Review: Hepatitis C virus replication and potential targets for direct-acting agents

O’Leary, Jacqueline G.; Davis, Gary L.

doi:10.1177/1756283x09353353

Cited by 16 publications

(9 citation statements)

References 67 publications

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“…Several such inhibitors have progressed to clinical trials. For example, VGX-410C (from VGX Pharmaceuticals) appeared to be safe in phase 2 trials, but was later found not to be effective ( 77 ).…”

Section: Targeting Ires Elements With Antisense Oligonucleotides and mentioning

confidence: 99%

Exploring Internal Ribosome Entry Sites as Therapeutic Targets

Komar

Hatzoglou

2015

Front. Oncol.

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Initiation of eukaryotic mRNA translation may proceed via several different routes, each requiring a different subset of factors and relying on different and specific interactions between the mRNA and the ribosome. Two modes predominate: (i) so-called cap-dependent initiation, which requires all canonical initiation factors and is responsible for about 95–97% of all initiation events in eukaryotic cells; and (ii) cap-independent internal initiation, which requires a reduced subset of initiation factors and accounts for up to 5% of the remaining initiation events. Internal initiation relies on the presence of so-called internal ribosome entry site (IRES) elements in the 5′ UTRs of some viral and cellular mRNAs. These elements (often possessing complex secondary and tertiary structures) promote efficient interaction of the mRNA with the 40S ribosome and allow for internal ribosome entry. Internal initiation of translation of specific mRNAs may contribute to development of severe disease and pathological states, such as hepatitis C and cancer. Therefore, this cellular mechanism represents an attractive target for pharmacological modulation. The purpose of this review is to provide insight into current strategies used to target viral and cellular IRESs and discuss the physiological consequences (and potential therapeutic implications) of abrogation/modulation of IRES-mediated translation.

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Section: Targeting Ires Elements With Antisense Oligonucleotides and mentioning

confidence: 99%

Exploring Internal Ribosome Entry Sites as Therapeutic Targets

Komar

Hatzoglou

2015

Front. Oncol.

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“…Following translation, the ∼3,000‐amino‐acid HCV polyprotein is co‐ and postprocessed by host peptidases and viral proteases into at least 11 viral proteins (Fig. 2) [22,23]. Viral proteins participate in the formation of a complex of small vesicles derived from the ER and embedded in a matrix known as the membranous web [24].…”

Section: Hcv Infection and Replicationmentioning

confidence: 99%

Treating hepatitis C: current standard of care and emerging direct‐acting antiviral agents

Poordad

Dieterich

2012

Journal of Viral Hepatitis

174

133

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Summary. During the late 1990s and early 2000s, major advances were made in the treatment of patients with chronic hepatitis C virus (HCV) infection. Interferon, combination interferon plus ribavirin (RBV) and pegylated interferon plus RBV increased sustained virologic response (SVR) rates from ~5% to ~40-80%, depending on the genotype of HCV infection. Advances in molecular biology have allowed investigators to begin to understand the mechanisms of HCV infection and replication. Advances in understanding of viral kinetics have provided tools to identify patients who are most likely to attain SVR. With the advances in the science of HCV infection, the first part of the 21st century has seen the development and early introduction of a number of direct-acting antiviral (DAA) drugs. These novel medications interfere with critical steps in HCV replication and have the potential to significantly increase SVR rates. This article will review the key elements of HCV replication and evaluate the various classes of new and investigational DAA that have the potential to create a revolution in the management of patients with chronic hepatitis C.

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“…However, the drug resistance of virus remains an important problem. Substantial efforts therefore are made to understand the mechanism of HCV infection, as well as to develop new antiviral therapies [1] – [4] . The HCV RNA genome is very heterogeneous because of the high error rate of the viral RNA polymerase NS5B.…”

Section: Introductionmentioning

confidence: 99%

A New Stochastic Model for Subgenomic Hepatitis C Virus Replication Considers Drug Resistant Mutants

et al. 2014

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As an RNA virus, hepatitis C virus (HCV) is able to rapidly acquire drug resistance, and for this reason the design of effective anti-HCV drugs is a real challenge. The HCV subgenomic replicon-containing cells are widely used for experimental studies of the HCV genome replication mechanisms, for drug testing in vitro and in studies of HCV drug resistance. The NS3/4A protease is essential for virus replication and, therefore, it is one of the most attractive targets for developing specific antiviral agents against HCV. We have developed a stochastic model of subgenomic HCV replicon replication, in which the emergence and selection of drug resistant mutant viral RNAs in replicon cells is taken into account. Incorporation into the model of key NS3 protease mutations leading to resistance to BILN-2061 (A156T, D168V, R155Q), VX-950 (A156S, A156T, T54A) and SCH 503034 (A156T, A156S, T54A) inhibitors allows us to describe the long term dynamics of the viral RNA suppression for various inhibitor concentrations. We theoretically showed that the observable difference between the viral RNA kinetics for different inhibitor concentrations can be explained by differences in the replication rate and inhibitor sensitivity of the mutant RNAs. The pre-existing mutants of the NS3 protease contribute more significantly to appearance of new resistant mutants during treatment with inhibitors than wild-type replicon. The model can be used to interpret the results of anti-HCV drug testing on replicon systems, as well as to estimate the efficacy of potential drugs and predict optimal schemes of their usage.

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Review: Hepatitis C virus replication and potential targets for direct-acting agents

Cited by 16 publications

References 67 publications

Exploring Internal Ribosome Entry Sites as Therapeutic Targets

Exploring Internal Ribosome Entry Sites as Therapeutic Targets

Treating hepatitis C: current standard of care and emerging direct‐acting antiviral agents

A New Stochastic Model for Subgenomic Hepatitis C Virus Replication Considers Drug Resistant Mutants

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