New therapeutic strategies in HCV: polymerase inhibitors

Gerber, Ludmila; Welzel, Tania M.; Zeuzem, Stefan

doi:10.1111/liv.12068

Cited by 49 publications

(57 citation statements)

References 26 publications

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“…As a result of the low genetic barrier of NNPI to resistance, these agents have been studied in combination with other DAAs to target several regions of HCV genome and prevent the emergence of resistance-associated variants to an individual drug. At present, the approved NNPI is dasabuvir, which binds to palm 1 site of RNA polymerase, and beclabuvir, which binds to thumb 1 site [32].…”

Section: Non-nucleoside Polymerase Inhibitors (Nnpi)mentioning

confidence: 99%

Resistance to Direct-Acting Antiviral Agents in Treatment of Hepatitis C Virus Infections

Awady¹,

Dawood²

2017

Update on Hepatitis C

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Compounds targeting nonstructural (NS) proteins of hepatitis C virus (HCV) demonstrate clinical promise, suggesting that NS3/NS4a, NS5A, or NS5B inhibitors are potential components in direct-acting antiviral (DAA) combination therapies. In vitro studies revealed dramatic inhibition of viral replication or alteration in subcellular localization of NS proteins. DAAs bind either to catalytic sites (NS3 and NS5B) or to domain-1 of NS5A. Although >90% of the patients clear HCV RNA from their sera, a significant portion of cirrhotic patients suffer from resistance or virological relapse. Mutations in specific residues (Q80K) in NS3 (M28, A30, L31, and Y93 in genotypes 1a and 1b or L28, L30, M31, and Y93 in genotype 4) in NS5A and A282T in NS5B are associated with resistance to DAA [resistance-associated variants (RAVs)]. Current knowledge on the NS functions, mode of action of DAAs, and impacts of RAVs on treatment response are discussed. Not only mutations affecting the binding of DAAs to target proteins but also substitutions affecting the replication fitness of mutant quasispecies are major determinants of treatment failures. These resistance-associated substitutions (RASs) are now considered the major viral mutants that influence the virological outcome after DAA treatment.

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Section: Non-nucleoside Polymerase Inhibitors (Nnpi)mentioning

confidence: 99%

Resistance to Direct-Acting Antiviral Agents in Treatment of Hepatitis C Virus Infections

Awady¹,

Dawood²

2017

Update on Hepatitis C

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“…In this respect, nucleos(t)ide polymerase inhibitors display very favorable characteristics. [19][20][21] In addition to a high antiviral efficacy, binding to the highly conserved active site of the RNA-dependent RNA-polymerase (RdRp) and incorporation as active triphosphates into the growing HCV RNA chain terminating its elongation, confers a pan-genotypic activity. Also, the low replication fitness of emergent Keywords ► interferon-free HCV treatment ► direct-acting antiviral agents ► NS3/4A protease inhibitors ► NS5A inhibitors ► non-nucleoside polymerase inhibitors ► host-targeting agents…”

mentioning

confidence: 99%

“…In contrast, most nonnucleoside NS5B inhibitors have a lower antiviral efficacy. 19,22 Binding to different allosteric sites of the RdRp (thumb 1 and 2, palm 1 and 2) results in conformational changes. As these domains are highly variable across genotypes, use of currently available non-nucleoside NS5B inhibitors is restricted to treatment of HCV genotype-1 infection.…”

mentioning

confidence: 99%

“…As these domains are highly variable across genotypes, use of currently available non-nucleoside NS5B inhibitors is restricted to treatment of HCV genotype-1 infection. 19 Also due to the drug classes low barrier to resistance, nonnucleoside polymerase inhibitors are so far only components in IFN-free multiclass DAA combination therapies. 19 Considerable progress was achieved with the ongoing development of NS3/4A and NS5A inhibitors.…”

mentioning

confidence: 99%

“…19 Also due to the drug classes low barrier to resistance, nonnucleoside polymerase inhibitors are so far only components in IFN-free multiclass DAA combination therapies. 19 Considerable progress was achieved with the ongoing development of NS3/4A and NS5A inhibitors. While the NS3/4A protease inhibitors telaprevir and boceprevir display a limited genotypic activity (mainly in genotype 1), simeprevir, faldaprevir, and ABT-450 have broader genotype coverage (genotypes 1, 2, 4, 5, 6).…”

mentioning

confidence: 99%

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Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Welzel

Zeuzem

2014

Semin Liver Dis

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The establishment of a robust hepatitis C virus (HCV) cell culture system and subsequent detailed characterization of the HCV life cycle was a key step toward the identification of putative antiviral targets and respective antiviral drugs. 1,2 These include direct-acting antiviral agents (DAAs) such as NS3/4A protease inhibitors, NS5A inhibitors, nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as hosttargeting agents (HTAs) directed against cellular factors involved in viral entry or replication. 3 Trials investigating different drug classes with and without pegylated interferon (PegIFN) and/or ribavirin have rapidly evolved, yielding highly promising sustained virologic response (SVR) rates. 4,5 In regard to the enormous public health impact of HCV infection with an estimated 184 million anti-HCV positive persons worldwide, the recent advances in HCV drug development, together with implementation of improved HCV screening programs, have the potential to substantially reduce the burden of HCV-associated advanced liver disease including hepatocellular carcinoma. 6-9The first-in-class NS3/4A inhibitors telaprevir and boceprevir were approved in 2011. Addition of these drugs to the PegIFN/ribavirin backbone has considerably improved response rates in HCV therapy naïve and experienced patients compared with PegIFN/ribavirin alone. [10][11][12][13] The poor side-effect profile of these IFN-based therapies, however, limits the wide clinical applicability. Proof of the principle that viral clearance can be achieved with an IFN-free DAA combination has fast-tracked design and the conduct of clinical trials investigating IFN-free DAA combinations. 14 Different HCV genotypes and multiple subtypes result in a genotype and subtype-dependent efficacy of many available DAAs. 15,16 Furthermore, viral clearance is challenged by the presence and selection of resistance-associated variants (RAVs). 17,18 Thus, essential prerequisites for DAAs in clinical development comprise a high antiviral efficacy, a broad and at best pan-genotypic activity, as well as a high barrier to resistance. In this respect, nucleos(t)ide polymerase inhibitors display very favorable characteristics. [19][20][21] In addition to a high antiviral efficacy, binding to the highly conserved active site of the RNA-dependent RNA-polymerase (RdRp) and incorporation as active triphosphates into the growing HCV RNA chain terminating its elongation, confers a pan-genotypic activity. Also, the low replication fitness of emergent Keywords ► interferon-free HCV treatment ► direct-acting antiviral agents ► NS3/4A protease inhibitors ► NS5A inhibitors ► non-nucleoside polymerase inhibitors ► host-targeting agents AbstractThe identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The...

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Hepatitis C Virus Infection

Tai

Chung

2015

Yamada' S Textbook of Gastroenterology

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New therapeutic strategies in HCV: polymerase inhibitors

Cited by 49 publications

References 26 publications

Resistance to Direct-Acting Antiviral Agents in Treatment of Hepatitis C Virus Infections

Resistance to Direct-Acting Antiviral Agents in Treatment of Hepatitis C Virus Infections

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Hepatitis C Virus Infection

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