The NS3/4A proteinase of the hepatitis C virus: unravelling structure and function of an unusual enzyme and a prime target for antiviral therapy

Bartenschlager, Ralf

doi:10.1046/j.1365-2893.1999.00152.x

Cited by 128 publications

(100 citation statements)

References 151 publications

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“…1). 45 Protease activity is required for polyprotein cleavage at four sites: NS3-4A, NS4A-4B, NS4B-5A and NS5A-5B. In addition, this protease plays a pivotal role in HCV immune evasion by cleaving the Toll-like receptor-3 adaptor molecule 1 (TICAM-1/ TRIF), 46 and the RIG-I adaptor MAVS, 47 two key adaptor proteins involved in innate immune response to viral infection.…”

Section: Hcv Proteinsmentioning

confidence: 99%

Hepatitis c virus and host cell lipids: An intimate connection

Alvisi¹,

Madan²,

2011

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Section: Hcv Proteinsmentioning

confidence: 99%

Hepatitis c virus and host cell lipids: An intimate connection

Alvisi¹,

Madan²,

2011

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“…The open reading frame is flanked by 5Ј-and 3Ј-untranslated regions, which have been shown to be involved in initiation of translation and viral replication (3). Processing of the precursor polyprotein requires both host and viral proteases to produce the structural (core, E1, E2, and p7) and nonstructural (NS2, NS3/4A, NS4B, NS5A, and NS5B) proteins of the virion (4).…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

The Hepatitis C Virus NS5A Protein Activates a Phosphoinositide 3-Kinase-dependent Survival Signaling Cascade

Street¹,

Macdonald

Crowder

et al. 2004

Journal of Biological Chemistry

204

184

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Hepatitis C virus (HCV) establishes a persistent infection, with up to 80% of infected individuals proceeding to chronic hepatitis, which in many cases may result in liver cirrhosis and hepatocellular carcinoma (HCC); indeed HCV infection is increasingly associated with the development of HCC. The long time period (up to 30 years) between primary infection and the onset of HCC implies that HCV is not directly oncogenic but in some way predisposes patients to develop tumors, though the mechanism for this is unclear as yet. We report here that NS5A binds directly to the Src homology 3 domain of the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K), and this interaction is mediated by a novel (nonproline-rich) motif within NS5A. Coimmunoprecipitation analysis revealed that NS5A bound native heterodimeric PI3K and enhanced the phosphotransferase activity of the catalytic (p110) subunit both in vitro and in human cell lines harboring a subgenomic HCV replicon or expressing NS5A alone. NS5A-mediated activation of PI3K resulted in increased phosphorylation and activity of Akt/protein kinase B and concomitantly provided protection against the induction of apoptosis in both replicon-harboring cells and cells stably expressing NS5A alone. These data suggest that stimulation of PI3K by NS5A may represent an indirect mechanism for development of HCC in HCV-infected patients and further suggests potential therapeutic strategies to counteract the occurrence of HCV-related HCC.

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“…During HCV replication, the post-translational processing and cleavage of the virus polyprotein produces ten structural and non-structural proteins. The crystal structures that have been determined for a number of these proteins are being used to facilitate both drug and vaccine development [2][3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Identification of ligands that target the HCV-E2 binding site on CD81

Olaby

Azzazy

Harris

et al. 2013

J Comput Aided Mol Des

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Hepatitis C is a global health problem. While many drug companies have active R&D efforts to develop new drugs for treating Hepatitis C virus (HCV), most target the viral enzymes. The HCV glycoprotein E2 has been shown to play an essential role in hepatocyte invasion by binding to CD81 and other cell surface receptors. This paper describes the use of AutoDock to identify ligand binding sites on the large extracellular loop of the open conformation of CD81 and to perform virtual screening runs to identify sets of small molecule ligands predicted to bind to two of these sites. The best sites selected by AutoLigand were located in regions identified by mutational studies to be the site of E2 binding. Thirty-six ligands predicted by AutoDock to bind to these sites were subsequently tested experimentally to determine if they bound to CD81-LEL. Binding assays conducted using surface Plasmon resonance revealed that 26 out of 36 (72 %) of the ligands bound in vitro to the recombinant CD81-LEL protein. Competition experiments performed using dual polarization interferometry showed that one of the ligands predicted to bind to the large cleft between the C and D helices was also effective in blocking E2 binding to CD81-LEL.

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The NS3/4A proteinase of the hepatitis C virus: unravelling structure and function of an unusual enzyme and a prime target for antiviral therapy

Cited by 128 publications

References 151 publications

Hepatitis c virus and host cell lipids: An intimate connection

Hepatitis c virus and host cell lipids: An intimate connection

The Hepatitis C Virus NS5A Protein Activates a Phosphoinositide 3-Kinase-dependent Survival Signaling Cascade

Identification of ligands that target the HCV-E2 binding site on CD81

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