Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

Wagner, Michael; Hofmann, Wolf Peter; Teuber, G.; Berg, Thomas; Goeser, Tobias; Spengler, Ulrich; Hinrichsen, Holger; Weidenbach, H; Gerken, Guido; Manns, Michael P.; Buggisch, Peter; Herrmann, Eva; Zeuzem, Stefan

doi:10.1002/hep.22483

Cited by 30 publications

(24 citation statements)

References 37 publications

(44 reference statements)

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“…Interestingly, we also found that low GGT levels together with high baseline alanine aminotransferase (ALT) levels were important baseline factors for SVR [11].These intriguing observations were also made in other studies [12,13].…”

Section: Introductionsupporting

confidence: 67%

The determination of GGT is the most reliable predictor of nonresponsiveness to interferon-alpha based therapy in HCV type-1 infection

et al. 2011

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Section: Introductionsupporting

confidence: 67%

The determination of GGT is the most reliable predictor of nonresponsiveness to interferon-alpha based therapy in HCV type-1 infection

et al. 2011

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“…However, other clinical studies failed to confirm a beneficial effect of monotherapy or combination treatment with IFN-α/ribavirin [75,76]. Further hopes that amantadine may inhibit HCV were fueled by the observation that amantadine prevents p7 ion channel activity in artificial membranes [33] and in a cell-based hemadsorption surrogate assay [48].…”

Section: P7-based Antiviral Strategiesmentioning

confidence: 99%

Hepatitis C Virus P7—A Viroporin Crucial for Virus Assembly and an Emerging Target for Antiviral Therapy

Steinmann¹,

Pietschmann²

2010

Viruses

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The hepatitis C virus (HCV), a hepatotropic plus-strand RNA virus of the family Flaviviridae, encodes a set of 10 viral proteins. These viral factors act in concert with host proteins to mediate virus entry, and to coordinate RNA replication and virus production. Recent evidence has highlighted the complexity of HCV assembly, which not only involves viral structural proteins but also relies on host factors important for lipoprotein synthesis, and a number of viral assembly co-factors. The latter include the integral membrane protein p7, which oligomerizes and forms cation-selective pores. Based on these properties, p7 was included into the family of viroporins comprising viral proteins from multiple virus families which share the ability to manipulate membrane permeability for ions and to facilitate virus production. Although the precise mechanism as to how p7 and its ion channel function contributes to virus production is still elusive, recent structural and functional studies have revealed a number of intriguing new facets that should guide future efforts to dissect the role and function of p7 in the viral replication cycle. Moreover, a number of small molecules that inhibit production of HCV particles, presumably via interference with p7 function, have been reported. These compounds should not only be instrumental in increasing our understanding of p7 function, but may, in the future, merit further clinical development to ultimately optimize HCV-specific antiviral treatments.

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“…These results suggest to us that although the ion channel activity of p7 is required for efficient HCV production, it is not absolutely essential for virus production. The controversial, mostly negative, clinical efficacy of currently available p7 ion channel inhibitors could be due to the modest impact of p7 ion channel activity on HCV production (47,48). However, it is likely that more potent p7 ion channel inhibitors in combination with other HCV inhibitors would benefit HCV therapy.…”

mentioning

confidence: 99%

Efficiency of E2-p7 Processing Modulates Production of Infectious Hepatitis C Virus

Shanmugam

2013

J Virol

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Previous studies indicate that the processing of hepatitis C virus (HCV) E2-p7-NS2 precursor mediated by host signal peptidase is relatively inefficient, resulting in the accumulation of E2-p7-NS2 and E2-p7 precursors in addition to E2 in mammalian cells. In this study, we discovered that a significant inhibition of the processing at an E2-p7 junction site is detrimental for HCV production, whether it was caused by the mutations in p7 or by the strategic introduction of a mutation at a terminal residue of E2 to block the signal peptidase-mediated cleavage of this junction site. However, complete separation of E2 and p7 by inserting an encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) between these two proteins also moderately inhibited virus production. These results indicate that optimal processing of the E2-p7 junction site is critical for efficient HCV production. We further demonstrated that disrupting E2-p7 processing inhibits both NS2 localization to the putative virus assembly sites near lipid droplets (LD) and NS2 interaction with NS3 and E2. However, the impact, if any, of the p7-NS2 processing efficiency on HCV production seems relatively minor. In conclusion, these results imply that effective release of E2 and p7 from the precursor E2-p7 promotes HCV production by enhancing NS2-associated virus assembly complex formation near LD. Hepatitis C virus (HCV) is one of the major agents responsible for causing severe liver diseases, including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (1, 2). It is an enveloped, positive-stranded RNA virus belonging to the Hepacivirus genus in the Flaviviridae family of viruses (3, 4). HCV encodes a single, large open reading frame encoding an ϳ3,000-amino-acid polyprotein flanked by 5= and 3= noncoding sequences. The internal ribosome entry site (IRES) located at the 5= noncoding region mediates translation of a polyprotein that is subsequently processed by both host-and virus-encoded proteases to yield 10 different proteins. The N-terminal one-third of the polyprotein encoding the structural proteins, including core and envelope proteins (E1 and E2), followed by p7 and NS2, is processed by host signal peptidase (5-7). Core protein is further processed by signal peptide peptidase into a mature form (8). The junction site between NS2 and NS3 is cleaved by an NS2-NS3 autoprotease (9, 10), and the remaining nonstructural proteins (NS3, NS4A, NS4B, NS5A, and NS5B) are processed by NS3 protease with its cofactor NS4A (11-13). Proteins NS3 to NS5B, along with the 5=-and 3=-terminal noncoding regions, were shown to be sufficient for the autonomous replication of HCV RNA (14).Recent advances in the infectious HCV cell culture model allowed the investigation of HCV virus particle assembly processes (15-18). We have learned that the association of HCV core protein with lipid droplets (LD) is critical for virus assembly since disrupting the core protein localization to LD inhibited infectious virus production (19,20). We also learned that the...

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Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

Cited by 30 publications

References 37 publications

The determination of GGT is the most reliable predictor of nonresponsiveness to interferon-alpha based therapy in HCV type-1 infection

The determination of GGT is the most reliable predictor of nonresponsiveness to interferon-alpha based therapy in HCV type-1 infection

Hepatitis C Virus P7—A Viroporin Crucial for Virus Assembly and an Emerging Target for Antiviral Therapy

Efficiency of E2-p7 Processing Modulates Production of Infectious Hepatitis C Virus

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