toxin A (DTA) and Ricin A chain (RTA), respectively, were fused to rationally designed inhibitor peptides/domains via an HCV NS3 protease-cleavable linker. The above toxins were then fused to the binding and translocation domains of Pseudomonas exotoxin A in order to enable translocation into the mammalian cells cytoplasm. We show that these toxins exhibit NS3 cleavage dependent increase in enzymatic activity upon NS3 protease cleavage in vitro. Moreover, a higher level of cytotoxicity was observed when zymoxins were applied to NS3 expressing cells or to HCV infected cells, demonstrating a potential therapeutic window. The increase in toxin activity correlated with NS3 protease activity in the treated cells, thus the therapeutic window was larger in cells expressing recombinant NS3 than in HCV infected cells. This suggests that the “zymoxin” approach may be most appropriate for application to life-threatening acute infections where much higher levels of the activating protease would be expected.

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“…HCV mainly spreads via blood supply, reuse of glass syringes and needles, unsterilized medical equipment, use of tooth brushes of HCV patients, etc [ 7 ] and causes of acute and chronic infections [ 8 ]. Clinical demonstrations of acute Hepatitus C Viral infection include Jaundice, Fever, Myalgia, Fatigue, Lethargy, Increased ALT, Anorexia and Fulminant hepatic failure [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Promiscuous prediction and conservancy analysis of CTL binding epitopes of HCV 3a viral proteome from Punjab Pakistan: an In Silico Approach

Shehzadi

Rehman

Idrees

2011

Virol J

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BackgroundHCV is a positive sense RNA virus affecting approximately 180 million people world wide and about 10 million Pakistani populations. HCV genotype 3a is the major cause of infection in Pakistani population. One of the major problems of HCV infection especially in the developing countries that limits the limits the antiviral therapy is the long term treatment, high dosage and side effects. Studies of antigenic epitopes of viral sequences of a specific origin can provide an effective way to overcome the mutation rate and to determine the promiscuous binders to be used for epitope based subunit vaccine design. An in silico approach was applied for the analysis of entire HCV proteome of Pakistani origin, aimed to identify the viral epitopes and their conservancy in HCV genotypes 1, 2 and 3 of diverse origin.ResultsImmunoinformatic tools were applied for the predictive analysis of HCV 3a antigenic epitopes of Pakistani origin. All the predicted epitopes were then subjected for their conservancy analysis in HCV genotypes 1, 2 and 3 of diverse origin (worldwide). Using freely available web servers, 150 MHC II epitopes were predicted as promiscuous binders against 51 subjected alleles. E2 protein represented the 20% of all the predicted MHC II epitopes. 75.33% of the predicted MHC II epitopes were (77-100%) conserve in genotype 3; 47.33% and 40.66% in genotype 1 and 2 respectively. 69 MHC I epitopes were predicted as promiscuous binders against 47 subjected alleles. NS4b represented 26% of all the MHC I predicted epitopes. Significantly higher epitope conservancy was represented by genotype 3 i.e. 78.26% and 21.05% for genotype 1 and 2.ConclusionsThe study revealed comprehensive catalogue of potential HCV derived CTL epitopes from viral proteome of Pakistan origin. A considerable number of predicted epitopes were found to be conserved in different HCV genotype. However, the number of conserved epitopes in HCV genotype 3 was significantly higher in contrast to its conservancy in HCV genotype 1 and 2. Despite of the lower conservancy in genotype 1 and 2, all the predicted epitopes have important implications in diagnostics as well as CTL-based rational vaccine design, effective for most population of the world and especially the Pakistani Population.

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Hepatitis C--new developments in the studies of the viral life cycle.

Cited by 8 publications

References 125 publications

HCV drug discovery aimed at viral eradication

HCV drug discovery aimed at viral eradication

Engineered Toxins “Zymoxins” Are Activated by the HCV NS3 Protease by Removal of an Inhibitory Protein Domain

Promiscuous prediction and conservancy analysis of CTL binding epitopes of HCV 3a viral proteome from Punjab Pakistan: an In Silico Approach

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