Skip to main content
Top
Published in: Archives of Virology 5/2014

01-05-2014 | Brief Review

Current and future therapies for hepatitis C virus infection: from viral proteins to host targets

Authors: Muhammad Imran, Sobia Manzoor, Nasir Mahmood Khattak, Madiha Khalid, Qazi Laeeque Ahmed, Fahed Parvaiz, Muqddas Tariq, Javed Ashraf, Waseem Ashraf, Sikandar Azam, Muhammad Ashraf

Published in: Archives of Virology | Issue 5/2014

Login to get access

Abstract

Hepatitis C virus (HCV) infection is the most important problem across the world. It causes acute and chronic liver infection. Different approaches are in use to inhibit HCV infection, including small organic compounds, siRNA, shRNA and peptide inhibitors. This review article summarizes the current and future therapies for HCV infection. PubMed and Google Scholar were searched for articles published in English to give an insight into the current inhibitors against this life-threatening virus. HCV NS3/4A protease inhibitors and nucleoside/nucleotide inhibitors of NS5B polymerase are presently in the most progressive stage of clinical development, but they are linked with the development of resistance and viral breakthrough. Boceprevir and telaprevir are the two most important protease inhibitors that have been approved recently for the treatment of HCV infection. These two drugs are now the part of standard-of-care treatment (SOC). There are also many other drugs in phase III of clinical development. When exploring the various host-cell-targeting compounds, the most hopeful results have been demonstrated by cyclophilin inhibitors. The current SOC treatment of HCV infection is Peg-interferon, ribavirin and protease inhibitors (boceprevir or telaprevir). The future treatment of this life-threatening disease must involve combinations of therapies hitting multiple targets of HCV and host factors. It is strongly expected that the near future, treatment of HCV infection will be a combination of direct-acting agents (DAA) without the involvement of interferon to eliminate its side effects.
Literature
1.
go back to reference Wands JR (2004) Prevention of hepatocellular carcinoma. N Engl J Med 351:1567–1570PubMed Wands JR (2004) Prevention of hepatocellular carcinoma. N Engl J Med 351:1567–1570PubMed
2.
go back to reference Global Burden of Hepatitis C Working Group (2004) Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol 44:20–29 Global Burden of Hepatitis C Working Group (2004) Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol 44:20–29
3.
go back to reference Miller RH, Purcell RH (1990) Hepatitis C virus shares amino acid sequence similarity with pestiviruses and flaviviruses as well as members of two plant virus supergroups. Proc Natl Acad Sci USA 87:2057–2061PubMedCentralPubMed Miller RH, Purcell RH (1990) Hepatitis C virus shares amino acid sequence similarity with pestiviruses and flaviviruses as well as members of two plant virus supergroups. Proc Natl Acad Sci USA 87:2057–2061PubMedCentralPubMed
4.
go back to reference Tellinghuisen TL, Evans MJ, von Hahn T, You S, Rice CM (2007) Studying hepatitis C virus: making the best of a bad virus. J Virol 8:8853–8867 Tellinghuisen TL, Evans MJ, von Hahn T, You S, Rice CM (2007) Studying hepatitis C virus: making the best of a bad virus. J Virol 8:8853–8867
5.
go back to reference Sharma SD (2010) Hepatitis C virus: molecular biology & current therapeutic options. Indian J Med Res 131:17–34PubMed Sharma SD (2010) Hepatitis C virus: molecular biology & current therapeutic options. Indian J Med Res 131:17–34PubMed
6.
go back to reference Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Reesink HW, Kwong AD, Zeuzem S (2007) Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 46:631–639PubMed Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Reesink HW, Kwong AD, Zeuzem S (2007) Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 46:631–639PubMed
7.
go back to reference Zeuzem S, Hultcrantz R, Bourliere M et al (2004) Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 40:993–999PubMed Zeuzem S, Hultcrantz R, Bourliere M et al (2004) Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 40:993–999PubMed
8.
go back to reference Farnik H, Lange CM, Sarrazin C et al (2010) Meta-analysis shows extended therapy improves response of patients with chronic hepatitis C virus genotype 1 infection. Clin Gastroenterol Hepatol 8:884–890PubMed Farnik H, Lange CM, Sarrazin C et al (2010) Meta-analysis shows extended therapy improves response of patients with chronic hepatitis C virus genotype 1 infection. Clin Gastroenterol Hepatol 8:884–890PubMed
9.
go back to reference Sarrazin C, Zeuzem S (2010) Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 138:447–462PubMed Sarrazin C, Zeuzem S (2010) Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 138:447–462PubMed
10.
go back to reference Cristofari G, Ivanyi-Nagy R, Gabus C et al (2004) The hepatitis C virus Core protein is a potent nucleic acid chaperone that directs dimerization of the viral (+) strand RNA in vitro. Nucleic Acids Res 32:2623–2631PubMedCentralPubMed Cristofari G, Ivanyi-Nagy R, Gabus C et al (2004) The hepatitis C virus Core protein is a potent nucleic acid chaperone that directs dimerization of the viral (+) strand RNA in vitro. Nucleic Acids Res 32:2623–2631PubMedCentralPubMed
11.
go back to reference Ivanyi-Nagy R, Kanevsky I, Gabus C, Lavergne JP, Ficheux D, Penin F, Fosse P, Darlix JL (2006) Analysis of hepatitis C virus RNA dimerization and core-RNA interactions. Nucleic Acids Res 34:2618–2633PubMedCentralPubMed Ivanyi-Nagy R, Kanevsky I, Gabus C, Lavergne JP, Ficheux D, Penin F, Fosse P, Darlix JL (2006) Analysis of hepatitis C virus RNA dimerization and core-RNA interactions. Nucleic Acids Res 34:2618–2633PubMedCentralPubMed
12.
go back to reference Kopp M, Murray CL, Jones CT, Rice CM (2010) Genetic analysis of the carboxy-terminal region of the Hepatitis C virus core protein. J Virol 84:1666–1673PubMedCentralPubMed Kopp M, Murray CL, Jones CT, Rice CM (2010) Genetic analysis of the carboxy-terminal region of the Hepatitis C virus core protein. J Virol 84:1666–1673PubMedCentralPubMed
13.
go back to reference Okamoto K, Mori Y, Komoda Y et al (2008) Intramembrane processing by signal peptide peptidase regulates the membrane localization of hepatitis C virus core protein and viral propagation. J Virol 82:8349–8361PubMedCentralPubMed Okamoto K, Mori Y, Komoda Y et al (2008) Intramembrane processing by signal peptide peptidase regulates the membrane localization of hepatitis C virus core protein and viral propagation. J Virol 82:8349–8361PubMedCentralPubMed
14.
go back to reference Hüssy P, Langen H, Mous J, Jacobsen H (1996) Hepatitis C virus core protein: carboxy-terminal boundaries of two processed species suggest cleavage by a signal peptide peptidase. Virology 224:93–104PubMed Hüssy P, Langen H, Mous J, Jacobsen H (1996) Hepatitis C virus core protein: carboxy-terminal boundaries of two processed species suggest cleavage by a signal peptide peptidase. Virology 224:93–104PubMed
15.
go back to reference Cristina J, Moreno-del PM, Moratorio G (2007) Hepatitis C virus genetic variability in patients undergoing antiviral therapy. Virus Res 127:185–194PubMed Cristina J, Moreno-del PM, Moratorio G (2007) Hepatitis C virus genetic variability in patients undergoing antiviral therapy. Virus Res 127:185–194PubMed
16.
go back to reference Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001–1009PubMed Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001–1009PubMed
17.
go back to reference Kota S, Scampavia L, Spicer T, Beeler AB, Takahashi V, Snyder JK, Porco JA Jr, Hodder P, Strosberg AD (2010) A homogeneous time resolved fluorescence assay for identifying inhibitors of Hepatitis C virus dimerization. Assay Drug Dev Technol 8:96–105PubMedCentralPubMed Kota S, Scampavia L, Spicer T, Beeler AB, Takahashi V, Snyder JK, Porco JA Jr, Hodder P, Strosberg AD (2010) A homogeneous time resolved fluorescence assay for identifying inhibitors of Hepatitis C virus dimerization. Assay Drug Dev Technol 8:96–105PubMedCentralPubMed
18.
go back to reference Strosberg AD, Kota S, Takahashi V, Snyder JK, Mousseau G (2010) Core as a novel viral target for hepatitis C drugs. Viruses 2:1734–1751PubMedCentralPubMed Strosberg AD, Kota S, Takahashi V, Snyder JK, Mousseau G (2010) Core as a novel viral target for hepatitis C drugs. Viruses 2:1734–1751PubMedCentralPubMed
19.
go back to reference Brummelkamp TR, Bernards R, Agami R (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science 296:550–553PubMed Brummelkamp TR, Bernards R, Agami R (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science 296:550–553PubMed
20.
go back to reference Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498PubMed Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498PubMed
21.
go back to reference Khaliq S, Jahan S, Ijaz B, Ahmad W, Asad S, Pervaiz A, Samreen B, Khan M, Hassan S (2010) Inhibition of core gene of HCV 3a genotype using synthetic and vector derived siRNAs. Virol J 7:318PubMedCentralPubMed Khaliq S, Jahan S, Ijaz B, Ahmad W, Asad S, Pervaiz A, Samreen B, Khan M, Hassan S (2010) Inhibition of core gene of HCV 3a genotype using synthetic and vector derived siRNAs. Virol J 7:318PubMedCentralPubMed
22.
go back to reference Liu M, Ding H, Zhao P, Qin ZL, Gao J, Cao MM, Luan J, Wu WB, Qi ZT (2006) RNA interference effectively inhibits mRNA accumulation and protein expression of hepatitis C virus core and E2 genes in human cells. Biosci Biotechnol Biochem 70:2049–2055PubMed Liu M, Ding H, Zhao P, Qin ZL, Gao J, Cao MM, Luan J, Wu WB, Qi ZT (2006) RNA interference effectively inhibits mRNA accumulation and protein expression of hepatitis C virus core and E2 genes in human cells. Biosci Biotechnol Biochem 70:2049–2055PubMed
24.
go back to reference Blanchard E, Belouzard S, Goueslain L, Wakita T, Dubuisson J, Wychowski C, Rouillé Y (2006) Hepatitis C virus entry depends on clathrin-mediated endocytosis. J Virol 80:6964–6972PubMedCentralPubMed Blanchard E, Belouzard S, Goueslain L, Wakita T, Dubuisson J, Wychowski C, Rouillé Y (2006) Hepatitis C virus entry depends on clathrin-mediated endocytosis. J Virol 80:6964–6972PubMedCentralPubMed
25.
go back to reference Khan N, Mukhtar H (2007) Tea polyphenols for health promotion. Life Sci 8:519–533 Khan N, Mukhtar H (2007) Tea polyphenols for health promotion. Life Sci 8:519–533
26.
go back to reference Nance CL, Siwak EB, Shearer WT (2009) Preclinical development of the green tea catechin, epigallocatechin gallate, as an HIV-1 therapy. J Allergy Clin Immunol 123:459–465PubMedCentralPubMed Nance CL, Siwak EB, Shearer WT (2009) Preclinical development of the green tea catechin, epigallocatechin gallate, as an HIV-1 therapy. J Allergy Clin Immunol 123:459–465PubMedCentralPubMed
27.
go back to reference Calland N, Albecka A, Belouzard S et al (2012) Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry. Hepatology 55:720–729PubMed Calland N, Albecka A, Belouzard S et al (2012) Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry. Hepatology 55:720–729PubMed
28.
go back to reference Hsu M, Zhang J, Flint M, Logvinoff C, Cheng MC, Rice CM, McKeating A (2003) Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. PNAS 100:7271–7276PubMedCentralPubMed Hsu M, Zhang J, Flint M, Logvinoff C, Cheng MC, Rice CM, McKeating A (2003) Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. PNAS 100:7271–7276PubMedCentralPubMed
29.
go back to reference Baldick CJ, Wichroski MJ, Pendri A et al (2010) A novel small molecule inhibitor of hepatitis C virus entry. PLoS Pathog 6:e1001086PubMedCentralPubMed Baldick CJ, Wichroski MJ, Pendri A et al (2010) A novel small molecule inhibitor of hepatitis C virus entry. PLoS Pathog 6:e1001086PubMedCentralPubMed
30.
go back to reference Liua R, Tewari M, Konga R et al (2010) A peptide derived from hepatitis C virus E2 envelope protein inhibits post-binding step in HCV entry. Antiviral Res 86:172–179 Liua R, Tewari M, Konga R et al (2010) A peptide derived from hepatitis C virus E2 envelope protein inhibits post-binding step in HCV entry. Antiviral Res 86:172–179
31.
go back to reference Montserret R, Saint N, Vanbelle C et al (2010) NMR structure and ion channel activity of the p7 protein from hepatitis C virus. J Biol Chem 285:31446–31461PubMedCentralPubMed Montserret R, Saint N, Vanbelle C et al (2010) NMR structure and ion channel activity of the p7 protein from hepatitis C virus. J Biol Chem 285:31446–31461PubMedCentralPubMed
32.
go back to reference Chew CF, Vijayan R, Chang J, Zitzmann N, Biggin PC (2009) Determination of pore-lining residues in the hepatitis C virus p7 protein. Biophys J 96:L10–L12PubMedCentralPubMed Chew CF, Vijayan R, Chang J, Zitzmann N, Biggin PC (2009) Determination of pore-lining residues in the hepatitis C virus p7 protein. Biophys J 96:L10–L12PubMedCentralPubMed
33.
go back to reference Mould JA, Drury JE, Frings SM, Kaupp UB, Pekosz A, Lamb RA, Pinto LH (2000) Permeation and activation of the M2 ion channel of influenza A virus. J Bio Chem 275:31038–31050 Mould JA, Drury JE, Frings SM, Kaupp UB, Pekosz A, Lamb RA, Pinto LH (2000) Permeation and activation of the M2 ion channel of influenza A virus. J Bio Chem 275:31038–31050
34.
go back to reference Ewart GD, Mills K, Cox GB, Gage PW (2002) Amiloride derivatives block ion channel activity and enhancement of virus-like particle budding caused by HIV-1 protein Vpu. Eur Biophys J 31:26–35PubMed Ewart GD, Mills K, Cox GB, Gage PW (2002) Amiloride derivatives block ion channel activity and enhancement of virus-like particle budding caused by HIV-1 protein Vpu. Eur Biophys J 31:26–35PubMed
35.
go back to reference Luscombe CA, Huang Z, Murray MG, Miller M, Wilkinson J, Ewart GD (2010) A novel Hepatitis C virus p7 ion channel inhibitor, BIT225, inhibits bovine viral diarrhea virus in vitro and shows synergism with recombinant interferon-alpha-2b and nucleoside analogues. Antivir Res 86:144–153PubMed Luscombe CA, Huang Z, Murray MG, Miller M, Wilkinson J, Ewart GD (2010) A novel Hepatitis C virus p7 ion channel inhibitor, BIT225, inhibits bovine viral diarrhea virus in vitro and shows synergism with recombinant interferon-alpha-2b and nucleoside analogues. Antivir Res 86:144–153PubMed
36.
go back to reference Peterson JR, Ora A, Van PN, Helenius A (1995) Transient, lectin-like association of calreticulin with folding intermediates of cellular and viral glycoproteins. Mol Biol Cell 6:1173–1184PubMedCentralPubMed Peterson JR, Ora A, Van PN, Helenius A (1995) Transient, lectin-like association of calreticulin with folding intermediates of cellular and viral glycoproteins. Mol Biol Cell 6:1173–1184PubMedCentralPubMed
37.
go back to reference Durantel D, Branza-Nichita N, Carrouée-Durantel S, Butters TD, Dwek RA, Zitzmann N (2001) Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. J Virol 75:8987–8998PubMedCentralPubMed Durantel D, Branza-Nichita N, Carrouée-Durantel S, Butters TD, Dwek RA, Zitzmann N (2001) Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. J Virol 75:8987–8998PubMedCentralPubMed
38.
go back to reference Pavlović D, Neville DC, Argaud O, Blumberg B, Dwek RA, Fischer WB, Zitzmann N (2003) The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc Natl Acad Sci USA 100:6104-6108. Epub 2003 Apr 28 Pavlović D, Neville DC, Argaud O, Blumberg B, Dwek RA, Fischer WB, Zitzmann N (2003) The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc Natl Acad Sci USA 100:6104-6108. Epub 2003 Apr 28
39.
go back to reference Erdtmann L, Franck N, Lerat H et al (2003) The hepatitis C virus NS2 protein is an inhibitor of CIDE-B-induced apoptosis. J Biol Chem 278:18256–18264PubMed Erdtmann L, Franck N, Lerat H et al (2003) The hepatitis C virus NS2 protein is an inhibitor of CIDE-B-induced apoptosis. J Biol Chem 278:18256–18264PubMed
40.
go back to reference Yang XJ, Liu J, Ye L, Liao QJ et al (2006) HCV NS2 protein inhibits cell proliferation and induces cell cycle arrest in the S-phase in mammalian cells through down-regulation of cyclin A expression. Virus Res 121:134–143PubMed Yang XJ, Liu J, Ye L, Liao QJ et al (2006) HCV NS2 protein inhibits cell proliferation and induces cell cycle arrest in the S-phase in mammalian cells through down-regulation of cyclin A expression. Virus Res 121:134–143PubMed
41.
go back to reference Kim KM, Kwon SN, Kang JI, Lee SH, Jang SK, Ahn BY, Kim YK (2007) Hepatitis C virus NS2 protein activates cellular cyclic AMP-dependent pathways. Biochem Biophys Res Commun 356:948–954PubMed Kim KM, Kwon SN, Kang JI, Lee SH, Jang SK, Ahn BY, Kim YK (2007) Hepatitis C virus NS2 protein activates cellular cyclic AMP-dependent pathways. Biochem Biophys Res Commun 356:948–954PubMed
42.
go back to reference Oem JK, Jackel CC, Li YP, Kang HN, Zhou Y, Babiuk LA, Liu Q (2008) Hepatitis C virus non-structural protein-2 activates CXCL-8 transcription through NF-kappaB. Arch Virol 153:293–301PubMed Oem JK, Jackel CC, Li YP, Kang HN, Zhou Y, Babiuk LA, Liu Q (2008) Hepatitis C virus non-structural protein-2 activates CXCL-8 transcription through NF-kappaB. Arch Virol 153:293–301PubMed
43.
go back to reference Oem JK, Jackel CC, Li YP, Zhou Y, Zhong J, Shimano H, Babiuk LA, Liu Q (2008) Activation of sterol regulatory element-binding protein 1c and fatty acid synthase transcription by hepatitis C virus non-structural protein 2. J Gen Virol 89:1225–1230PubMed Oem JK, Jackel CC, Li YP, Zhou Y, Zhong J, Shimano H, Babiuk LA, Liu Q (2008) Activation of sterol regulatory element-binding protein 1c and fatty acid synthase transcription by hepatitis C virus non-structural protein 2. J Gen Virol 89:1225–1230PubMed
44.
go back to reference Lorenz IC (2010) The Hepatitis C virus nonstructural protein 2 (NS2): an up-and-coming antiviral drug target. Viruses 2:1635–1646PubMedCentralPubMed Lorenz IC (2010) The Hepatitis C virus nonstructural protein 2 (NS2): an up-and-coming antiviral drug target. Viruses 2:1635–1646PubMedCentralPubMed
45.
go back to reference Thibeault D, Maurice R, Pilote L, Lamarre D, Pause A (2001) In vitro characterization of a purified NS2/3 protease variant of hepatitis C virus. J Biol Chem 276:46678–46684PubMed Thibeault D, Maurice R, Pilote L, Lamarre D, Pause A (2001) In vitro characterization of a purified NS2/3 protease variant of hepatitis C virus. J Biol Chem 276:46678–46684PubMed
46.
go back to reference Kim JL, Morgenstern KA, Lin C, Fox T et al (1996) Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87:343–355PubMed Kim JL, Morgenstern KA, Lin C, Fox T et al (1996) Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87:343–355PubMed
47.
go back to reference Wyles DL (2010) Moving beyond interferon alfa: investigational drugs for hepatitis C virus infection. Top HIV Med 18:132–136PubMed Wyles DL (2010) Moving beyond interferon alfa: investigational drugs for hepatitis C virus infection. Top HIV Med 18:132–136PubMed
48.
go back to reference Belon CA, High YD, Lin TI, Pauwels F, Frick DN (2010) Mechanism and specificity of a symmetrical benzimidazolephenylcarboxamide helicase inhibitor. Biochemistry 49:1822–1832PubMedCentralPubMed Belon CA, High YD, Lin TI, Pauwels F, Frick DN (2010) Mechanism and specificity of a symmetrical benzimidazolephenylcarboxamide helicase inhibitor. Biochemistry 49:1822–1832PubMedCentralPubMed
50.
go back to reference Forestier N, Larrey D, Guyader D, Marcellin P, Rouzier R, Patat A, Smith P, Bradford W, Porter S, Blatt L, Seiwert SD, Zeuzem S (2011) Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study. Hepatol 54:1130–1136 Forestier N, Larrey D, Guyader D, Marcellin P, Rouzier R, Patat A, Smith P, Bradford W, Porter S, Blatt L, Seiwert SD, Zeuzem S (2011) Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study. Hepatol 54:1130–1136
51.
go back to reference Thomson JA, Perni RB (2006) Hepatitis C virus NS3/4A protease inhibitors: countering viral subversion in vitro and showing promise in the clinic. Curr Opin Drug Discov Dev 9:606–617 Thomson JA, Perni RB (2006) Hepatitis C virus NS3/4A protease inhibitors: countering viral subversion in vitro and showing promise in the clinic. Curr Opin Drug Discov Dev 9:606–617
52.
go back to reference Tsantrizos YS (2009) TMC-435, an NS3/4A protease inhibitor for the treatment of HCV infection. Curr Opin Investig Drugs 10:871–881PubMed Tsantrizos YS (2009) TMC-435, an NS3/4A protease inhibitor for the treatment of HCV infection. Curr Opin Investig Drugs 10:871–881PubMed
53.
go back to reference Manns M, Reesink H, Berg T, Dusheiko G, Flisiak R, Marcellin P, Moreno C, Lenz O, Meyvisch P, Peeters M, Sekar V, Simmen K, Verloes R (2011) Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial. Antivir Ther 16:1021–1033PubMed Manns M, Reesink H, Berg T, Dusheiko G, Flisiak R, Marcellin P, Moreno C, Lenz O, Meyvisch P, Peeters M, Sekar V, Simmen K, Verloes R (2011) Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial. Antivir Ther 16:1021–1033PubMed
54.
go back to reference Llinàs-Brunet M, Bailey MD, Goudreau N, Bhardwaj PK, Bordeleau J, Bös M, Bousquet Y, Cordingley MG, Duan J, Forgione P, Garneau M, Ghiro E, Gorys V, Goulet S, Halmos T, Kawai SH, Naud J, Poupart MA, White PW (2010) Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). J Med Chem 53:6466–6476PubMed Llinàs-Brunet M, Bailey MD, Goudreau N, Bhardwaj PK, Bordeleau J, Bös M, Bousquet Y, Cordingley MG, Duan J, Forgione P, Garneau M, Ghiro E, Gorys V, Goulet S, Halmos T, Kawai SH, Naud J, Poupart MA, White PW (2010) Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). J Med Chem 53:6466–6476PubMed
55.
go back to reference Duan J, Yong CL, Garneau M, Amad M, Bolger G, De Marte J, Montpetit H, Otis F, Jutras M, Rhéaume M, White PW, Llinàs-Brunet M, Bethell RC, Cordingley MG (2012) Cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV genotype 1 NS3/4A protease inhibitor. Xenobiotica 42:164–172PubMed Duan J, Yong CL, Garneau M, Amad M, Bolger G, De Marte J, Montpetit H, Otis F, Jutras M, Rhéaume M, White PW, Llinàs-Brunet M, Bethell RC, Cordingley MG (2012) Cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV genotype 1 NS3/4A protease inhibitor. Xenobiotica 42:164–172PubMed
56.
go back to reference Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Müllhaupt B, Gane E, Schuchmann M, Lohse A, Pol S, Bronowicki JP, Roberts S, Arasteh K, Zoulim F, Heim M, Stern JO, Kukolj G, Nehmiz G, Haefner C, Boecher WO (2011) Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 14:2047–2055 Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Müllhaupt B, Gane E, Schuchmann M, Lohse A, Pol S, Bronowicki JP, Roberts S, Arasteh K, Zoulim F, Heim M, Stern JO, Kukolj G, Nehmiz G, Haefner C, Boecher WO (2011) Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 14:2047–2055
57.
go back to reference Choi J, Ou JHJ (2006) Mechanisms of liver injury III. Oxidative stress in the pathogenesis of hepatitis C virus. American Journal of Physiology-Gastrointestinal and Liver. Physiology 290:G847–G851 Choi J, Ou JHJ (2006) Mechanisms of liver injury III. Oxidative stress in the pathogenesis of hepatitis C virus. American Journal of Physiology-Gastrointestinal and Liver. Physiology 290:G847–G851
58.
go back to reference Zhu ZW, Wilson AT, Mathahs MM et al (2008) Heme Oxygenase-1 Suppresses Hepatitis C Virus Replication and Increases Resistance of Hepatocytes to Oxidant Injury. Hepatology 48:1430–1439PubMedCentralPubMed Zhu ZW, Wilson AT, Mathahs MM et al (2008) Heme Oxygenase-1 Suppresses Hepatitis C Virus Replication and Increases Resistance of Hepatocytes to Oxidant Injury. Hepatology 48:1430–1439PubMedCentralPubMed
59.
go back to reference Ryter SW, Morse D, Choi AMK (2007) Carbon monoxide and bilirubin-Potential therapies for pulmonary/vascular injury and disease. Am J Resp Cell Mol Biol 36:175–182 Ryter SW, Morse D, Choi AMK (2007) Carbon monoxide and bilirubin-Potential therapies for pulmonary/vascular injury and disease. Am J Resp Cell Mol Biol 36:175–182
60.
go back to reference Fillebeen C, Rivas-Estilla AM, Bisaillon M et al (2005) Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus. J Biol Chem 280:9049–9057PubMed Fillebeen C, Rivas-Estilla AM, Bisaillon M et al (2005) Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus. J Biol Chem 280:9049–9057PubMed
61.
go back to reference Lehmann E, EL-Tantawy WH, Ocker M et al (2010) The Heme Oxygenase 1 product biliverdin interferes with Hepatitis C virus replication by increasing antiviral interferon response. Hepatology 51:398–404PubMed Lehmann E, EL-Tantawy WH, Ocker M et al (2010) The Heme Oxygenase 1 product biliverdin interferes with Hepatitis C virus replication by increasing antiviral interferon response. Hepatology 51:398–404PubMed
62.
go back to reference Zhu Z, Wilson AT, Luxon BA, Brown KE, Mathahs MM, Bandyopadhyay S, McCaffrey AP, Schmidt WN (2010) Biliverdin inhibits hepatitis C virus nonstructural 3/4A protease activity: mechanism for the antiviral effects of heme oxygenase? Hepatology 52:1897–1905PubMedCentralPubMed Zhu Z, Wilson AT, Luxon BA, Brown KE, Mathahs MM, Bandyopadhyay S, McCaffrey AP, Schmidt WN (2010) Biliverdin inhibits hepatitis C virus nonstructural 3/4A protease activity: mechanism for the antiviral effects of heme oxygenase? Hepatology 52:1897–1905PubMedCentralPubMed
63.
go back to reference Rajagopalan R, Misialek S, Stevens S, Myszka D, Brandhuber B, Ballard J et al (2009) Inhibition and binding kinetics of the hepatitis C virus NS3 protease inhibitor ITMN-191 reveals tight binding and slow dissociative behavior. Biochemistry 48:2559–2568PubMed Rajagopalan R, Misialek S, Stevens S, Myszka D, Brandhuber B, Ballard J et al (2009) Inhibition and binding kinetics of the hepatitis C virus NS3 protease inhibitor ITMN-191 reveals tight binding and slow dissociative behavior. Biochemistry 48:2559–2568PubMed
64.
go back to reference Bradford WZ, Rubino C, Porter S, Forrest A, Blatt LM, Patat A (2008) A phase 1 study of the safety, tolerability, and pharmacokinetics of single ascending oral doses of the NS3/4A protease inhibitor ITMN-191 in healthy subjects. Hepatology 48:1146A Bradford WZ, Rubino C, Porter S, Forrest A, Blatt LM, Patat A (2008) A phase 1 study of the safety, tolerability, and pharmacokinetics of single ascending oral doses of the NS3/4A protease inhibitor ITMN-191 in healthy subjects. Hepatology 48:1146A
65.
go back to reference Gane EJ, Roberts SK, Stedman C et al (2009) First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1. J Hepatol 50:S380 Gane EJ, Roberts SK, Stedman C et al (2009) First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1. J Hepatol 50:S380
66.
go back to reference Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP (2010) MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease. Antimicrob Agents Chemother 54:305–311PubMedCentralPubMed Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP (2010) MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease. Antimicrob Agents Chemother 54:305–311PubMedCentralPubMed
67.
go back to reference Manns MP, Gane E, Rodriguez-Torres M, Stoehr A, Yeh CT, Marcellin P, Wiedmann RT, Hwang PM, Caro L, Barnard RJ, Lee AW (2012) MK-7009 Protocol 007 Study Group. Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: a randomized phase II study. Hepatology 56:884–893PubMed Manns MP, Gane E, Rodriguez-Torres M, Stoehr A, Yeh CT, Marcellin P, Wiedmann RT, Hwang PM, Caro L, Barnard RJ, Lee AW (2012) MK-7009 Protocol 007 Study Group. Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: a randomized phase II study. Hepatology 56:884–893PubMed
68.
go back to reference Sarrazin C, Zeuzem S (2010) Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 138:447–462PubMed Sarrazin C, Zeuzem S (2010) Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 138:447–462PubMed
69.
go back to reference Mederacke I, Wedemeyer H, Manns MP (2009) Boceprevir, an NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection. Curr Opin Investig Drugs 10:181–189PubMed Mederacke I, Wedemeyer H, Manns MP (2009) Boceprevir, an NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection. Curr Opin Investig Drugs 10:181–189PubMed
70.
go back to reference Malcolm BA, Liu R, Lahser F, Agrawal S, Belanger B et al (2006) SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother 50:1013–1020PubMedCentralPubMed Malcolm BA, Liu R, Lahser F, Agrawal S, Belanger B et al (2006) SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother 50:1013–1020PubMedCentralPubMed
71.
go back to reference Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP, SPRINT-2 Investigators (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364:1195–1206PubMedCentralPubMed Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP, SPRINT-2 Investigators (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364:1195–1206PubMedCentralPubMed
72.
go back to reference Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP, SPRINT-2 Investigators (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364:1195–1206PubMedCentralPubMed Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP, SPRINT-2 Investigators (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364:1195–1206PubMedCentralPubMed
73.
go back to reference McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Garg J, Bsharat M, George S, Kauffman RS, Adda N, Di Bisceglie AM, PROVE3 Study Team (2010) Telaprevir for previously treated chronic HCV infection. N Engl J Med 362:1292–1303PubMed McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Garg J, Bsharat M, George S, Kauffman RS, Adda N, Di Bisceglie AM, PROVE3 Study Team (2010) Telaprevir for previously treated chronic HCV infection. N Engl J Med 362:1292–1303PubMed
74.
go back to reference Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S, ADVANCE Study Team (2011) Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364:2405–2416PubMed Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S, ADVANCE Study Team (2011) Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364:2405–2416PubMed
75.
go back to reference Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, Fried MW, Adler M, Reesink HW, Martin M, Sankoh AJ, Adda N, Kauffman RS, George S, Wright CI, Poordad F, ILLUMINATE Study Team (2011) Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 365:1014–1024PubMed Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, Fried MW, Adler M, Reesink HW, Martin M, Sankoh AJ, Adda N, Kauffman RS, George S, Wright CI, Poordad F, ILLUMINATE Study Team (2011) Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 365:1014–1024PubMed
76.
go back to reference Chatel CL, Baril M, Lamarre D (2010) Hepatitis C virus NS3/4A protease inhibitors: a light at the end of the tunnel. Viruses 2:1752–1765 Chatel CL, Baril M, Lamarre D (2010) Hepatitis C virus NS3/4A protease inhibitors: a light at the end of the tunnel. Viruses 2:1752–1765
77.
go back to reference Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, Ferenci P, Nevens F, Müllhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M, REALIZE Study Team (2011) Telaprevir for retreatment of HCV infection. N Engl J Med 364:2417–2428PubMed Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, Ferenci P, Nevens F, Müllhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M, REALIZE Study Team (2011) Telaprevir for retreatment of HCV infection. N Engl J Med 364:2417–2428PubMed
78.
go back to reference Li K, Frankowski KJ, Belon CA, Neuenswander B, Ndjomou J, Hanson AM, Shanahan MA, Schoenen FJ, Blagg BS, Aubé J, Frick DN (2012) Optimization of potent Hepatitis C Virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline. J Med Chem 55:3319–3330PubMedCentralPubMed Li K, Frankowski KJ, Belon CA, Neuenswander B, Ndjomou J, Hanson AM, Shanahan MA, Schoenen FJ, Blagg BS, Aubé J, Frick DN (2012) Optimization of potent Hepatitis C Virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline. J Med Chem 55:3319–3330PubMedCentralPubMed
79.
go back to reference Salam KA, Furuta A, Noda N, Tsuneda S, Sekiguchi Y, Yamashita A, Moriishi K, Nakakoshi M, Tsubuki M, Tani H, Tanaka J, Akimitsu N (2012) Inhibition of hepatitis C virus NS3 helicase by manoalide. J Nat Prod 75:650–654PubMed Salam KA, Furuta A, Noda N, Tsuneda S, Sekiguchi Y, Yamashita A, Moriishi K, Nakakoshi M, Tsubuki M, Tani H, Tanaka J, Akimitsu N (2012) Inhibition of hepatitis C virus NS3 helicase by manoalide. J Nat Prod 75:650–654PubMed
80.
go back to reference Wolk B, Sansonno D, Krausslich HG, Dammacco F, Rice CM, Blum HE, Moradpour D (2000) Subcellular localization, stability, and trans-cleavage competence of the hepatitis C virus NS3-NS4A complex expressed in tetracycline-regulated cell lines. J Virol 74:2293–2304PubMedCentralPubMed Wolk B, Sansonno D, Krausslich HG, Dammacco F, Rice CM, Blum HE, Moradpour D (2000) Subcellular localization, stability, and trans-cleavage competence of the hepatitis C virus NS3-NS4A complex expressed in tetracycline-regulated cell lines. J Virol 74:2293–2304PubMedCentralPubMed
81.
go back to reference Asabe SI, Tanji Y, Satoh S, Kaneko T, Kimura K, Shimotohno K (1997) The N-terminal region of hepatitis C virus-encoded NS5A is important for NS4A-dependent phosphorylation. J Virol 71:790–796PubMedCentralPubMed Asabe SI, Tanji Y, Satoh S, Kaneko T, Kimura K, Shimotohno K (1997) The N-terminal region of hepatitis C virus-encoded NS5A is important for NS4A-dependent phosphorylation. J Virol 71:790–796PubMedCentralPubMed
82.
go back to reference Huang M, Sun Y, Yang W et al (2007) ACH-806: a potent inhibitor of HCV replication with a novel mechanism of action. J Hepatol 46:S221 Huang M, Sun Y, Yang W et al (2007) ACH-806: a potent inhibitor of HCV replication with a novel mechanism of action. J Hepatol 46:S221
83.
go back to reference Gouttenoire J, Penin F, Moradpour D (2010) Hepatitis C virus nonstructural protein 4B: a journey into unexplored territory. Rev Med Virol 20:117–129PubMed Gouttenoire J, Penin F, Moradpour D (2010) Hepatitis C virus nonstructural protein 4B: a journey into unexplored territory. Rev Med Virol 20:117–129PubMed
84.
go back to reference Einav S, Gerber D, Bryson P, Sklan E, Elazar M, Glenn JS, Quake S (2008) Inhibitors of a new hepatitis C target discovered bymicrofluidic affinity analysis. Nat Biotechnol 26:1019–1027PubMed Einav S, Gerber D, Bryson P, Sklan E, Elazar M, Glenn JS, Quake S (2008) Inhibitors of a new hepatitis C target discovered bymicrofluidic affinity analysis. Nat Biotechnol 26:1019–1027PubMed
85.
go back to reference Einav S, Dvory SH, Gehrig EG (2010) The Hepatitis C virus (HCV) NS4B RNA binding inhibitor, clemizole, is highly synergistic with HCV protease inhibitors, submitted for publication. Antiviral Res 87:1–8PubMedCentralPubMed Einav S, Dvory SH, Gehrig EG (2010) The Hepatitis C virus (HCV) NS4B RNA binding inhibitor, clemizole, is highly synergistic with HCV protease inhibitors, submitted for publication. Antiviral Res 87:1–8PubMedCentralPubMed
86.
go back to reference Bryson PD, Cho NJ, Einav S, Lee C, Tai V, Bechtel J, Sivaraja M, Roberts C, Schmitz U, Glenn JS (2010) A small molecule inhibits HCV replication and alters NS4B’s subcellular distribution. Antiviral Res 87:1–8PubMedCentralPubMed Bryson PD, Cho NJ, Einav S, Lee C, Tai V, Bechtel J, Sivaraja M, Roberts C, Schmitz U, Glenn JS (2010) A small molecule inhibits HCV replication and alters NS4B’s subcellular distribution. Antiviral Res 87:1–8PubMedCentralPubMed
87.
go back to reference Lundin M, Lindström H, Grönwall C, Persson MA (2006) Dual topology of the processed hepatitis C virus protein NS4B is influenced by the NS5A protein. J Gen Virol 87:3263–3272PubMed Lundin M, Lindström H, Grönwall C, Persson MA (2006) Dual topology of the processed hepatitis C virus protein NS4B is influenced by the NS5A protein. J Gen Virol 87:3263–3272PubMed
88.
go back to reference Cho NJ, Dvory-Sobol H, Lee C, Cho SJ, Bryson P, Masek M, Elazar M, Frank CW, Glenn JS (2010) Identification of a class of HCV inhibitors directed against the nonstructural protein NS4B. Sci Transl Med 2:15ra6 Cho NJ, Dvory-Sobol H, Lee C, Cho SJ, Bryson P, Masek M, Elazar M, Frank CW, Glenn JS (2010) Identification of a class of HCV inhibitors directed against the nonstructural protein NS4B. Sci Transl Med 2:15ra6
89.
go back to reference Moradpour D, Kary P, Rice CM, Blum HE (1998) Continuous human cell lines inducibly expressing hepatitis C virus structural and nonstructural proteins. Hepatology 28:192–201PubMed Moradpour D, Kary P, Rice CM, Blum HE (1998) Continuous human cell lines inducibly expressing hepatitis C virus structural and nonstructural proteins. Hepatology 28:192–201PubMed
90.
go back to reference Gao M, Nettles RE, Belema M, Snyder LB et al (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465:96–100PubMed Gao M, Nettles RE, Belema M, Snyder LB et al (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465:96–100PubMed
92.
93.
go back to reference Lee C, Ma H, Hang JQ, Leveque V, Sklan EH, Elazar M, Klumpp K, Glenn JS (2011) The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein. Virology 414:10–18PubMedCentralPubMed Lee C, Ma H, Hang JQ, Leveque V, Sklan EH, Elazar M, Klumpp K, Glenn JS (2011) The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein. Virology 414:10–18PubMedCentralPubMed
95.
go back to reference Spreen W, Wilfret D, Bechtel J, Adkison K, Lou Y, Jones L, Willsie S, Glass S, Roberts C (2011) GSK2336805 HCV NS5A Inhibitor Demonstrates Potent Antiviral Activity in Chronic Hepatitis C (CHC) Genotype 1 Infection: Results from a First Time in Human (FTIH) Single and Repeat Dose Study. 62th Annual Meeting of the American Association for the Study of liver diseases. http://www.natap.org/2011/AASLD/AASLD_30.htm. Accessed 5–9 Nov 2011 Spreen W, Wilfret D, Bechtel J, Adkison K, Lou Y, Jones L, Willsie S, Glass S, Roberts C (2011) GSK2336805 HCV NS5A Inhibitor Demonstrates Potent Antiviral Activity in Chronic Hepatitis C (CHC) Genotype 1 Infection: Results from a First Time in Human (FTIH) Single and Repeat Dose Study. 62th Annual Meeting of the American Association for the Study of liver diseases. http://​www.​natap.​org/​2011/​AASLD/​AASLD_​30.​htm. Accessed 5–9 Nov 2011
97.
go back to reference Gane EJ, Roberts SK, Stedman CA et al (2009) Combination therapy with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) Inhibitor in HCV: Safety, pharmacokinetics, and virologic results from INFORM-1. Hepatology 50:394A–395A Gane EJ, Roberts SK, Stedman CA et al (2009) Combination therapy with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) Inhibitor in HCV: Safety, pharmacokinetics, and virologic results from INFORM-1. Hepatology 50:394A–395A
98.
go back to reference Miller RH, Purcell RH (1990) Hepatitis C virus shares amino acid sequence similarity with pestiviruses and flaviviruses as well as members of two plant virus supergroups. Proc Natl Acad Sci USA 87:2057–2061PubMedCentralPubMed Miller RH, Purcell RH (1990) Hepatitis C virus shares amino acid sequence similarity with pestiviruses and flaviviruses as well as members of two plant virus supergroups. Proc Natl Acad Sci USA 87:2057–2061PubMedCentralPubMed
99.
go back to reference Doublié S, Tabor S, Long AM, Richardson CC, Ellenberger T (1998) Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 A resolution. Nature 391:251–258PubMed Doublié S, Tabor S, Long AM, Richardson CC, Ellenberger T (1998) Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 A resolution. Nature 391:251–258PubMed
100.
go back to reference Kolykhalov AA, Mihalik K, Feinstone SM, Rice CM (2000) Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. J Virol 74:2046–2051PubMedCentralPubMed Kolykhalov AA, Mihalik K, Feinstone SM, Rice CM (2000) Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. J Virol 74:2046–2051PubMedCentralPubMed
101.
go back to reference Heck JA, Lam AM, Narayanan N, Frick DN (2008) Effects of mutagenic and chain-terminating nucleotide analogs on enzymes isolated from hepatitis C virus strains of various genotypes. Antimicrob Agents Chemother 52:1901–1911PubMedCentralPubMed Heck JA, Lam AM, Narayanan N, Frick DN (2008) Effects of mutagenic and chain-terminating nucleotide analogs on enzymes isolated from hepatitis C virus strains of various genotypes. Antimicrob Agents Chemother 52:1901–1911PubMedCentralPubMed
102.
go back to reference McCown MF, Rajyaguru S, Pogam SL et al (2008) The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to non-nucleoside polymerase or protease inhibitors. Antimicrob Agents Chemother 52:1604–1612PubMedCentralPubMed McCown MF, Rajyaguru S, Pogam SL et al (2008) The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to non-nucleoside polymerase or protease inhibitors. Antimicrob Agents Chemother 52:1604–1612PubMedCentralPubMed
103.
go back to reference Ali S, Leveque V, Le Pogam S et al (2008) Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479. Antimicrob Agents Chemother 52:4356–4369PubMedCentralPubMed Ali S, Leveque V, Le Pogam S et al (2008) Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479. Antimicrob Agents Chemother 52:4356–4369PubMedCentralPubMed
104.
go back to reference Erhardt A, Deterding K, Benhamou Y, Reiser M, Forns X et al (2009) Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment. Antivir Ther 14:23–32PubMed Erhardt A, Deterding K, Benhamou Y, Reiser M, Forns X et al (2009) Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment. Antivir Ther 14:23–32PubMed
105.
go back to reference Lam AM, Murakami E, Espiritu C, Steuer HM, Niu C, Keilman M et al (2010) PSI-7851, a pronucleotide of beta-D-2’-deoxy-2’-fluoro-2’-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication. Antimicrob Agents Chemother 54:3187–3196PubMedCentralPubMed Lam AM, Murakami E, Espiritu C, Steuer HM, Niu C, Keilman M et al (2010) PSI-7851, a pronucleotide of beta-D-2’-deoxy-2’-fluoro-2’-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication. Antimicrob Agents Chemother 54:3187–3196PubMedCentralPubMed
106.
go back to reference McGuigan C, Madela K, Aljarah M, Gilles A, Brancale A et al (2010) Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus. Bioorg Med Chem Lett 20:4850–4854PubMed McGuigan C, Madela K, Aljarah M, Gilles A, Brancale A et al (2010) Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus. Bioorg Med Chem Lett 20:4850–4854PubMed
107.
go back to reference Vernachio JH, Bleiman B, Bryant KD et al (2011) INX-08189, a phosphoramidate prodrug of 6-O-methyl-2’-C-methyl guanosine, is a potent inhibitor of hepatitis C virus replication with excellent pharmacokinetic and pharmacodynamic properties. Antimicrob Agents Chemother 55:1843–1851PubMedCentralPubMed Vernachio JH, Bleiman B, Bryant KD et al (2011) INX-08189, a phosphoramidate prodrug of 6-O-methyl-2’-C-methyl guanosine, is a potent inhibitor of hepatitis C virus replication with excellent pharmacokinetic and pharmacodynamic properties. Antimicrob Agents Chemother 55:1843–1851PubMedCentralPubMed
109.
go back to reference Kong L, Li S, Han X, Xiang Z, Fang X, Li B, Wang W, Zhong H, Gao J, Ye L (2007) Inhibition of HCV RNA-dependent RNA polymerase activity by aqueous extract from Fructus Ligustri Lucidi. Virus Res 128:9–17PubMed Kong L, Li S, Han X, Xiang Z, Fang X, Li B, Wang W, Zhong H, Gao J, Ye L (2007) Inhibition of HCV RNA-dependent RNA polymerase activity by aqueous extract from Fructus Ligustri Lucidi. Virus Res 128:9–17PubMed
110.
go back to reference Kong L, Li S, Liao Q, Zhang Y, Sun R, Zhu X, Zhang Q, Wang J, Wu X, Fang X, Zhu Y (2013) Oleanolic acid and ursolic acid: Novel hepatitis C virus antivirals that inhibit NS5B activity. Antiviral Res 98:44–53PubMed Kong L, Li S, Liao Q, Zhang Y, Sun R, Zhu X, Zhang Q, Wang J, Wu X, Fang X, Zhu Y (2013) Oleanolic acid and ursolic acid: Novel hepatitis C virus antivirals that inhibit NS5B activity. Antiviral Res 98:44–53PubMed
111.
go back to reference Jilg N, Chung RT (2012) Adding to the toolbox: Receptor tyrosine kinases as potential targets in the treatment of hepatitis C. J Hepatol 56:282–284PubMed Jilg N, Chung RT (2012) Adding to the toolbox: Receptor tyrosine kinases as potential targets in the treatment of hepatitis C. J Hepatol 56:282–284PubMed
112.
go back to reference Shinohara Y, Imajo K, Yoneda M, Tomeno W, Ogawa Y, Kirikoshi H, Funakoshi K, Ikeda M, Kato N, Nakajima A, Saito S (2013) Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy. Biochem Biophys Res Commun 432:326–332PubMed Shinohara Y, Imajo K, Yoneda M, Tomeno W, Ogawa Y, Kirikoshi H, Funakoshi K, Ikeda M, Kato N, Nakajima A, Saito S (2013) Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy. Biochem Biophys Res Commun 432:326–332PubMed
113.
go back to reference Rosnoblet C, Fritzinger B, Legrand D, Launay H, Wieruszeski JM, Lippens G, Hanoulle X (2012) Hepatitis C virus NS5B and host cyclophilin A share a common binding site on NS5A. J Biol Chem 287:44249–44260PubMedCentralPubMed Rosnoblet C, Fritzinger B, Legrand D, Launay H, Wieruszeski JM, Lippens G, Hanoulle X (2012) Hepatitis C virus NS5B and host cyclophilin A share a common binding site on NS5A. J Biol Chem 287:44249–44260PubMedCentralPubMed
114.
go back to reference Chatterji U, Lim P, Bobardt MD et al (2010) HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A cyclophilin A interaction to cyclophilin inhibitors. J Hepatol 53:50–56PubMedCentralPubMed Chatterji U, Lim P, Bobardt MD et al (2010) HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A cyclophilin A interaction to cyclophilin inhibitors. J Hepatol 53:50–56PubMedCentralPubMed
115.
go back to reference Ma S, Boerner JE, TiongYip C et al (2006) NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother 50:2976–2982PubMedCentralPubMed Ma S, Boerner JE, TiongYip C et al (2006) NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother 50:2976–2982PubMedCentralPubMed
116.
go back to reference Hopkins S, Scorneaux B, Huang Z et al (2010) SCY-635: A Novel Non-Immunosuppressive Analog of Cyclosporin A that Exhibits Potent Inhibition of Hepatitis C Virus RNA Replication in vitro. Antimicrob Agents Chemother 54:660–672PubMedCentralPubMed Hopkins S, Scorneaux B, Huang Z et al (2010) SCY-635: A Novel Non-Immunosuppressive Analog of Cyclosporin A that Exhibits Potent Inhibition of Hepatitis C Virus RNA Replication in vitro. Antimicrob Agents Chemother 54:660–672PubMedCentralPubMed
117.
go back to reference Landrieu I, Hanoulle X, Bonachera F et al (2010) Structural basis for the non-immunosuppressive character of the Cyclosporin A analog Debio 025. Biochemistry 49:4679–4686PubMed Landrieu I, Hanoulle X, Bonachera F et al (2010) Structural basis for the non-immunosuppressive character of the Cyclosporin A analog Debio 025. Biochemistry 49:4679–4686PubMed
118.
go back to reference Flisiak R, Feinman SV, Jablkowski M et al (2009) The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naive hepatitis C patients. Hepatology 49:1460–1468PubMed Flisiak R, Feinman SV, Jablkowski M et al (2009) The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naive hepatitis C patients. Hepatology 49:1460–1468PubMed
119.
go back to reference Pianko S, Zeuzem S, Chuang WL, Foster GR, Sarin SK, Flisiak R, Lee CM, Andreone P, Piratvisuth T, Shah S, Sood A, George J, Gould M, Komolmit P (2012) Randomized trial of albinterferon alfa-2b every 4 weeks for chronic hepatitis C virus genotype 2/3. J Viral Hepat 19:623–634PubMed Pianko S, Zeuzem S, Chuang WL, Foster GR, Sarin SK, Flisiak R, Lee CM, Andreone P, Piratvisuth T, Shah S, Sood A, George J, Gould M, Komolmit P (2012) Randomized trial of albinterferon alfa-2b every 4 weeks for chronic hepatitis C virus genotype 2/3. J Viral Hepat 19:623–634PubMed
120.
go back to reference Elazar M, Liu M, McKenna SA et al (2009) The antihepatitis C agent nitazoxanide induces phosphorylation of eukaryotic initiation factor 2alpha via protein kinase activated by double-stranded RNA activation. Gastroenterology 137:1827–1835PubMed Elazar M, Liu M, McKenna SA et al (2009) The antihepatitis C agent nitazoxanide induces phosphorylation of eukaryotic initiation factor 2alpha via protein kinase activated by double-stranded RNA activation. Gastroenterology 137:1827–1835PubMed
121.
go back to reference Rossignol JF, Kabil SM, El Gohary Y et al (2008) Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4. Aliment Pharmacol Ther 28:574–580PubMed Rossignol JF, Kabil SM, El Gohary Y et al (2008) Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4. Aliment Pharmacol Ther 28:574–580PubMed
122.
go back to reference Mederacke I, Wedemeyer H (2009) Nitazoxanide for the treatment of chronic hepatitis C New opportunities but new challenges? Ann Hepatol 8:166–168PubMed Mederacke I, Wedemeyer H (2009) Nitazoxanide for the treatment of chronic hepatitis C New opportunities but new challenges? Ann Hepatol 8:166–168PubMed
123.
go back to reference Goldstein AL, Thymosins Badamchian M (2004) Chemistry and biological properties in health and disease. Expert Opin Biol Ther 4:559–573PubMed Goldstein AL, Thymosins Badamchian M (2004) Chemistry and biological properties in health and disease. Expert Opin Biol Ther 4:559–573PubMed
124.
go back to reference Ciancio A, Andreone P, Kaiser S, Mangia A, Milella M, Solà R, Pol S, Tsianos E, De Rosa A, Camerini R, McBeath R, Rizzetto M (2012) Thymosin alpha-1 with peginterferon alfa-2a/ribavirin for chronic hepatitis C not responsive to IFN/ribavirin: an adjuvant role? J Viral Hepat 19(Suppl 1):52–59PubMed Ciancio A, Andreone P, Kaiser S, Mangia A, Milella M, Solà R, Pol S, Tsianos E, De Rosa A, Camerini R, McBeath R, Rizzetto M (2012) Thymosin alpha-1 with peginterferon alfa-2a/ribavirin for chronic hepatitis C not responsive to IFN/ribavirin: an adjuvant role? J Viral Hepat 19(Suppl 1):52–59PubMed
125.
go back to reference Niepmann M (2009) Activation of hepatitis C virus translation by liver-specific microRNA. Cell Cycle 8:1473–1477PubMed Niepmann M (2009) Activation of hepatitis C virus translation by liver-specific microRNA. Cell Cycle 8:1473–1477PubMed
126.
go back to reference Jangra RK, Yi M, Lemon SM (2010) Regulation of hepatitis C virus translation and infectious virus production by the microRNA miR-122. J Virol 84:6615–6625PubMedCentralPubMed Jangra RK, Yi M, Lemon SM (2010) Regulation of hepatitis C virus translation and infectious virus production by the microRNA miR-122. J Virol 84:6615–6625PubMedCentralPubMed
127.
go back to reference Fluiter K, Mook OR, Baas F (2009) The therapeutic potential of LNA-modified siRNAs: reduction of off-target effects by chemical modification of the siRNA sequence. Methods Mol Biol 487:189–203PubMed Fluiter K, Mook OR, Baas F (2009) The therapeutic potential of LNA-modified siRNAs: reduction of off-target effects by chemical modification of the siRNA sequence. Methods Mol Biol 487:189–203PubMed
128.
go back to reference Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME et al (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327:198–201PubMedCentralPubMed Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME et al (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327:198–201PubMedCentralPubMed
Metadata
Title
Current and future therapies for hepatitis C virus infection: from viral proteins to host targets
Authors
Muhammad Imran
Sobia Manzoor
Nasir Mahmood Khattak
Madiha Khalid
Qazi Laeeque Ahmed
Fahed Parvaiz
Muqddas Tariq
Javed Ashraf
Waseem Ashraf
Sikandar Azam
Muhammad Ashraf
Publication date
01-05-2014
Publisher
Springer Vienna
Published in
Archives of Virology / Issue 5/2014
Print ISSN: 0304-8608
Electronic ISSN: 1432-8798
DOI
https://doi.org/10.1007/s00705-013-1803-7

Other articles of this Issue 5/2014

Archives of Virology 5/2014 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.