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Special Issue "Antivirals Against Hepatitis C Virus"

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Antivirals & Vaccines".

Deadline for manuscript submissions: closed (31 May 2010)

Special Issue Editor

Guest Editor
Dr. Brett Lindenbach

Section of Microbial Pathogenesis, Yale University, School of Medicine, 295 Congress Ave., BCMM 354C, New Haven, CT 06536-0812, USA
Website | E-Mail
Phone: 2037854705
Fax: +1 203 737 2630
Interests: positive-strand RNA viruses; flaviviruses; hepatitis C virus; Zika virus; yellow fever virus; dengue virus

Published Papers (11 papers)

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Review

Open AccessReview The Future of HCV Therapy: NS4B as an Antiviral Target
Viruses 2010, 2(11), 2481-2492; doi:10.3390/v2112481
Received: 19 August 2010 / Revised: 28 September 2010 / Accepted: 13 October 2010 / Published: 10 November 2010
Cited by 22 | PDF Full-text (166 KB)
Abstract
Chronic hepatitis C virus (HCV) infection is a major worldwide cause of liver disease, including cirrhosis and hepatocellular carcinoma. It is estimated that more than 170 million individuals are infected with HCV, with three to four million new cases each year. The current
[...] Read more.
Chronic hepatitis C virus (HCV) infection is a major worldwide cause of liver disease, including cirrhosis and hepatocellular carcinoma. It is estimated that more than 170 million individuals are infected with HCV, with three to four million new cases each year. The current standard of care, combination treatment with interferon and ribavirin, eradicates the virus in only about 50% of chronically infected patients. Notably, neither of these drugs directly target HCV. Many new antiviral therapies that specifically target hepatitis C (e.g. NS3 protease or NS5B polymerase inhibitors) are therefore in development, with a significant number having advanced into clinical trials. The nonstructural 4B (NS4B) protein, is among the least characterized of the HCV structural and nonstructural proteins and has been subjected to few pharmacological studies. NS4B is an integral membrane protein with at least four predicted transmembrane (TM) domains. A variety of functions have been postulated for NS4B, such as the ability to induce the membranous web replication platform, RNA binding and NTPase activity. This review summarizes potential targets within the nonstructural protein NS4B, with a focus on novel classes of NS4B inhibitors. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Open AccessReview Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase NS5B
Viruses 2010, 2(10), 2169-2195; doi:10.3390/v2102169
Received: 29 July 2010 / Revised: 6 September 2010 / Accepted: 6 September 2010 / Published: 28 September 2010
Cited by 48 | PDF Full-text (640 KB)
Abstract
More than 20 years after the identification of the hepatitis C virus (HCV) as a novel human pathogen, the only approved treatment remains a combination of pegylated interferon-α and ribavirin. This rather non-specific therapy is associated with severe side effects and by far
[...] Read more.
More than 20 years after the identification of the hepatitis C virus (HCV) as a novel human pathogen, the only approved treatment remains a combination of pegylated interferon-α and ribavirin. This rather non-specific therapy is associated with severe side effects and by far not everyone benefits from treatment. Recently, progress has been made in the development of specifically targeted antiviral therapy for HCV (STAT-C). A major target for such direct acting antivirals (DAAs) is the HCV RNA-dependent RNA polymerase or non-structural protein 5B (NS5B), which is essential for viral replication. This review will examine the current state of development of inhibitors targeting the polymerase and issues such as the emergence of antiviral resistance during treatment, as well as strategies to address this problem. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Figures

Open AccessReview Last Stop Before Exit – Hepatitis C Assembly and Release as Antiviral Drug Targets
Viruses 2010, 2(8), 1782-1803; doi:10.3390/v2081782
Received: 15 June 2010 / Revised: 16 July 2010 / Accepted: 4 August 2010 / Published: 24 August 2010
Cited by 3 | PDF Full-text (3519 KB) | HTML Full-text | XML Full-text
Abstract
Chronic Hepatitis C infection is a global health problem. While primary infection is often inapparent, it becomes chronic in most cases. Chronic infection with Hepatitis C virus (HCV) frequently leads to liver cirrhosis or liver cancer. Consequently, HCV infection is one of the
[...] Read more.
Chronic Hepatitis C infection is a global health problem. While primary infection is often inapparent, it becomes chronic in most cases. Chronic infection with Hepatitis C virus (HCV) frequently leads to liver cirrhosis or liver cancer. Consequently, HCV infection is one of the leading causes for liver transplantation in industrialized countries. Current treatment is not HCV specific and is only effective in about half of the infected patients. This situation underlines the need for new antivirals against HCV. To develop new and more efficient drugs, it is essential to specifically target the different steps of the viral life cycle. Of those steps, the targeting of HCV assembly has the potential to abolish virus production. This review summarizes the advances in our understanding of HCV particle assembly and the identification of new antiviral targets of potential interest in this late step of the HCV life cycle. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Open AccessReview Core as a Novel Viral Target for Hepatitis C Drugs
Viruses 2010, 2(8), 1734-1751; doi:10.3390/v2081734
Received: 18 June 2010 / Revised: 6 August 2010 / Accepted: 16 August 2010 / Published: 20 August 2010
Cited by 16 | PDF Full-text (290 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C virus (HCV) infects over 130 million people worldwide and is a major cause of liver disease. No vaccine is available. Novel specific drugs for HCV are urgently required, since the standard-of-care treatment of pegylated interferon combined with ribavirin is poorly tolerated
[...] Read more.
Hepatitis C virus (HCV) infects over 130 million people worldwide and is a major cause of liver disease. No vaccine is available. Novel specific drugs for HCV are urgently required, since the standard-of-care treatment of pegylated interferon combined with ribavirin is poorly tolerated and cures less than half of the treated patients. Promising, effective direct-acting drugs currently in the clinic have been described for three of the ten potential HCV target proteins: NS3/NS4A protease, NS5B polymerase and NS5A, a regulatory phosphoprotein. We here present core, the viral capsid protein, as another attractive, non-enzymatic target, against which a new class of anti-HCV drugs can be raised. Core plays a major role in the virion’s formation, and interacts with several cellular proteins, some of which are involved in host defense mechanisms against the virus. This most conserved of all HCV proteins requires oligomerization to function as the organizer of viral particle assembly. Using core dimerization as the basis of transfer-of-energy screening assays, peptides and small molecules were identified which not only inhibit core-core interaction, but also block viral production in cell culture. Initial chemical optimization resulted in compounds active in single digit micromolar concentrations. Core inhibitors could be used in combination with other HCV drugs in order to provide novel treatments of Hepatitis C. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Open AccessReview Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel
Viruses 2010, 2(8), 1752-1765; doi:10.3390/v2081752
Received: 3 June 2010 / Revised: 12 August 2010 / Accepted: 18 August 2010 / Published: 20 August 2010
Cited by 31 | PDF Full-text (364 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C virus (HCV) infection is a serious and growing threat to human health. The current treatment provides limited efficacy and is poorly tolerated, highlighting the urgent medical need for novel therapeutics. The membrane-targeted NS3 protein in complex with the NS4A comprises a
[...] Read more.
Hepatitis C virus (HCV) infection is a serious and growing threat to human health. The current treatment provides limited efficacy and is poorly tolerated, highlighting the urgent medical need for novel therapeutics. The membrane-targeted NS3 protein in complex with the NS4A comprises a serine protease domain (NS3/4A protease) that is essential for viral polyprotein maturation and contributes to the evasion of the host innate antiviral immunity by HCV. Therefore, the NS3/4A protease represents an attractive target for drug discovery, which is tied in with the challenge to develop selective small-molecule inhibitors. A rational drug design approach, based on the discovery of N-terminus product inhibition, led to the identification of potent and orally bioavailable NS3 inhibitors that target the highly conserved protease active site. This review summarizes the NS3 protease inhibitors currently challenged in clinical trials as one of the most promising antiviral drug class, and possibly among the first anti-HCV agents to be approved for the treatment of HCV infection. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Figures

Open AccessReview Targeting HCV Entry For Development of Therapeutics
Viruses 2010, 2(8), 1718-1733; doi:10.3390/v2081718
Received: 28 June 2010 / Revised: 5 August 2010 / Accepted: 16 August 2010 / Published: 18 August 2010
Cited by 22 | PDF Full-text (182 KB) | HTML Full-text | XML Full-text
Abstract
Recent progress in defining the molecular mechanisms of Hepatitis C Virus (HCV) entry affords the opportunity to exploit new viral and host targets for therapeutic intervention. Entry inhibitors would limit the expansion of the infected cell reservoir, and would complement the many replication
[...] Read more.
Recent progress in defining the molecular mechanisms of Hepatitis C Virus (HCV) entry affords the opportunity to exploit new viral and host targets for therapeutic intervention. Entry inhibitors would limit the expansion of the infected cell reservoir, and would complement the many replication inhibitors now under development. The current model for the pathway of entry involves the initial docking of the virus onto the cell surface through interactions of virion envelope and associated low density lipoproteins (LDL) with cell surface glycosaminoglycans and lipoprotein receptors, followed by more specific utilization with other hepatocyte membrane proteins: Scavenger Receptor Class B type 1 (SR-BI), CD81, Claudin 1 (CLDN1) and Occludin (OCLN). The use of blockers of these interactions, e.g. specific antibodies, suggests that inhibition of any one step in the entry pathway can inhibit infection. Despite this knowledge base, the tools for compound screening, HCV pseudoparticles (HCVpp) and cell culture virus (HCVcc), and the ability to adapt them to industrial use are only recently available and as a result drug discovery initiatives are in their infancy. Several therapies aiming at modulating the virus envelope to prevent host cell binding are in early clinical testing. The first test case for blocking a cellular co-receptor is an SR-BI modulator. ITX 5061, an orally active small molecule, targets SR-BI and has shown potent antiviral activity against HCVpp and HCVcc. ITX 5061 has exhibited good safety in previous clinical studies, and is being evaluated in the clinic in chronic HCV patients and patients undergoing liver transplantation. Entry inhibitors promise to be valuable players in the future development of curative therapy against HCV. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Open AccessReview The Hepatitis C Virus Nonstructural Protein 2 (NS2): An Up-and-Coming Antiviral Drug Target
Viruses 2010, 2(8), 1635-1646; doi:10.3390/v2081635
Received: 30 June 2010 / Revised: 3 August 2010 / Accepted: 4 August 2010 / Published: 6 August 2010
Cited by 9 | PDF Full-text (131 KB) | HTML Full-text | XML Full-text
Abstract
Infection with Hepatitis C Virus (HCV) continues to be a major global health problem. To overcome the limitations of current therapies using interferon-a in combination with ribavirin, there is a need to develop drugs that specifically block viral proteins. Highly efficient protease and
[...] Read more.
Infection with Hepatitis C Virus (HCV) continues to be a major global health problem. To overcome the limitations of current therapies using interferon-a in combination with ribavirin, there is a need to develop drugs that specifically block viral proteins. Highly efficient protease and polymerase inhibitors are currently undergoing clinical testing and will become available in the next few years. However, with resistance mutations emerging quickly, additional enzymatic activities or functions of HCV have to be targeted by novel compounds. One candidate molecule is the nonstructural protein 2 (NS2), which contains a proteolytic activity that is essential for viral RNA replication. In addition, NS2 is crucial for the assembly of progeny virions and modulates various cellular processes that interfere with viral replication. This review describes the functions of NS2 in the life cycle of HCV and highlights potential antiviral strategies involving NS2. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Figures

Open AccessReview Possibilities for RNA Interference in Developing Hepatitis C Virus Therapeutics
Viruses 2010, 2(8), 1647-1665; doi:10.3390/v2081647
Received: 6 July 2010 / Revised: 4 August 2010 / Accepted: 4 August 2010 / Published: 6 August 2010
Cited by 3 | PDF Full-text (211 KB) | HTML Full-text | XML Full-text
Abstract
The discovery and characterization of the RNA interference (RNAi) pathway has been one of the most important scientific developments of the last 12 years. RNAi is a cellular pathway wherein small RNAs control the expression of genes by either degrading homologous RNAs or
[...] Read more.
The discovery and characterization of the RNA interference (RNAi) pathway has been one of the most important scientific developments of the last 12 years. RNAi is a cellular pathway wherein small RNAs control the expression of genes by either degrading homologous RNAs or preventing the translation of RNAs with partial homology. It has impacted basic biology on two major fronts. The first is the discovery of microRNAs (miRNAs), which regulate almost every cellular process and are required for some viral infections, including hepatitis C virus (HCV). The second front is the use of small interfering RNAs (siRNAs) as the first robust tool for mammalian cellular genetics. This has led to the identification of hundreds of cellular genes that are important for HCV infection. There is now a major push to adapt RNAi technology to the clinic. In this review, we explore the impact of RNAi in understanding HCV biology, the progress in design of RNAi-based therapeutics for HCV, and remaining obstacles. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Open AccessReview Interferon-λ in HCV Infection and Therapy  
Viruses 2010, 2(8), 1589-1602; doi:10.3390/v2081589
Received: 28 June 2010 / Accepted: 28 July 2010 / Published: 5 August 2010
Cited by 16 | PDF Full-text (207 KB) | HTML Full-text | XML Full-text
Abstract
Chronic infection with hepatitis C virus (HCV) is associated with significant liver disease and is therefore an important public health problem. The current standard-of-care therapy for chronic HCV infection consists of a combination of pegylated (PEG) interferon (IFN)-α and ribavirin. Although this therapy
[...] Read more.
Chronic infection with hepatitis C virus (HCV) is associated with significant liver disease and is therefore an important public health problem. The current standard-of-care therapy for chronic HCV infection consists of a combination of pegylated (PEG) interferon (IFN)-α and ribavirin. Although this therapy effectively generates a sustained viral response in approximately half of treated individuals, it is associated with significant hematological and neurological side effects. A new family of IFN-related proteins (IFN-λ1, 2, and 3; or alternately, IL-29, 28A, 28B, respectively) possesses properties that may make these cytokines superior to PEG-IFN-α for HCV therapy. Genetic studies have also implicated these proteins in both the natural and therapy-induced resolution of HCV infection. This review summarizes the basic aspects of IFN-λ biology, the potential role of these cytokines in HCV infection, and the outlook for their therapeutic application. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Open AccessReview Cyclophilin Inhibitors as a Novel HCV Therapy
Viruses 2010, 2(8), 1621-1634; doi:10.3390/v2081621
Received: 17 June 2010 / Revised: 23 July 2010 / Accepted: 4 August 2010 / Published: 5 August 2010
Cited by 10 | PDF Full-text (140 KB) | HTML Full-text | XML Full-text
Abstract
A critical role of Cyclophilins, mostly Cyclophilin A (CyPA), in the replication of HCV is supported by a growing body of in vitro and in vivo evidence. CyPA probably interacts directly with nonstructural protein 5A to exert its effect, through its peptidyl-prolyl isomerase
[...] Read more.
A critical role of Cyclophilins, mostly Cyclophilin A (CyPA), in the replication of HCV is supported by a growing body of in vitro and in vivo evidence. CyPA probably interacts directly with nonstructural protein 5A to exert its effect, through its peptidyl-prolyl isomerase activity, on maintaining the proper structure and function of the HCV replicase. The major proline substrates are located in domain II of NS5A, centered around a “DY” dipeptide motif that regulates CyPA dependence and CsA resistance. Importantly, Cyclosporine A derivatives that lack immunosuppressive function efficiently block the CyPA-NS5A interaction and inhibit HCV in cell culture, an animal model, and human trials. Given the high genetic barrier to development of resistance and the distinctness of their mechanism from that of either the current standard of care or any specifically targeted antiviral therapy for HCV (STAT-C), CyP inhibitors hold promise as a novel class of anti-HCV therapy. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
Figures

Open AccessReview Targeting microRNA-122 to Treat Hepatitis C Virus Infection
Viruses 2010, 2(7), 1382-1393; doi:10.3390/v2071382
Received: 31 May 2010 / Revised: 28 June 2010 / Accepted: 2 July 2010 / Published: 5 July 2010
Cited by 19 | PDF Full-text (199 KB) | HTML Full-text | XML Full-text
Abstract
An important host factor for hepatitis C virus (HCV) is microRNA-122 (miR-122). miR-122 is a liver-specific member of a family of small, non-coding RNA molecules known as microRNAs that play major roles in the regulation of gene expression by direct interaction with RNA
[...] Read more.
An important host factor for hepatitis C virus (HCV) is microRNA-122 (miR-122). miR-122 is a liver-specific member of a family of small, non-coding RNA molecules known as microRNAs that play major roles in the regulation of gene expression by direct interaction with RNA targets. miR-122 binds directly to two sites in the 5′ untranslated region (UTR) of HCV RNA and positively regulates the viral life cycle. The mechanism by which this regulation occurs is still not fully understood. There has been a great deal of interest in potential therapeutics based on small RNAs, and targeting miR-122 to combat HCV is one of the furthest advanced. Chemical inhibitors of miR-122 can be introduced into mammals intravenously and result in potent and specific knockdown of the microRNA, with no detectable adverse effects on liver physiology. This strategy was recently applied to chimpanzees chronically infected with HCV and resulted in a sustained reduction in viral load in the animals. Inhibition of miR-122 therefore presents a very attractive novel approach to treating HCV, a virus for which improved therapeutics are urgently needed. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)

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