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Littérature scientifique sur le sujet « NS5A inhibitor »

Auteur : Grafiati
Publié le 9 mars 2023
Mis à jour le 10 mars 2023

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Articles de revues sur le sujet "NS5A inhibitor"

1

Chatterji, Udayan, Jose A. Garcia-Rivera, James Baugh, Katarzyna Gawlik, Kelly A. Wong, Weidong Zhong, Clifford A. Brass, Nikolai V. Naoumov et Philippe A. Gallay. « The Combination of Alisporivir plus an NS5A Inhibitor Provides Additive to Synergistic Anti-Hepatitis C Virus Activity without Detectable Cross-Resistance ». Antimicrobial Agents and Chemotherapy 58, no 6 (31 mars 2014) : 3327–34. http://dx.doi.org/10.1128/aac.00016-14.

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ABSTRACTAlisporivir (ALV), a cyclophilin inhibitor, is a host-targeting antiviral (HTA) with multigenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. Recent advances have supported the concept of interferon (IFN)-free regimens to treat chronic hepatitis C. As the most advanced oral HTA, ALV with direct-acting antivirals (DAAs) represents an attractive drug combination for IFN-free therapy. In this study, we investigated whether particular DAAs exhibit additive, synergistic, or antagonistic effects when combined with ALV. Drug combinations of ALV with NS3 protease, NS5B polymerase, and NS5A inhibitors were investigated in HCV replicons from genotypes 1a, 1b, 2a, 3, and 4a (GT1a to -4a). Combinations of ALV with DAAs exerted an additive effect on GT1 and -4. A significant and specific synergistic effect was observed with ALV-NS5A inhibitor combination on GT2 and -3. Furthermore, ALV was fully active against DAA-resistant variants, and ALV-resistant variants were fully susceptible to DAAs. ALV blocks the contact between cyclophilin A and domain II of NS5A, and NS5A inhibitors target domain I of NS5A; our data suggest a molecular basis for the use of these two classes of inhibitors acting on two distinct domains of NS5A. These results providein vitroevidence that ALV with NS5A inhibitor combination represents an attractive strategy and a potentially effective IFN-free regimen for treatment of patients with chronic hepatitis C. Due to its high barrier and lack of cross-resistance, ALV could be a cornerstone drug partner for DAAs.
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Qiu, Dike, Julie A. Lemm, Donald R. O’Boyle, Jin-Hua Sun, Peter T. Nower, Van Nguyen, Lawrence G. Hamann et al. « The effects of NS5A inhibitors on NS5A phosphorylation, polyprotein processing and localization ». Journal of General Virology 92, no 11 (1 novembre 2011) : 2502–11. http://dx.doi.org/10.1099/vir.0.034801-0.

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Hepatitis C virus (HCV) non-structural protein 5A (NS5A) is a multi-functional protein that is expressed in basally phosphorylated (p56) and in hyperphosphorylated (p58) forms. NS5A phosphorylation has been implicated in regulating multiple aspects of HCV replication. We recently reported the identification of a class of compounds that potently inhibit HCV RNA replication by targeting NS5A. Although the precise mechanism of inhibition of these compounds is not well understood, one activity that has been described is their ability to block expression of the hyperphosphorylated form of NS5A. Here, we report that an NS5A inhibitor impaired hyperphosphorylation without affecting basal phosphorylation at the C-terminal region of NS5A. This inhibitor activity did not require NS5A domains II and III and was distinct from that of a cellular kinase inhibitor that also blocked NS5A hyperphosphorylation, results that are consistent with an inhibitor-binding site within the N-terminal region of NS5A. In addition, we observed that an NS5A inhibitor promoted the accumulation of an HCV polyprotein intermediate, suggesting that inhibitor binding to NS5A may occur prior to the completion of polyprotein processing. Finally, we observed that NS5A p56 and p58 separated into different membrane fractions during discontinuous sucrose gradient centrifugation, consistent with these NS5A phosphoforms performing distinct replication functions. The p58 localization pattern was disrupted by an NS5A inhibitor. Collectively, our results suggest that NS5A inhibitors probably impact several aspects of HCV expression and regulation. These findings may help to explain the exceptional potency of this class of HCV replication complex inhibitors.
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Kati, Warren, Gennadiy Koev, Michelle Irvin, Jill Beyer, Yaya Liu, Preethi Krishnan, Thomas Reisch et al. « In VitroActivity and Resistance Profile of Dasabuvir, a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor ». Antimicrobial Agents and Chemotherapy 59, no 3 (22 décembre 2014) : 1505–11. http://dx.doi.org/10.1128/aac.04619-14.

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ABSTRACTDasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC50) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC50resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.
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Bukhtiyarova, Marina, Christopher J. Rizzo, Charles A. Kettner, Bruce D. Korant, Helen T. Scarnati et Robert W. King. « Inhibition of the Bovine Viral Diarrhoea Virus NS3 Serine Protease by a Boron-Modified Peptidyl Mimetic of its Natural Substrate ». Antiviral Chemistry and Chemotherapy 12, no 6 (décembre 2001) : 367–73. http://dx.doi.org/10.1177/095632020101200607.

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Bovine viral diarrhoea virus (BVDV) is closely related to hepatitis C virus (HCV), and has been used as a surrogate virus in drug development for HCV infection. Similar to HCV, BVDV-encoded NS3 serine proteinase is responsible for multiple cleavages in the viral polyprotein, generating mature NS4A, NS4B, NS5A and NS5B proteins. NS3-dependent cleavage sites of BVDV contain a strictly conserved leucine at P1, and either serine or alanine at P1′. The full length BVDV NS3/4A serine protease has been cloned and expressed in bacterial cells. The enzyme has been purified from the soluble portion of Escherichia coli via a two-step purification procedure employing chromatography on heparin resin and gel filtration. The protease activity was characterized using in vitro translated BVDV NS4A/B and NS5A/B polyprotein substrates. A boronic acid analogue of the BVDV NS4A/NS4B cleavage site was synthesized and shown to be an efficient inhibitor of the NS3 serine protease in vitro. The compound, designated DPC-AB9144–00, inhibited approximately 75% of the NS3/4 activity at 10 μM with the NS4A/B substrate. However, no antiviral activity was detected with DPC-AB9144–00 in BVDV-infected Madin—Darby bovine kidney cells at concentrations as great as 90 μM, suggesting permeability or that other cellular-derived limitations were present.
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O'Boyle, Donald R., Peter T. Nower, Min Gao, Robert Fridell, Chunfu Wang, Piyasena Hewawasam, Omar Lopez et al. « Synergistic Activity of Combined NS5A Inhibitors ». Antimicrobial Agents and Chemotherapy 60, no 3 (28 décembre 2015) : 1573–83. http://dx.doi.org/10.1128/aac.02639-15.

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Daclatasvir (DCV) is a first-in-class hepatitis C virus (HCV) nonstructural 5A replication complex inhibitor (NS5A RCI) that is clinically effective in interferon-free combinations with direct-acting antivirals (DAAs) targeting alternate HCV proteins. Recently, we reported NS5A RCI combinations that enhance HCV inhibitory potentialin vitro, defining a new class of HCV inhibitors termed NS5A synergists (J. Sun, D. R. O’Boyle II, R. A. Fridell, D. R. Langley, C. Wang, S. Roberts, P. Nower, B. M. Johnson F. Moulin, M. J. Nophsker, Y. Wang, M. Liu, K. Rigat, Y. Tu, P. Hewawasam, J. Kadow, N. A. Meanwell, M. Cockett, J. A. Lemm, M. Kramer, M. Belema, and M. Gao, Nature 527:245–248, 2015, doi:10.1038/nature15711). To extend the characterization of NS5A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a, and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV and NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multilog drop in HCV, followed by rebound due to the emergence of resistance. DCV–NS5A-Syn combinations were highly efficient at clearing cells of viruses, in line with the trend seen in replicon studies. The retreatment of resistant viruses that emerged using DCV monotherapy with DCV–NS5A-Syn resulted in a multilog drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on wild-type (WT) virus. A triple combination of DCV, NS5A-Syn, and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV and NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy and tools for explorations of NS5A function.
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McCormick, Christopher J., David Brown, Stephen Griffin, Lisa Challinor, David J. Rowlands et Mark Harris. « A link between translation of the hepatitis C virus polyprotein and polymerase function ; possible consequences for hyperphosphorylation of NS5A ». Journal of General Virology 87, no 1 (1 janvier 2006) : 93–102. http://dx.doi.org/10.1099/vir.0.81180-0.

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Hyperphosphorylation of NS5A is thought to play a key role in controlling hepatitis C virus (HCV) RNA replication. Using a tetracycline-regulable baculovirus delivery system to introduce non-culture-adapted HCV replicons into HepG2 cells, we found that a point mutation in the active site of the viral polymerase, NS5B, led to an increase in NS5A hyperphosphorylation. Although replicon transcripts lacking elements downstream of NS5A also had altered NS5A hyperphosphorylation, this did not explain the changes resulting from polymerase inactivation. Instead, two additional findings may be related to the link between polymerase activity and NS5A hyperphosphorylation. Firstly, we found that disabling polymerase activity, either by targeted mutation of the polymerase active site or by use of a synthetic inhibitor, stimulated translation from the replicon transcript. Secondly, when the rate of translation of non-structural proteins from replicon transcripts was reduced by use of a defective encephalomyocarditis virus internal ribosome entry site, there was a substantial decrease in NS5A hyperphosphorylation, but this was not observed when non-structural protein expression was reduced by simply lowering replicon transcript levels using tetracycline. Therefore, one possibility is that the point mutation within the active site of NS5B causes an increase in NS5A hyperphosphorylation because of an increase in translation from each viral transcript. These findings represent the first demonstration that NS5A hyperphosphorylation can be modulated without use of kinase inhibitors or mutations within non-structural proteins and, as such, provide an insight into a possible means by which HCV replication is controlled during a natural infection.
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Garcia-Rivera, Jose A., Michael Bobardt, Udayan Chatterji, Sam Hopkins, Matthew A. Gregory, Barrie Wilkinson, Kai Lin et Philippe A. Gallay. « Multiple Mutations in Hepatitis C Virus NS5A Domain II Are Required To Confer a Significant Level of Resistance to Alisporivir ». Antimicrobial Agents and Chemotherapy 56, no 10 (16 juillet 2012) : 5113–21. http://dx.doi.org/10.1128/aac.00919-12.

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ABSTRACTAlisporivir is the most advanced host-targeting antiviral cyclophilin (Cyp) inhibitor in phase III studies and has demonstrated a great deal of promise in decreasing hepatitis C virus (HCV) viremia in infected patients. In an attempt to further elucidate the mechanism of action of alisporivir, HCV replicons resistant to the drug were selected. Interestingly, mutations constantly arose in domain II of NS5A. To demonstrate that these mutations are responsible for drug resistance, they were reintroduced into the parental HCV genome, and the resulting mutant viruses were tested for replication in the presence of alisporivir or in the absence of the alisporivir target, CypA. We also examined the effect of the mutations on NS5A binding to itself (oligomerization), CypA, RNA, and NS5B. Importantly, the mutations did not affect any of these interactions. Moreover, the mutations did not preserve NS5A-CypA interactions from alisporivir rupture. NS5A mutations alone render HCV only slightly resistant to alisporivir. In sharp contrast, when multiple NS5A mutations are combined, significant resistance was observed. The introduction of multiple mutations in NS5A significantly restored viral replication in CypA knockdown cells. Interestingly, the combination of NS5A mutations renders HCV resistant to all classes of Cyp inhibitors. This study suggests that a combination of multiple mutations in domain II of NS5A rather than a single mutation is required to render HCV significantly and universally resistant to Cyp inhibitors. This in accordance within vivodata that suggest that alisporivir is associated with a low potential for development of viral resistance.
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Lemm, Julie A., Donald O'Boyle, Mengping Liu, Peter T. Nower, Richard Colonno, Milind S. Deshpande, Lawrence B. Snyder et al. « Identification of Hepatitis C Virus NS5A Inhibitors ». Journal of Virology 84, no 1 (7 octobre 2009) : 482–91. http://dx.doi.org/10.1128/jvi.01360-09.

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ABSTRACT Using a cell-based replicon screen, we identified a class of compounds with a thiazolidinone core structure as inhibitors of hepatitis C virus (HCV) replication. The concentration of one such compound, BMS-824, that resulted in a 50% inhibition of HCV replicon replication was ∼5 nM, with a therapeutic index of >10,000. The compound showed good specificity for HCV, as it was not active against several other RNA and DNA viruses. Replicon cells resistant to BMS-824 were isolated, and mutations were identified. A combination of amino acid substitutions of leucine to valine at residue 31 (L31V) and glutamine to leucine at residue 54 (Q54L) in NS5A conferred resistance to this chemotype, as did a single substitution of tyrosine to histidine at amino acid 93 (Y93H) in NS5A. To further explore the region(s) of NS5A involved in inhibitor sensitivity, genotype-specific NS5A inhibitors were used to evaluate a series of genotype 1a/1b hybrid replicons. Our results showed that, consistent with resistance mapping, the inhibitor sensitivity domain also mapped to the N terminus of NS5A, but it could be distinguished from the key resistance sites. In addition, we demonstrated that NS5A inhibitors, as well as an active-site inhibitor that specifically binds NS3 protease, could block the hyperphosphorylation of NS5A, which is believed to play an essential role in the viral life cycle. Clinical proof of concept has recently been achieved with derivatives of these NS5A inhibitors, indicating that small molecules targeting a nontraditional viral protein like NS5A, without any known enzymatic activity, can also have profound antiviral effects on HCV-infected subjects.
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Wong, Mun-Teng, et Steve S. Chen. « Human Choline Kinase-α Promotes Hepatitis C Virus RNA Replication through Modulation of Membranous Viral Replication Complex Formation ». Journal of Virology 90, no 20 (3 août 2016) : 9075–95. http://dx.doi.org/10.1128/jvi.00960-16.

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ABSTRACTHepatitis C virus (HCV) infection reorganizes cellular membranes to create an active viral replication site named the membranous web (MW). The role that human choline kinase-α (hCKα) plays in HCV replication remains elusive. Here, we first showed that hCKα activity, not the CDP-choline pathway, promoted viral RNA replication. Confocal microscopy and subcellular fractionation of HCV-infected cells revealed that a small fraction of hCKα colocalized with the viral replication complex (RC) on the endoplasmic reticulum (ER) and that HCV infection increased hCKα localization to the ER. In the pTM-NS3-NS5B model, NS3-NS5B expression increased the localization of the wild-type, not the inactive D288A mutant, hCKα on the ER, and hCKα activity was required for effective trafficking of hCKα and NS5A to the ER. Coimmunoprecipitation showed that hCKα was recruited onto the viral RC presumably through its binding to NS5A domain 1 (D1). hCKα silencing or treatment with CK37, an hCKα activity inhibitor, abolished HCV-induced MW formation. In addition, hCKα depletion hindered NS5A localization on the ER, interfered with NS5A and NS5B colocalization, and mitigated NS5A-NS5B interactions but had no apparent effect on NS5A-NS4B and NS4B-NS5B interactions. Nevertheless, hCKα activity was not essential for the binding of NS5A to hCKα or NS5B. These findings demonstrate that hCKα forms a complex with NS5A and that hCKα activity enhances the targeting of the complex to the ER, where hCKα protein, not activity, mediates NS5A binding to NS5B, thereby promoting functional membranous viral RC assembly and viral RNA replication.IMPORTANCEHCV infection reorganizes the cellular membrane to create an active viral replication site named the membranous web (MW). Here, we report that human choline kinase-α (hCKα) acts as an essential host factor for HCV RNA replication. A fraction of hCKα colocalizes with the viral replication complex (RC) on the endoplasmic reticulum (ER) in HCV-infected cells. NS3-NS5B expression increases ER localization of wild-type, but not D288A mutant, hCKα, and hCKα activity facilitates the transport of itself and NS5A to the ER. Silencing or inactivation of hCKα abrogates MW formation. Moreover, hCKα is recruited by NS5A independent of hCKα activity, presumably through binding to NS5A D1. hCKα activity then mediates the ER targeting of the hCKα-NS5A complex. On the ER membrane, hCKα protein,per se, induces NS5A binding to NS5B, thereby promoting membranous RC formation and viral RNA replication. Our study may benefit the development of hCKα-targeted anti-HCV therapeutics.
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Liu, Dandan, Juan Ji, Tanya P. Ndongwe, Eleftherios Michailidis, Charles M. Rice, Robert Ralston et Stefan G. Sarafianos. « Fast Hepatitis C Virus RNA Elimination and NS5A Redistribution by NS5A Inhibitors Studied by a Multiplex Assay Approach ». Antimicrobial Agents and Chemotherapy 59, no 6 (6 avril 2015) : 3482–92. http://dx.doi.org/10.1128/aac.00223-15.

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ABSTRACTWhile earlier therapeutic strategies for the treatment of hepatitis C virus (HCV) infection relied exclusively on interferon (IFN) and ribavirin (RBV), four direct-acting antiviral agents (DAAs) have now been approved, aiming for an interferon-free strategy with a short treatment duration and fewer side effects. To facilitate studies on the mechanism of action (MOA) and efficacy of DAAs, we established a multiplex assay approach, which employs flow cytometry, aGaussialuciferase reporter system, Western blot analysis, reverse transcription-quantitative PCR (RT-qPCR), a limited dilution assay (50% tissue culture infectious dose [TCID50]), and an image profiling assay that follows the NS5A redistribution in response to drug treatment. We used this approach to compare the relative potency of various DAAs and the kinetics of their antiviral effects as a potential preclinical measure of their potential clinical utility. We evaluated the NS5A inhibitors ledipasvir (LDV) and daclatasvir (DCV), the NS3/4A inhibitor danoprevir (DNV), and the NS5B inhibitor sofosbuvir (SOF). In terms of kinetics, our data demonstrate that the NS5A inhibitor LDV, followed closely by DCV, has the fastest effect on suppression of viral proteins and RNA and on redistribution of NS5A. In terms of MOA, LDV has a more pronounced effect than DCV on the viral replication, assembly, and infectivity of released virus. Our approach can be used to facilitate the study of the biological processes involved in HCV replication and help identify optimal drug combinations.
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Thèses sur le sujet "NS5A inhibitor"

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Taube, Stefan. « Charakterisierung des Hepatitis-Virus NS5A-Proteins als funktionalen Inhibitor der Interferon induzierten antiviralen Immunantwort ». [S.l.] : [s.n.], 2005. http://www.diss.fu-berlin.de/2006/75/index.html.

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REGHELLIN, VERONICA. « Studies on the mechanism of action of antiviral agents targeting the replication complex of hepatitis c virus ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/52708.

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At the moment, several companies are studying the clinical potential of different all-oral combinations of direct-acting antivirals in ongoing studies. The most promising interferon-free combination therapies that are on the horizon include linear or cyclic NS3/4A protease inhibitors, nucleoside as well as non-nucleoside NS5B polymerase inhibitors , and NS5A inhibitors. DAAs that target NS3/4A (protease) and NS5B (RNA-dependent RNA polymerase) inhibit the enzymatic activity of these proteins. NS5A replication complex inhibitors will likely form a component of future interferon-free drug regimens but despite their remarkable potential to treat chronic hepatitis C, the detailed mechanism of action for this class of drug remains unclear. The goal of my work was to investigate the mechanism of action of different classes of antiviral agents believed to target the NS5A protein in the replication complex in order to improve the possibility to translate basic knowledge to a more meaningful clinical application. More specifically I focused my research on two classes of compounds, characterized by distinct resistance patterns in NS5A: a first class – with examples at the final stages of clinical development, represented by Daclatasvir (Lemm et al., 2011), and a second class - at earlier stages of development - represented by anilino-quinazolines such as A-831/AZD-2836 (Quinkert et al., 2008). I contributed to demonstrate that both of these inhibitor classes, by binding respectively to either HCV NS5A or to an NS5A-associated protein, PI4KIIIα, eventually interfere with the accumulation of PI4P 98 and cholesterol in the HCV replication membranous compartment, thus abrogating the ability of the virus form to replicate its RNA genome.
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Aissa, Larousse Jameleddine. « Etude de la variabilité génétique des régions NS3, NS5A et NS5B du virus de l'hépatite C chez des patients Tunisiens non traités ». Thesis, Bordeaux, 2015. http://www.theses.fr/2015BORD0434/document.

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Introduction : Le virus de l’hépatite C (VHC), est l’une des premières causes de pathologie hépatique dans le monde. Ce virus à ARN est responsable de l’hépatite C qui aboutit au développement de la cirrhose et du cancer du foie. Selon l’Organisation Mondiale de la Santé, le VHC infecte actuellement plus de 170 millions de personnes dans le monde, soit 3% de la population. L’hépatite C chronique connait toujours en Tunisie un taux de guérison faible pour le génotype 1 car le traitement standard actuellement disponible est la bithérapie interféron pégylé associé à la ribavirine. A l’heure actuelle, le développement de différentes molécules ciblant spécifiquement le VHC, appelées les antiviraux à action directe (AAD), apparait comme une potentielle révolution dans le traitement de l’infection par le VHC.Ces AAD comprennent les inhibiteurs de protéase (IP), les inhibiteurs nucléos(t)idiques (IN) et les inhibiteurs non-nucléosidiques (INN) de la polymérase NS5B ainsi que les inhibiteurs de la protéine NS5A. La quasi-espèce virale est formée d’un mélange complexe de variants viraux parmi lesquels se trouvent des variants associés à des degrés variables à la résistance aux AAD. Ces variants peuvent donc exister naturellement en absence de toute pression médicamenteuse et sont susceptibles d’avoir un impact sur la réponse aux différents traitements par AAD. Notre objectif était de déterminer la prévalence des variants associés à la résistance dans les souches tunisiennes circulantes en préambule à l’introduction deces molécules en Tunisie. Méthodes : L’amplification et le séquençage direct de la protéase NS3, de la polymérase NS5B ainsi que la région NS5A ont été effectuées chez 149 patients tunisiens naïfs de traitement et infectés par le VHC de génotype 1 (génotype 1b = 142 ; génotype 1a = 7). Résultats : Douze séquences NS3 (12/131 ; 9,2%) ont montré des mutations connes pour conférer une résistance aux IP. Une seule séquence (1/95 ; 1,1%) a montré la mutation V321I connue pour conférer une résistance aux IN-NS5B. Trente quatre séquences (34/95 ; 35,8%) ont montré des mutations connues pour diminuer la sensibilité des INN-NS5B. Une seule séquence de génotype 1a (1/7 ; 14,3%) et 17 séquences de génotype 1b (17/112 ; 16,2%) ont montré des mutations connues pour conférer une résistance au inhibiteurs de la protéine NS5A. Conclusions : Notre étude a permis de mettre en évidence la présence de substitutions conférant une diminution de la sensibilité aux AAD chez des patients tunisiens naïfs de tout traitement anti-VHC. Des études in situ seront nécessaires pour évaluer l’impact de ces mutations sur la réponse au traitement
Introduction: Hepatitis C virus (HCV) is a major cause of liver disease worldwide. This RNA virus is responsible for hepatitis C, which leads to the development of cirrhosis and liver cancer. According to the World Health Organization, HCV infects more than 170 million people worldwide, about 3% of the population. Chronic hepatitis C still know in Tunisia low cure rates for genotype 1, because the currently standard treatment available is combination therapy of pegylated interferon plus ribavirin. At present, the development of different molecules that specifically target HCV, called direct-acting antivirals (DAA) appears as a potential revolution in the treatment of HCV infection. These DAA include protease inhibitors (PI), nucleos(t)ide (NI) and non-nucleoside inhibitors (NNI) for NS5B polymerase and NS5A inhibitors. The viral quasispecies is formed by a complex mixture of viral variants including variants associated with variable degrees of resistance to DAA. These variants may therefore exist naturally in absence of drug pressure and may affect response to different treatments by DAA. Our objective was to determine the prevalence of variants associated with resistance in circulating Tunisian strains preamble to the introduction of these molecules in Tunisia. Methods: Amplification and direct sequencing of NS3 protease, NS5B polymerase and NS5A region were performed in 149 Tunisian naïve patients infected with HCV genotype 1 (genotype 1b = 142; genotype 1a = 7) . Results: Twelve sequences NS3 (12/131; 9.2%) showed mutations known to confer resistance to PI. One sequence (1/95; 1.1%) showed the V321I mutation known to confer resistance to NS5B-IN. Thirty four sequences (34/95; 35.8%) showed mutations known to reduce the sensitivity of NS5B-INN. One genotype 1a sequence (1/7; 14.3%) and 17 genotype 1b sequences (17/112; 16.2%) showed mutations known to confer resistance to NS5A inhibitors.Conclusions: Our study highlighted the presence of substitutions conferring decreased susceptibility to DAA in naïve patients infected with HCV genotype 1. Field studies will be needed to evaluate the impact of these mutations on the treatment response
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Grimm, Christian [Verfasser], Robert [Gutachter] Tampé et Christoph [Gutachter] Welsch. « Charakterisierung des Lipidbindungsverhaltens und der Proteinfaltung von HCV NS5A unter Einfluss des NS5A-Inhibitors Daclatasvir / Christian Grimm ; Gutachter : Robert Tampé, Christoph Welsch ». Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2021. http://d-nb.info/1239730276/34.

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Kelly, Lorna Jane. « Development of tools to investigate resistance of HCV genotype 3 to NS5A inhibitors ». Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/19307/.

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HCV infection leads to liver failure. Genotype 3 (GT3) is known to respond poorly to newly-developed direct-acting antivirals, especially inhibitors of the multifunctional NS5A protein. This work reports the establishment of efficient transient replication of the S52 GT3 sub-genomic replicon (SGR) by further culture adaptation of S52 in the context of an optimised luciferase reporter. Also documented is the development of hepatoma cells with immune-attenuating modifications and expressing the lipid binding factor hSEC14L2 to support transient replication of S52. In parallel, stable replication of S52 in SGR-harbouring cells was used to investigate the differences between early and established replication. Differences in sensitivity to the NS5A inhibitor Daclatasvir (DCV) in both transient and stable S52 were observed compared to other genotypes, and between transient and stable replication. In addition, it is shown here that the resistance-associated substitution (RAS) Y93H conferred a significant fitness cost which is not apparent for stable S52 selected with DCV, despite this RAS being detected. This thesis explores the molecular basis of such an observation and highlights a potential mechanism which warrants further research. The role of RAS in the development of resistance is still unclear though this work reports that the presence of a RAS within a mixed population greatly influenced the development of resistance to DCV in vitro. Moreover, this work identified that a cellular metabolism-regulating factor, AMP-mediated protein kinase (AMPK), may be differentially regulated during GT3 infection compared to other GTs. This thesis presents the hypothesis that AMPK regulation by HCV may contribute to hepatic steatosis as a direct consequence of viral infection, which is unique to GT3. More insight into the propensity of GT3 to develop resistance can aid further antiviral design, and an understanding of the molecular basis of steatosis offers a rationale for treating the symptoms of HCV in addition to direct targeting of the virus.
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Tran, Tuan Anh. « Screening against the dengue virus polymerase ». Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4006.

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La dengue, une des maladies les plus largement émergents actuellement, avec 390 millions d'infections chaque année (OMS), est causée par le virus de la dengue contre lequel il n’existe pas de traitements. La protéine NS5 a un rôle important dans le cycle de réplication. Cette protéine se compose d'une méthionine S-transférase d’adénosyl en N-terminal et une ARN polymérase dépendante de l'ARN (RdRp) en C-terminal. Cette NS5 RdRp peut catalyser non seulement la synthèse du brin négatif de l'ARN, utilisé comme matrice pour synthétiser l'ARN brin plus-supplémentaire, mais aussi pour la synthèse d'un ARN complémentaire à partir d'une matrice court e d'ARN sans amorce (de novo). Dans ce travail de thèse, nous présentons la production et le test de l'activité de la protéine NS5, ainsi que du domaine polymérase RdRp pour les quatre sérotypes du virus de la dengue en développant un nouveau test enzymatique, en utilisant comme un réactif fluorescent. L'utilisation de ce réactif fluorescent a également contribué à la détermination des conditions optimisées pour développer un essai de criblage de l'activité polymérase pour identifier des inhibiteurs contre le virus de la dengue. En outre, quatre flavonoïdes, Hinokiflavone, apigénine, la quercétine et Amentoflavone ont montré des valeurs d’IC50 équivalentes contre toutes les constructions NS5 et les domaines polymérase des quatre sérotypes
Dengue fever, one of the most widely emerging diseases nowadays with 390 million infections each year (WHO), is caused by Dengue virus in which no official antiviral reagent or vaccine is available. The NS5 protein has an important role in the replication cycle. This protein consists of a S-adenosyl methionine transferase at N-terminal and a RNA dependent RNA polymerase (RdRp) at C-terminal. This NS5 RdRp can catalyse for not only synthesis of minus-strand RNA to be used as the template to synthesize additional plus-strand RNA but also synthesizing a complement RNA from a short RNA template without primer (de novo). In this research we present the production and activity test for NS5 protein and N-terminal extended sequence 266-900 from NS5 RdRp of all first four serotypes of Dengue virus and a construct of sequence 273-900 using a new enzymatic assay, using Picogreen as fluorescent reagent. Using this fluorescent reagent also helped determining the optimised conditions to develop a screening assay for inhibitors against dengue polymerase activity. In addition, four flavonoids, Hinokiflavone, Apigenin, Quercetin and Amentoflavone showed approximate IC50 values when testing on all NS5 and polymerase protein constructs of all four serotypes
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Paterson, Morris. « Inhibition of the cellular responses to interferon alpha by the hepatitis C virus NS5A protein ». Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325537.

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Fourar, Monia. « Dynamique structurale de l'ARN polymérase ARN dépendante NS5B : une nouvelle cible pour l'inhibition de la réplication du virus de l'hépatite C ». Thesis, Montpellier 2, 2013. http://www.theses.fr/2013MON20137.

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L'une des principales cibles pour la thérapie visant le virus de l'hépatite C (VHC) est l'ARN polymérase dépendante de l'ARN NS5B indispensable à la réplication du génome virale. NS5B est l'une des enzymes clefs du cycle virale de VHC et son activation met en jeu aussi bien des interactions intramoléculaires que des interactions avec des cofacteurs viraux et cellulaires au sein du complexe de réplication. Nous avons développé une nouvelle stratégie d'inhibition de NS5B basée sur l'élaboration de peptides courts dérivés de motifs exposés à la surface de l'enzyme dans le but de cibler les nombreuses interactions impliquées dans l'activation de cette protéine. En associant une analyse fine de la structure cristallographique de NS5B avec de la modélisation moléculaire, nous avons élaboré des peptides courts mimant les motifs « hotspot » de la protéine. Ces peptides ont été évalués sur système réplicon de génotype 1b et nous avons ainsi identifié un peptide leader Moon1 de 15 résidus correspondant à un motif hautement conservé du domaine "thumb". Dans ce travail, nous avons étudié en détail la structure et le mécanisme moléculaire de ce nouvel inhibiteur de NS5B. Moon1 inhibe l'activité polymérase de la forme sauvage de NS5B ainsi que celle de mutants résistants au inhibiteurs nucléosidiques et non nucléosidiques. Nous avons démontré que la fixation de Moon1 entraine un changement de conformation de NS5B et se fait préférentiellement avec NS5B dans une conformation fermée. Ce peptide inhibe spécifiquement l'interaction entre NS5B et l'ARN double brin, indépendamment de la présence d'ions métalliques et de manière dose-dépendante. Moon1 bloque la transition entre l'étape d'initiation de novo de la synthèse d'ARN et l'extension du primer. Nous avons démontré que les résidus essentiels à l'activité de Moon1 sont hautement conservés à travers les différents génotypes et sous-types de VHC. De plus, nous avons établi une séquence minimale pour l'activité de Moon1. Nos travaux permettent de valider l'intérêt d'une stratégie interfaciale ciblant une enzyme clef du cycle du VHC et les interactions intra et intermoléculaires nécessaires à son activation
The non-structural protein RNA-dependent RNA polymerase (RdRp) NS5B plays a key role in hepatitis C virus (HCV) replication and is currently considered as one of the most relevant target to develop safe anti-HCV agents. Although many small molecules have been identified as inhibitors of NS5B, very few are active in clinic. The structure and function of NS5B have been well characterized and as other polymerases, NS5B adopts a typical “right-hand” conformation containing the characteristic fingers, palm and thumb subdomains. The activation of NS5B requires conformational changes involving intramolecular contacts as well interactions with viral proteins and host factors in the replication complex. We developed a new strategy for NS5B inhibition based on short interfacial peptides derived from NS5B surface accessible motifs that target protein-protein interfaces or essential motifs involved in NS5B-activation. Combining the NS5B crystallogaphic structure and molecular modelling, we have designed short peptides derived from NS5B surface “hotspots” that were screened using HCV genotype 1b replicon cell system. We have identified Moon1, a short 15-residu peptide, derived from a well-conserved motif located in the NS5B thumb domain that inhibits HCV replication in the low nanomolar range. Moon1 tightly binds NS5B in a conformational-dependent manner and induces NS5B conformational changes. This peptide specifically inhibits double-stranded RNA/NS5B interactions in a dose-dependent and metal ions-independent manner. Moon1 blocks the transition between RNA de novo initiation and primer-extension. We showed that residues required for Moon-1 anti-polymerase activity are well-conserved among HCV genotypes and subtypes and a minimal Moon1 active motif was established. Taken together, these results demonstrate that NS5B structural dynamics constitute an attractive target for HCV chemotherapeutics and for the design of more specific new antiviral drugs
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Meguellati, Amel. « Synthèse de biomolécules agissant comme inhibiteurs de l'ARN polymérase ARN dépendante du virus de l'hépatite C et développement de nouveaux surfactants comme stabilisants des protéines membranaires par réseaux de ponts salins ». Thesis, Université Grenoble Alpes (ComUE), 2015. http://www.theses.fr/2015GRENV001.

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Le projet de thèse se focalise sur la synthèse de biomolécules et se subdivise en deux parties. La première partie concerne la conception et la synthèse de dérivés de produits naturels d'intérêt thérapeutique nommés aurones en vue de mettre au point de nouvelles molécules à activité antivirale. Récemment, les aurones ont été identifiées comme étant des inhibiteurs de l'ARN-polymérase ARN-dépendante (NS5B) du virus de l'hépatite C (VHC). Cette enzyme, présente chez le virus mais absente chez l'homme, joue un rôle central dans la réplication virale. Suite à ces résultats antérieurs, les efforts ont été poursuivis et, dans le cadre de cette thèse, nous avons entrepris,d'une part, la synthèse d'analogues originaux dont le cycle B des aurones a été remplacé par des hétérocycles et, d'autre part, la synthèse depseudodimères d'aurones dans le but d'affiner les exigences structurales pour améliorer l'effet inhibiteur.L'activité a été évaluée selon des tests enzymatiques et cellulaires et a permis d'identifier quelques candidats doués d'une bonne activité inhibitrice et d'une faible toxicité. La deuxième partie du projet de thèse, sans lien avec la première partie,concerne des aspects plus fondamentaux et porte sur la synthèse de nouveaux surfactants agissant comme agents stabilisants lors des procédures d'extraction et de cristallisation des protéines membranaires. Les surfactants sont des composants clés dans le domaine de la biologie structurale et de la biochimie des protéines membranaire. Ils sont nécessaires pour maintenir les protéines membranaires dans leur état fonctionnel après extraction. La grande majorité des protéines membranaires est riche en résidus basiques à l'interface. Sur la base de cette caractéristique, une nouvelle famille de surfactants est développée et testée sur des protéines membranaires appartenant aux pompes d'efflux ABC multi-résistantes
The PhD project focuses on biomolecules and is divided into two parts. The first part concerns the design and synthesis of natural product derivatives with therapeutic interest in order to develop new molecules with antiviral activity. Recently, aurones were identified as new inhibitors of hepatitis C virus (HCV) NS5B polymerase. Following these results, efforts were continuedand we undertook, on the one hand,the synthesis of original analogues in which the aurone B-ring was replaced by a heterocyclic rings and, on the other hand, the synthesis of aurone pseudodimers in order to refine the structural requirements to improve the inhibitory effect. The potent NS5B inhibitory activity combined with their low toxicity make aurones attractive drug candidates against HCV infection. The second part of the PhD thesis is unrelated to the first part and concerns more fundamental aspects. It focused on the synthesis of new surfactants acting as stabilizing agents during extraction of membrane proteins (PM). Surfactants are required for maintaining PM in their functional state after extraction from membrane lipid matrix. The vast majority of PM shares a net enrichment in basic residues at the interface between membrane and cytoplasm, a property known as the positive inside rule. Based on this feature, a new family of surfactants is developed and tested on membrane proteins belonging to the multidrug ABC efflux pumps family
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Powdrill, Megan. « Characterization of the hepatitis C virus NS5b RNA-dependent RNA polymerase : novel inhibitors and antiviral resistance ». Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=107791.

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The hepatitis C virus polymerase NS5b is required for replication of the viral genome, making it an attractive target for antiviral development. The polymerase contains no proof-reading activity and generates viral variants during replication with a high degree of genetic heterogeneity, complicating the development of effective antiviral therapies since resistance mutations are readily selected under drug pressure. A successful treatment regimen will likely require a combination therapy that can suppress the emergence of resistance. Here, we have described the mechanism of action of a novel class of polymerase active site inhibitors, pyrophosphate analogues. We studied interactions between these compounds and NS5b in the presence of the resistance mutations G152E and P156L and have identified interactions leading to resistance. Additionally, we have combined the pyrophosphate analogues with a second class of polymerase active site inhibitors, nucleoside analogue inhibitors (NIs). We found that the combination can interfere with excision, a potential mechanism of resistance to NIs. We have also examined fidelity of the polymerase to better understand its contribution to variability in the viral genome. Our biochemical findings suggest that the efficiency of nucleotide mismatch formation during replication influences the prevalence of resistance mutations within the viral quasispecies population. This is supported by deep-sequencing data from an HCV-infected patient cohort. Based on these findings, we have developed a mathematical model showing that combining inhibitors selecting for resistance mutations generated through difficult-to-form nucleotide mismatches could delay the onset of resistance.We extended this study by performing transient kinetic assays to characterize incorporation of NIs by NS5b and compared this to the efficiency of mismatched nucleotide incorporation. These studies demonstrate that current NIs incorporate more efficiently than mismatched nucleotides. The incorporation efficiency of the guanosine analogue ribavirin was low as compared to other NIs tested and also as compared to G:U and U:G mismatches examined in our fidelity study, suggesting its incorporation during RNA synthesis does not cause error catastrophe. Overall, these studies provide a greater understanding of the mechanism of action of polymerase inhibitors, and of the role of the polymerase in the development of antiviral resistance.
La polymérase NS5b du virus de l'hépatite C est nécessaire pour la réplication du génome viral et représente donc une cible importante pour la découverte et le développement de nouveaux médicaments. La polymérase contient aucune activité de relecture et génère des variantes du virus avec un haut degré d'hétérogénéité génétique lors de sa réplication. Ceci nuit au développement de traitements antiviraux efficaces puisque les mutations de résistance sont facilement sélectionnées sous pression de médicaments. Un traitement efficace exigera probablement une combinaison thérapeutique qui pourrait empêcher la résistance. Ici, nous avons décrit le mécanisme d'action d'une nouvelle classe d'inhibiteurs du site actif de la polymérase, les analogues du pyrophosphate. Nous avons étudié les interactions entre ces inhibiteurs et NS5b, en présence des mutations de résistance G152E et P156L en plus d'identifier des interactions conduisant à la résistance. De plus, nous avons combiné les analogues du pyrophosphate avec une deuxième classe d'inhibiteurs du site actif de la polymérase, les inhibiteurs nucléotidiques (INs). Nous avons constaté que la combinaison peut interférer avec l'excision, un mécanisme potentiel de résistance aux INs. Nous avons également examiné la fidélité de la polymérase pour mieux comprendre sa contribution à la variabilité du génome viral. Nos résultats biochimiques suggèrent que l'efficacité de la formation de décalage lors de la réplication influence la prévalence des mutations de résistance au sein de la population virale quasi-espèces. Ceci est soutenu par les données obtenues suite au séquençage à très haut débit d'une cohorte de patients infectés par le VHC. Basé sur ces résultats, nous avons développé un modèle mathématique démontrant que la combinaison d'inhibiteurs qui sélectionnent des mutations de résistance générées par des mésappariements nucléotidiques difficiles à former pourrait retarder l'apparition de la résistance. Nous avons poursuivi cette étude en caractérisant l'incorporation des INs par NS5b et en comparant cela à l'efficacité de l'incorporation de nucléotides dépareillés. Ces études démontrent que les INs actuelles sont incorporées avec plus d'efficacité que les nucléotides dépareillés. L'efficacité d'incorporation de l'analogue ribavirine était faible par rapport aux autres INs testés et aussi par rapport aux mésappariements G: U et U: G examinés dans notre étude de fidélité. Ceci suggère que l'incorporation de la ribavirine lors de la synthèse d'ARN ne provoque pas d'erreur catastrophique. Globalement, ces études nous mènent à une meilleure compréhension du mécanisme d'action des inhibiteurs de la polymérase NS5b, et du rôle de la polymérase dans le développement de la résistance aux antiviraux.
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Chapitres de livres sur le sujet "NS5A inhibitor"

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Belema, Makonen, Shawn K. Pack et Nicholas A. Meanwell. « Daclatasvir (Daklinza) : The First-in-Class HCV NS5A Replication Complex Inhibitor ». Dans Innovative Drug Synthesis, 43–60. Hoboken, NJ, USA : John Wiley & Sons, Inc, 2015. http://dx.doi.org/10.1002/9781118819951.ch3.

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Meanwell, Nicholas A., et Makonen Belema. « The Discovery and Development of Daclatasvir : An Inhibitor of the Hepatitis C Virus NS5A Replication Complex ». Dans Topics in Medicinal Chemistry, 27–55. Cham : Springer International Publishing, 2019. http://dx.doi.org/10.1007/7355_2018_47.

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Link, John O. « The Discovery of Ledipasvir (GS-5885) : The Potent Once-Daily Oral HCV NS5A Inhibitor in the Single-Tablet Regimen Harvoni® ». Dans Topics in Medicinal Chemistry, 57–80. Cham : Springer International Publishing, 2019. http://dx.doi.org/10.1007/7355_2019_66.

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Link, John O. « The Discovery of Velpatasvir (GS-5816) : The Potent Pan-Genotypic Once-Daily Oral HCV NS5A Inhibitor in the Single-Tablet Regimens Epclusa and Vosevi® ». Dans Topics in Medicinal Chemistry, 81–110. Cham : Springer International Publishing, 2019. http://dx.doi.org/10.1007/7355_2019_67.

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Tong, Ling, Joseph A. Kozlowski, Louis-Charles Campeau et Jingjun Yin. « Discovery and Development of Ruzasvir : An Investigational Next Generation Pan-Genotype HCV Nonstructural Protein 5A (NS5A) Inhibitor for the Cure of Hepatitis C Virus Infections ». Dans ACS Symposium Series, 115–49. Washington, DC : American Chemical Society, 2018. http://dx.doi.org/10.1021/bk-2018-1307.ch005.

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Watkins, William J. « Evolution of HCV NS5B Non-nucleoside Inhibitors ». Dans Topics in Medicinal Chemistry, 171–91. Cham : Springer International Publishing, 2019. http://dx.doi.org/10.1007/7355_2018_35.

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Cho, Aesop. « Evolution of HCV NS5B Nucleoside and Nucleotide Inhibitors ». Dans Topics in Medicinal Chemistry, 117–39. Cham : Springer International Publishing, 2019. http://dx.doi.org/10.1007/7355_2018_36.

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Belema, Makonen, Nicholas A. Meanwell, John A. Bender, Omar D. Lopez, Piyasena Hewawasam et David R. Langley. « CHAPTER 1. Discovery and Clinical Validation of HCV Inhibitors Targeting the NS5A Protein ». Dans Drug Discovery, 3–28. Cambridge : Royal Society of Chemistry, 2013. http://dx.doi.org/10.1039/9781849737814-00003.

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Schinazi, Raymond F., Junxing Shi et Tony Whitaker. « Sofosbuvir (Sovaldi) : The First-in-Class HCV NS5B Nucleotide Polymerase Inhibitor ». Dans Innovative Drug Synthesis, 61–80. Hoboken, NJ, USA : John Wiley & Sons, Inc, 2015. http://dx.doi.org/10.1002/9781118819951.ch4.

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LaFemina, Robert L. « Hepatitis C Virus Genetics and the Discovery of Mechanism-Based Inhibitors of the NS3/4A Protease and NS5B Polymerase ». Dans Translational Research in Biomedicine, 63–93. Basel : KARGER, 2008. http://dx.doi.org/10.1159/000140936.

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Actes de conférences sur le sujet "NS5A inhibitor"

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Wong, Yu Jun, Rajneesh Kumar, Chen Hua Liu, Jia Horng Kao, Vicky Wing-Ki Hui, Grace Wong et Prem Harichander Thurairajah. « IDDF2021-ABS-0167 Real-world efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir in NS5A-inhibitor experienced patients : an international multicenter study from Asia ». Dans Abstracts of the International Digestive Disease Forum (IDDF), Hong Kong, 4–5 September 2021. BMJ Publishing Group Ltd and British Society of Gastroenterology, 2021. http://dx.doi.org/10.1136/gutjnl-2021-iddf.99.

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Rupp, C., T. Hippchen, P. Sauer, J. Pfeiffenberger, W. Stremmel, P. Schemmer, DN Gotthardt, A. Mehrabi et KH Weiss. « High SVR12 rates with combination of NS5A- and NS5B- inhibitors for 24 weeks in liver transplanted patients ». Dans Viszeralmedizin 2017. Georg Thieme Verlag KG, 2017. http://dx.doi.org/10.1055/s-0037-1605033.

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Marnolia, A., E. P. Toepak, S. Siregar, D. Kerami et U. S. F. Tambunan. « Computational screening of flavonoid based inhibitor targeting DENV NS5 methyltransferase ». Dans PROCEEDINGS OF THE 3RD INTERNATIONAL SYMPOSIUM ON CURRENT PROGRESS IN MATHEMATICS AND SCIENCES 2017 (ISCPMS2017). Author(s), 2018. http://dx.doi.org/10.1063/1.5064067.

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Moraes, Paula de F. de, Raquel A. C. Leão, Daniel Brian Nichols, Amartya Basu, Maksim Chudayeu, Tanaji T. Talele, Neerja Kaushik-Basu et Paulo R. R. Costa. « Coumarins and Neoflavones : Synthesis and HCV NS5B Polymerase Inhibition ». Dans 15th Brazilian Meeting on Organic Synthesis. São Paulo : Editora Edgard Blücher, 2013. http://dx.doi.org/10.5151/chempro-15bmos-bmos2013_2013818222912.

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Sulistyawati, Indah, Sulistyo Dwi K. P. et Mochammad Ichsan. « Inhibitor candidates’s identification of HCV’s RNA polymerase NS5B using virtual screening against iPPI-library ». Dans 5TH INTERNATIONAL CONFERENCE AND WORKSHOP ON BASIC AND APPLIED SCIENCES (ICOWOBAS 2015). AIP Publishing LLC, 2016. http://dx.doi.org/10.1063/1.4943314.

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Stephanie, Filia, Mutiara Saragih, Ahmad Husein Alkaff, Mochammad Arfin Fardiansyah Nasution et Usman Sumo Friend Tambunan. « Screening of Potential Northern African Natural Product Compounds as Dengue Virus NS5 Methyltransferase Inhibitor : An in Silico Approach ». Dans 2019 IEEE 19th International Conference on Bioinformatics and Bioengineering (BIBE). IEEE, 2019. http://dx.doi.org/10.1109/bibe.2019.00046.

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Putra, Hersal Hermana, Mutiara Saragih, Yulianti et Usman Sumo Friend Tambunan. « Identification of natural product compounds as NS5 RDRP inhibitor for dengue virus serotype 1-4 through in silico analysis ». Dans THE 14TH JOINT CONFERENCE ON CHEMISTRY 2019. AIP Publishing, 2020. http://dx.doi.org/10.1063/5.0005236.

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Siregar, S., A. Marnolia, M. A. F. Nasution, D. Kerami et U. S. F. Tambunan. « Computational insight into flavonoid-based compound for inhibition activity on SAH-binding site of dengue virus NS5 methyltransferase : Molecular docking and in silico ADME-Tox studies ». Dans PROCEEDINGS OF THE 3RD INTERNATIONAL SYMPOSIUM ON CURRENT PROGRESS IN MATHEMATICS AND SCIENCES 2017 (ISCPMS2017). Author(s), 2018. http://dx.doi.org/10.1063/1.5064060.

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