Advances in hepatitis C: What is coming in the next 5 years?

Locarnini, Stephen; Bartholomeusz, Angeline

doi:10.1046/j.1440-1746.2002.02768.x

Cited by 10 publications

(7 citation statements)

References 44 publications

(87 reference statements)

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“…It is noteworthy that the most effective compounds identified by this screening method are monocations, which are significantly more potent than related dicationic molecules. Due to the inability to grow HCV effectively in cell culture, current investigations of potential therapeutic agents involve in vitro subgenomic HCV replicon assays with selected compounds advanced into a chimpanzee animal model or a transgenic mouse model for HCV infection (28). The limited availability and significant expense of the chimpanzee animal model and the transgenic mouse model require that in vitro screening be performed to identify the leading compounds.…”

Section: Discussionmentioning

confidence: 99%

Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

Givens

Dykstra

Brock

et al. 2003

Antimicrob Agents Chemother

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Bovine viral diarrhea virus (BVDV) is an economically significant pathogen of cattle and a problematic contaminant in the laboratory. BVDV is often used as an in vitro model for hepatitis C virus during drug discovery efforts. Aromatic dicationic molecules have exhibited inhibitory activity against several RNA viruses. Thus, the purpose of this research was to develop and apply a method for screening the aromatic cationic compounds for in vitro cytotoxicity and activity against a noncytopathic strain of BVDV. The screening method evaluated the concentration of BVDV in medium and cell lysates after 72 h of cell culture in the presence of either a 25 or 5 M concentration of the test compound. Five of 93 screened compounds were selected for further determination of inhibitory (90 and 50%) and cytotoxic (50 and 10%) concentration endpoints. The screening method identified compounds that exhibited inhibition of BVDV at nanomolar concentrations while exhibiting no cytotoxicity at 25 M concentrations. The leading compounds require further investigation to determine their mechanism of action, in vivo activity, and specific activity against hepatitis C virus.Bovine viral diarrhea virus (BVDV), which is the prototype of the Pestivirus genus of the Flaviviridae family, causes early embryonic death, abortion, teratogenesis, respiratory problems, chronic wasting syndrome, and immune system dysfunction in cattle throughout the world. Acute infections of immunocompetent cattle with different strains of BVDV have caused mortality rates of 17 to 32% (8,15,31). Vaccines have provided inconsistent protection against infection with BVDV (36).In addition to being a pathogen of cattle, BVDV can be a problematic contaminant in the laboratory. Two biotypes of BVDV (noncytopathic and cytopathic), which are based on their effects in cell cultures, are recognized (3). Noncytopathic biotypes of BVDV have been identified in commercially available lots of fetal bovine serum despite testing by the manufacturer (6, 45). Consequently, BVDV has been identified in commercially available bovine, canine, feline, and primate cell lines (16,19), human viral vaccines for measles-mumps-rubella (18, 21), and interferons for human use (20). Viral contamination of biologicals for human use may be the reason BVDV-specific antibodies have been found in some samples of human serum (17). No antiviral pharmaceuticals are currently available for controlling BVDV in the laboratory or on the farm.Hepatitis C virus (HCV), a member of the Hepacivirus genus of the family Flaviviridae, is a major cause of human liver disease throughout the world. The World Health Organization estimates that 170 million people are chronically infected with HCV (2). The organization of the HCV genome encoding the proteins for viral replication is very similar to that of BVDV (with the exception of the 5Ј-terminal protease) (4). The inability to propagate HCV efficiently by cell culture has caused researchers to adopt BVDV as a viral model for HCV (2). Because of the relatedness of BVDV...

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Section: Discussionmentioning

confidence: 99%

Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

Givens

Dykstra

Brock

et al. 2003

Antimicrob Agents Chemother

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“…Rational drug-design, with regard to 'Specifically Targeted Anti-viral Therapy for hepatitis C' (STAT-C), has been made possible via the crystallisation and determination of high-resolution three-dimensional (3-D) structures of key viral enzymes, often complexed with their substrates, cofactors and/or inhibitors, the activities of which are tested by specific in vitro assays (summarised by Locarnini & Bartholomeusz [283]). The yeast two-hybrid system, with HCV core protein used as 'bait' to screen a human liver cDNA expression library, has been used to identify cellular proteins that interact with the HCV core protein (284).…”

Section: Development and Improvement Of Therapies And Vaccines: Identmentioning

confidence: 99%

An Assessment of the Use of Chimpanzees in Hepatitis C Research Past, Present and Future: 2. Alternative Replacement Methods

Bailey

2010

Altern Lab Anim

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The use of chimpanzees in hepatitis C virus (HCV) research was examined in the report associated with this paper (1: Validity of the Chimpanzee Model), in which it was concluded that claims of past necessity of chimpanzee use were exaggerated, and that claims of current and future indispensability were unjustifiable. Furthermore, given the serious scientific and ethical issues surrounding chimpanzee experimentation, it was proposed that it must now be considered redundant -particularly in light of the demonstrable contribution of alternative methods to past and current scientific progress, and the future promise that these methods hold. This paper builds on this evidence, by examining the development of alternative approaches to the investigation of HCV, and by reviewing examples of how these methods have contributed, and are continuing to contribute substantially, to progress in this field. It augments the argument against chimpanzee use by demonstrating the comprehensive nature of these methods and the valuable data they deliver. The entire life-cycle of HCV can now be investigated in a human (and much more relevant) context, without recourse to chimpanzee use. This also includes the testing of new therapies and vaccines. Consequently, there is no sound argument against the changes in public policy that propose a move away from chimpanzee use in US laboratories.

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“…Translation starts after the formation of a binary complex between the 40S ribosomal subunit and the HCV internal ribosome entry site (IRES), which resides within the 5′‐untranslated region (UTR) of HCV genome [50,51]. The most important HCV‐specific targets for new antiviral agent development include the processing of HCV polyprotein by NS3 helicase, NS3 (+NS4A) serine protease, or NS2/NS3 metalloprotease, the HCV replication using NS5B polymerase and NS3 helicase, and the HCV regulatory elements such as the 5′‐UTR encoding for IRES or the 3′‐UTR used in the generation of both plus and minus strand synthesis [36,52]. The recent development of cell culture models for HCV, mainly the HCV replicon system [53], allowed the initial evaluation of several promising antiviral agents before the onset of studies in animals and patients [36].…”

Section: Inhibitors Of Hcv Replicationmentioning

confidence: 99%

Chronic hepatitis C and no response to antiviral therapy: potential current and future therapeutic options

Papatheodoridis

2004

Journal of Viral Hepatitis

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A significant proportion of chronic hepatitis C patients fails to achieve sustained virologic response even after treatment with the current, more potent, combination of pegylated interferon-alpha (IFNa) plus ribavirin. Such patients represent a rather heterogeneous group and may be divided initially into relapsers and nonresponders. Both the type of previous therapy and of previous response are very important factors for the indication and the type of re-treatment. The combination of pegylated IFNa and ribavirin seems to be a rational approach for patients who failed to respond to IFNa monotherapy. Pegylated IFNa-based regimens appear to induce sustained responses in 40-68% of relapsers but in only 11% of nonresponders to previous therapy with standard IFNa plus ribavirin. Thus, new therapeutic approaches are needed for the latter subgroup of patients as well as those who fail to respond to pegylated IFNa-based regimens. Such new approaches currently under evaluation include the triple combination of pegylated IFNa, ribavirin, and amantadine, alternative types of IFN, use of agents with ribavirin like activity but lesser degrees of side-effects, inhibitors of hepatitis C virus (HCV) replication, mainly inhibitors of NS3 protease or helicase, antisense oligonucleotides, and ribozymes, and several immunomodulators. Moreover, maintenance antifibrotic therapy, mostly with low doses of pegylated IFNa, are under evaluation in patients with advanced fibrosis. Thus, even in the current era of the potent pegylated IFNa-based regimens, the management of these difficult-to-treat patients represents an increasingly frequent problem and perhaps the most challenging therapeutic task in chronic hepatitis C.

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Advances in hepatitis C: What is coming in the next 5 years?

Cited by 10 publications

References 44 publications

Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

An Assessment of the Use of Chimpanzees in Hepatitis C Research Past, Present and Future: 2. Alternative Replacement Methods

Chronic hepatitis C and no response to antiviral therapy: potential current and future therapeutic options

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