A Cell Protection Screen Reveals Potent Inhibitors of Multiple Stages of the Hepatitis C Virus Life Cycle

Chockalingam, Karuppiah; Simeon, Rudo; Rice, Charles M.; Chen, Zhilei

doi:10.1016/j.antiviral.2010.02.369

Cited by 13 publications

(23 citation statements)

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“…Indeed, licensed molecules such as erlotinib (an EGFR inhibitor) and ezetimibe (an NPC1L1 inhibitor) have been shown to impair HCV entry. Finally, clathrin-dependent endocytosis is another potential target for the development of anti-HCV molecules 78 79. Although targeting cellular factors is a promising antiviral approach, interactions of blocking agents with cellular proteins could interfere with the natural function of these host proteins and potentially induce unwanted side effects.…”

Section: Hcv Entrymentioning

confidence: 99%

“…The cell-culture system for HCV has allowed the optimisation of drug screening assays which might indicate novel molecules acting at different steps in the viral life cycle, including virus assembly 78 79 146. As for the other steps, blocking virus assembly can be achieved by targeting viral components or cellular factors (figure 2).…”

Section: Hcv Assembly As a Therapeutic Targetmentioning

confidence: 99%

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New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets

Ploß

Dubuisson

2012

Gut

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Hepatitis C virus (HCV) causes chronic infection in almost 2% of the world's population. If untreated, chronic carriers can develop severe liver disease including fibrosis, cirrhosis and hepatocellular carcinoma. Until recently, hepatitis C was treated with a combination of pegylated interferon and ribavirin, a treatment which was only partially effective and was plagued with side effects. In 2011 two inhibitors of the virally encoded NS3/4 protease have become part of standard therapy, which have improved treatment rates but can exacerbate the problematic side effects. While the addition of these first directly acting antivirals (DAAs) marks a milestone in anti-HCV therapy, new and improved combinations of drugs are desperately needed. New generations of drugs will have to address genetic variability of HCV and issues of viral resistance. Furthermore, combination therapies have to be tailored to effectively cure patient populations that have traditionally been hardest to treat, including patients with cirrhosis, those receiving liver transplants and individuals who are co-infected with HIV or hepatitis B virus. Since the discovery of HCV a plethora of experimental tools have been developed which enabled detailed analysis of various aspects of the viral life cycle and the interaction of HCV with its human host. Such studies have revealed a growing list of targets for therapeutic intervention, some of which will be discussed in this review.

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Section: Hcv Entrymentioning

confidence: 99%

Section: Hcv Assembly As a Therapeutic Targetmentioning

confidence: 99%

New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets

Ploß

Dubuisson

2012

Gut

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“…Vertex Pharmaceuticals Inc. accounted various aminothiadiazoliums which also exhibit anti-helicase activity but with lower efficacy [63]. Two derivatives of 2-arylbenzofuran isolated from Mori cortex radicis have shown potent inhibition against HCV NS3 helicase [62].…”

Section: Antiviral Drugs and Their Mode Of Actionmentioning

confidence: 99%

Antiviral drugs against hepatitis C virus

Rehman

Ashfaq

Javed

2011

Genet Vaccines Ther

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Hepatitis C virus (HCV) infection is a major worldwide problem causes acute and chronic HCV infection. Current treatment of HCV includes pegylated interferon-α (PEG IFN- α) plus ribavirin (RBV) which has significant side effects depending upon the type of genotype. Currently, there is a need to develop antiviral agents, both from synthetic chemistry and Herbal sources. In the last decade, various novel HCV replication, helicase and entry inhibitors have been synthesized and some of which have been entered in different phases of clinical trials. Successful results have been acquired by executing combinational therapy of compounds with standard regime in different HCV replicons. Even though, diverse groups of compounds have been described as antiviral targets against HCV via Specifically Targeted Antiviral Therapy for hepatitis C (STAT-C) approach (in which compounds are designed to directly block HCV or host proteins concerned in HCV replication), still there is a need to improve the properties of existing antiviral compounds. In this review, we sum up potent antiviral compounds against entry, unwinding and replication of HCV and discussed their activity in combination with standard therapy. Conclusively, further innovative research on chemical compounds will lead to consistent standard therapy with fewer side effects.

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“…To circumvent the need for secondary toxicity screening, Chockalingam et a l, (2010) very recently reported the development of an HCVcc cell protection assay, which measures cell viability as a readout of anti-HCV compound activity. As such, viability indicates not only effective blocking of HCV infection, but also the lack of drug-induced cytotoxicity[35]. Using this approach, the authors successfully screened a 1280 compound library and identified 55 compounds targeting HCV at the level of entry, replication and virus production[35].…”

Section: Hcv Experimental Systems Available For Antiviral Drug Researchmentioning

confidence: 99%

“…As such, viability indicates not only effective blocking of HCV infection, but also the lack of drug-induced cytotoxicity[35]. Using this approach, the authors successfully screened a 1280 compound library and identified 55 compounds targeting HCV at the level of entry, replication and virus production[35]. …”

Section: Hcv Experimental Systems Available For Antiviral Drug Researchmentioning

confidence: 99%

Hepatitis C virus experimental model systems and antiviral drug research

Uprichard

2010

Virol. Sin.

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An estimated 130 million people worldwide are chronically infected with hepatitis C virus (HCV) making it a leading cause of liver disease worldwide. Because the currently available therapy of pegylated interferon-alpha and ribavirin is only effective in a subset of patients, the development of new HCV antivirals is a healthcare imperative. This review discusses the experimental models available for HCV antiviral drug research, recent advances in HCV antiviral drug development, as well as active research being pursued to facilitate development of new HCV-specific therapeutics. KeywordsHepatitis C virus; Chronic liver disease; Experimental model systems; High throughput screening; Drug targets Hepatitis C virus (HCV), a member of the Flaviviridae family of enveloped positive-strand RNA viruses, is a leading cause of liver disease worldwide. Although HCV infection is usually asymptomatic and 10-30% of infected individuals successfully clear the infection [2,145], 70% of infections persist with the risk of progressive liver complications, such as fibrosis, cirrhosis, steatosis, insulin resistance, and/or hepatocellular carcinoma (HCC) [4,5,43,71,111,133,148,149], which can ultimately necessitate liver transplantation if HCV infection is not successfully treated (Fig. 1).To date, combination pegylated interferon-alpha (pIFN-α) and ribavirin [52] is the licensed standard of care (SOC) treatment for HCV; however, several limitations restrict its use and efficacy. First, because viral, host, and environmental factors significantly affect the success of SOC treatment (reviewed in [162]), numerous contraindications limit the number of patients eligible for therapy. Of those who are treated, sustained virological response (SVR) is only achieved in ~80% of individuals infected with genotypes 2 or 3 and 40%-50% of individuals infected with genotypes 1 or 4 [3]. In addition, therapy itself has a spectrum of toxic side effects and complications, which severely limit patient compliance and thus treatment efficacy [45]. Hence, with an estimated 130 million people worldwide chronically infected [4], and the number of HCV patients needing medical care is expected to increase dramatically over the next decade [171], the development of new more specific HCV antivirals is a healthcare imperative. This review will discuss the experimental models available for HCV antiviral drug research, the most recent advances in HCV antiviral drug development, as well as future research directions focused on developing new HCV-specific therapeutics. HCV EXPERIMENTAL SYSTEMS AVAILABLE FOR ANTIVIRAL DRUG RESEARCHSince it's discovery in 1989 as the causative agent on non-A non-B hepatitis [37], the HCV lifecycle and host-virus interactions that determine infection outcome have been difficult to study because experimental HCV cell culture infection systems and suitable small animal models have not been readily available. Consequently, the development of preventive vaccines and anti-HCV therapeutics has been severely hampered. Notably however...

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A Cell Protection Screen Reveals Potent Inhibitors of Multiple Stages of the Hepatitis C Virus Life Cycle

Cited by 13 publications

References 0 publications

New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets

New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets

Antiviral drugs against hepatitis C virus

Hepatitis C virus experimental model systems and antiviral drug research

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