Artigos de revistas: "NS5A inhibitors"

1

Chatterji, Udayan, Michael Bobardt, Andrew Tai, Malcolm Wood e Philippe A. Gallay. "Cyclophilin and NS5A Inhibitors, but Not Other Anti-Hepatitis C Virus (HCV) Agents, Preclude HCV-Mediated Formation of Double-Membrane-Vesicle Viral Factories". Antimicrobial Agents and Chemotherapy 59, n.º 5 (9 de fevereiro de 2015): 2496–507. http://dx.doi.org/10.1128/aac.04958-14.

Texto completo da fonte

Resumo:

ABSTRACTAlthough the mechanisms of action (MoA) of nonstructural protein 3 inhibitors (NS3i) and NS5B inhibitors (NS5Bi) are well understood, the MoA of cyclophilin inhibitors (CypI) and NS5A inhibitors (NS5Ai) are not fully defined. In this study, we examined whether CypI and NS5Ai interfere with hepatitis C virus (HCV) RNA synthesis of replication complexes (RCs) or with an earlier step of HCV RNA replication, the creation of double-membrane vesicles (DMVs) essential for HCV RNA replication. In contrast to NS5Bi, both CypI and NS5Ai do not block HCV RNA synthesis by way of RCs, suggesting that they exert their antiviral activity prior to the establishment of enzymatically active RCs. We found that viral replication is not a precondition for DMV formation, since the NS3-NS5B polyprotein or NS5A suffices to create DMVs. Importantly, only CypI and NS5Ai, but not NS5Bi, mir-122, or phosphatidylinositol-4 kinase IIIα (PI4KIIIα) inhibitors, prevent NS3-NS5B-mediated DMV formation. NS3-NS5B was unable to create DMVs in cyclophilin A (CypA) knockdown (KD) cells. We also found that the isomerase activity of CypA is absolutely required for DMV formation. This not only suggests that NS5A and CypA act in concert to build membranous viral factories but that CypI and NS5Ai mediate their early anti-HCV effects by preventing the formation of organelles, where HCV replication is normally initiated. This is the first investigation to examine the effect of a large panel of anti-HCV agents on DMV formation, and the results reveal that CypI and NS5Ai act at the same membranous web biogenesis step of HCV RNA replication, thus indicating a new therapeutic target of chronic hepatitis C.

Estilos ABNT, Harvard, Vancouver, APA, etc.

2

O’Brien, Christopher, e Nicholas Agresti. "NS5A Inhibitors". Current Hepatitis Reports 11, n.º 3 (10 de agosto de 2012): 181–87. http://dx.doi.org/10.1007/s11901-012-0138-2.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

3

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, n.º 3 (28 de dezembro de 2015): 1573–83. http://dx.doi.org/10.1128/aac.02639-15.

Texto completo da fonte

Resumo:

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.

Estilos ABNT, Harvard, Vancouver, APA, etc.

4

Chatterji, Udayan, Jose A. Garcia-Rivera, James Baugh, Katarzyna Gawlik, Kelly A. Wong, Weidong Zhong, Clifford A. Brass, Nikolai V. Naoumov e 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, n.º 6 (31 de março de 2014): 3327–34. http://dx.doi.org/10.1128/aac.00016-14.

Texto completo da fonte

Resumo:

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.

Estilos ABNT, Harvard, Vancouver, APA, etc.

5

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, n.º 11 (1 de novembro de 2011): 2502–11. http://dx.doi.org/10.1099/vir.0.034801-0.

Texto completo da fonte

Resumo:

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.

Estilos ABNT, Harvard, Vancouver, APA, etc.

6

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, n.º 1 (7 de outubro de 2009): 482–91. http://dx.doi.org/10.1128/jvi.01360-09.

Texto completo da fonte

Resumo:

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.

Estilos ABNT, Harvard, Vancouver, APA, etc.

7

Reghellin, V., L. Donnici, S. Fenu, V. Berno, V. Calabrese, M. Pagani, S. Abrignani, F. Peri, R. De Francesco e P. Neddermann. "NS5A Inhibitors Impair NS5A–Phosphatidylinositol 4-Kinase IIIα Complex Formation and Cause a Decrease of Phosphatidylinositol 4-Phosphate and Cholesterol Levels in Hepatitis C Virus-Associated Membranes". Antimicrobial Agents and Chemotherapy 58, n.º 12 (15 de setembro de 2014): 7128–40. http://dx.doi.org/10.1128/aac.03293-14.

Texto completo da fonte

Resumo:

ABSTRACTThe hepatitis C virus (HCV) nonstructural (NS) protein 5A is a multifunctional protein that plays a central role in viral replication and assembly. Antiviral agents directly targeting NS5A are currently in clinical development. Although the elucidation of the mechanism of action (MOA) of NS5A inhibitors has been the focus of intensive research, a detailed understanding of how these agents exert their antiviral effect is still lacking. In this study, we observed that the downregulation of NS5A hyperphosphorylation is associated with the actions of NS5A inhibitors belonging to different chemotypes. NS5A is known to recruit the lipid kinase phosphatidylinositol 4-kinase IIIα (PI4KIIIα) to the HCV-induced membranous web in order to generate phosphatidylinositol 4-phosphate (PI4P) at the sites of replication. We demonstrate that treatment with NS5A inhibitors leads to an impairment in the NS5A-PI4KIIIα complex formation that is paralleled by a significant reduction in PI4P and cholesterol levels within the endomembrane structures of HCV-replicating cells. A similar decrease in PI4P and cholesterol levels was also obtained upon treatment with a PI4KIIIα-targeting inhibitor. In addition, both the NS5A and PI4KIIIα classes of inhibitors induced similar subcellular relocalization of the NS5A protein, causing the formation of large cytoplasmic NS5A-containing clusters previously reported to be one of the hallmarks of inhibition of the action of PI4KIIIα. Because of the similarities between the effects induced by treatment with PI4KIIIα or NS5A inhibitors and the observation that agents targeting NS5A impair NS5A-PI4KIIIα complex formation, we speculate that NS5A inhibitors act by interfering with the function of the NS5A-PI4KIIIα complex.

Estilos ABNT, Harvard, Vancouver, APA, etc.

8

Garcia-Rivera, Jose A., Michael Bobardt, Udayan Chatterji, Sam Hopkins, Matthew A. Gregory, Barrie Wilkinson, Kai Lin e 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, n.º 10 (16 de julho de 2012): 5113–21. http://dx.doi.org/10.1128/aac.00919-12.

Texto completo da fonte

Resumo:

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.

Estilos ABNT, Harvard, Vancouver, APA, etc.

9

Aldunate, Fabián, Natalia Echeverría, Daniela Chiodi, Pablo López, Adriana Sánchez-Cicerón, Alvaro Fajardo, Martín Soñora, Juan Cristina, Nelia Hernández e Pilar Moreno. "Pretreatment Hepatitis C Virus NS5A/NS5B Resistance-Associated Substitutions in Genotype 1 Uruguayan Infected Patients". Disease Markers 2018 (14 de agosto de 2018): 1–9. http://dx.doi.org/10.1155/2018/2514901.

Texto completo da fonte

Resumo:

Hepatitis C Virus (HCV) infection treatment has dramatically changed with the advent of direct-acting antiviral agents (DAAs). However, the efficacy of DAAs can be attenuated by the presence of resistance-associated substitutions (RASs) before and after treatment. Indeed, RASs detected in DAA treatment-naïve HCV-infected patients could be useful for clinical management and outcome prediction. Although the frequency of naturally occurring HCV NS5A and NS5B RASs has been addressed in many countries, there are only a few reports on their prevalence in the South American region. The aim of this study was to investigate the presence of RASs to NS5A and NS5B inhibitors in a DAA treatment naïve cohort of Uruguayan patients infected with chronic hepatitis C and compare them with reports from other South American countries. Here, we found that naturally occurring substitutions conferring resistance to NS5A and NS5B inhibitors were present in 8% and 19.2%, respectively, of treatment-naïve HCV genotype 1 infected patients. Importantly, the baseline substitutions in NS5A and NS5B herein identified differ from the studies previously reported in Brazil. Furthermore, Uruguayan strains subtype 1a clustered within all major world clades, showing that HCV variants currently circulating in this country are characterized by a remarkable genetic diversity.

Estilos ABNT, Harvard, Vancouver, APA, etc.

10

McCormick, Christopher J., David Brown, Stephen Griffin, Lisa Challinor, David J. Rowlands e 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, n.º 1 (1 de janeiro de 2006): 93–102. http://dx.doi.org/10.1099/vir.0.81180-0.

Texto completo da fonte

Resumo:

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.

Estilos ABNT, Harvard, Vancouver, APA, etc.

11

Liu, Dandan, Juan Ji, Tanya P. Ndongwe, Eleftherios Michailidis, Charles M. Rice, Robert Ralston e 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, n.º 6 (6 de abril de 2015): 3482–92. http://dx.doi.org/10.1128/aac.00223-15.

Texto completo da fonte

Resumo:

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.

Estilos ABNT, Harvard, Vancouver, APA, etc.

12

Gao, Min, Donald R. O’Boyle e Susan Roberts. "HCV NS5A replication complex inhibitors". Current Opinion in Pharmacology 30 (outubro de 2016): 151–57. http://dx.doi.org/10.1016/j.coph.2016.07.014.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

13

Suk-Fong Lok, Anna. "HCV NS5A Inhibitors in Development". Clinics in Liver Disease 17, n.º 1 (fevereiro de 2013): 111–21. http://dx.doi.org/10.1016/j.cld.2012.09.006.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

14

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, n.º 3 (22 de dezembro de 2014): 1505–11. http://dx.doi.org/10.1128/aac.04619-14.

Texto completo da fonte

Resumo:

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.

Estilos ABNT, Harvard, Vancouver, APA, etc.

15

Malov, V. A., E. A. Ubeeva, I. P. Ubeeva, S. M. Nikolaev e K. T. Umbetova. "Treatment of chronic viral hepatitis C with direct acting antiviral agent: review". Terapevticheskii arkhiv 91, n.º 11 (15 de novembro de 2019): 86–89. http://dx.doi.org/10.26442/00403660.2019.11.000307.

Texto completo da fonte

Resumo:

HCV infection treatment regimens are viewed from positions of HCV life cycle and replication, effects of NS3/4A protease inhibitors and NS5A/NS5B inhibitors on HCV strain replication. Evolution of HCV treatment regimens from its discovery to modern DAA agents had led to substantial progress although drug resistance poses a new issue to be addressed.

Estilos ABNT, Harvard, Vancouver, APA, etc.

16

Hikita, Hayato, e Tetsuo Takehara. "NS5A-P32 Deletion in Hepatitis C Genotype 1b Infection is the Most Refractory Treatment-Mediated Amino Acid Change Exhibiting Resistance to all NS5A Inhibitors". Seminars in Liver Disease 40, n.º 02 (13 de dezembro de 2019): 143–53. http://dx.doi.org/10.1055/s-0039-3402001.

Texto completo da fonte

Resumo:

AbstractNS5A-P32 deletion (P32del) is a resistance-associated amino acid change that has recently gained popularity in direct-acting antiviral treatment for chronic hepatitis C. Although not yet detected in naive patients, it appears in 5 to 10% of hepatitis C genotype 1b patients who fail to respond to daclatasvir/asunaprevir and sofosbuvir/ledipasvir treatments. In contrast to signature resistance-associated substitutions, such as substitutions at the NS5A-L31 and NS5A-Y93 positions, it shows complete resistance to all NS5A inhibitors in replicon and cell culture. Studies of humanized liver mice suggest that P32del retains good replication fitness and requires two classes of antivirals, except NS5A inhibitors, to be suppressed effectively. Patients with the P32del virus do not respond to glecaprevir/pibrentasvir but do respond to sofosbuvir/velpatasvir/voxilaprevir, presumably to sofosbuvir + glecaprevir/pibrentasvir, and at least partially to sofosbuvir/velpatasvir + ribavirin. Attention should be given to P32del in patients who experience failure with any NS5A inhibitor, especially those with genotype 1b infection.

Estilos ABNT, Harvard, Vancouver, APA, etc.

17

Pelosi, Lenore A., Stacey Voss, Mengping Liu, Min Gao e Julie A. Lemm. "Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir". Antimicrobial Agents and Chemotherapy 56, n.º 10 (30 de julho de 2012): 5230–39. http://dx.doi.org/10.1128/aac.01209-12.

Texto completo da fonte

Resumo:

ABSTRACTThree hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additive-synergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic.

Estilos ABNT, Harvard, Vancouver, APA, etc.

18

Bartels, Doug J., James C. Sullivan, Eileen Z. Zhang, Ann M. Tigges, Jennifer L. Dorrian, Sandra De Meyer, Darin Takemoto et al. "Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment". Journal of Virology 87, n.º 3 (14 de novembro de 2012): 1544–53. http://dx.doi.org/10.1128/jvi.02294-12.

Texto completo da fonte

Resumo:

ABSTRACTThe prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3- to 25-fold increased 50% inhibitor concentration [IC50]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC50) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.

Estilos ABNT, Harvard, Vancouver, APA, etc.

19

Lemm, Julie A., John E. Leet, Donald R. O'Boyle, Jeffrey L. Romine, Xiaohua Stella Huang, Daniel R. Schroeder, Jeffrey Alberts et al. "Discovery of Potent Hepatitis C Virus NS5A Inhibitors with Dimeric Structures". Antimicrobial Agents and Chemotherapy 55, n.º 8 (16 de maio de 2011): 3795–802. http://dx.doi.org/10.1128/aac.00146-11.

Texto completo da fonte

Resumo:

ABSTRACTThe exceptionalin vitropotency of the hepatitis C virus (HCV) NS5A inhibitor BMS-790052 has translated into anin vivoeffect in proof-of-concept clinical trials. Although the 50% effective concentration (EC50) of the initial lead, the thiazolidinone BMS-824, was ∼10 nM in the replicon assay, it underwent transformation to other inhibitory species after incubation in cell culture medium. The biological profile of BMS-824, including the EC50, the drug concentration required to reduce cell growth by 50% (CC50), and the resistance profile, however, remained unchanged, triggering an investigation to identify the biologically active species. High-performance liquid chromatography (HPLC) biogram fractionation of a sample of BMS-824 incubated in medium revealed that the most active fractions could readily be separated from the parental compound and retained the biological profile of BMS-824. From mass spectral and nuclear magnetic resonance data, the active species was determined to be a dimer of BMS-824 derived from an intermolecular radical-mediated reaction of the parent compound. Based upon an analysis of the structural elements of the dimer deemed necessary for anti-HCV activity, the stilbene derivative BMS-346 was synthesized. This compound exhibited excellent anti-HCV activity and showed a resistance profile similar to that of BMS-824, with changes in compound sensitivity mapped to the N terminus of NS5A. The N terminus of NS5A has been crystallized as a dimer, complementing the symmetry of BMS-346 and allowing a potential mode of inhibition of NS5A to be discussed. Identification of the stable, active pharmacophore associated with these NS5A inhibitors provided the foundation for the design of more potent inhibitors with broad genotype inhibition. This culminated in the identification of BMS-790052, a compound that preserves the symmetry discovered with BMS-346.

Estilos ABNT, Harvard, Vancouver, APA, etc.

20

Randolph, John T., Charles A. Flentge, Pamela Donner, Todd W. Rockway, Sachin V. Patel, Lissa Nelson, Douglas K. Hutchinson et al. "Discovery of fluorobenzimidazole HCV NS5A inhibitors". Bioorganic & Medicinal Chemistry Letters 26, n.º 22 (novembro de 2016): 5462–67. http://dx.doi.org/10.1016/j.bmcl.2016.10.030.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

21

Nutt, Jamie, James Grantham, Marilyn Smith, Emily Smith, Ashley Wedin, Aaron Tyler, Mauricio Miralles, Steve Kleiboeker e Mark Wissel. "Performance of NS3, NS5a AND NS5b Hepatitis C Virus (HCV) Antiviral Resistance Sequencing Assays". Open Forum Infectious Diseases 4, suppl_1 (2017): S40. http://dx.doi.org/10.1093/ofid/ofx162.097.

Texto completo da fonte

Resumo:

Abstract Background HCV genotype 1a (HCV g1a) followed by HCV g1b, –g2, and –g3 are the most common etiologic agents in the ~3 million current HCV-infections in the US. To achieve effective therapy, antiviral drug resistance testing is often essential but not fully available. Knowledge of both the genotype and the presence of HCV mutations in the genes of the major drug targets (NS3, NS5A and NS5B) can assist in optimal treatment selection. Methods The HCV genotype of 1000 HCV positive clinical plasmas and sera was determined (HCVg Direct, GenMark). Ten independent Sanger sequencing assays detecting antiviral drug resistance mutations in the genes encoding NS3, NS5a, and NS5b were developed. Six of these assays address mutations in all three genes in the two most common genotypes (HCV g1a and g1b). In addition, four more assays address mutations in NS5a and NS5b of HCV g2 and g3. These mutations are resistance determinants against 11 anti-HCV drugs as shown in Figure 1. A streamlined workflow employs conventional reverse transcriptase PCR, gel electrophoresis, spectrophotometry, bi-directional Sanger sequencing and reporting. The assays were designed to cover hot spot regions and capturing all known resistance mutations in NS3, NS5a and NS5b. Results Consistent with previous US HCV incidence reports, g1a, g1b, g2, and g3 comprised 99% of 1000 sequentially tested HCV patient specimens (62%, 12%, 11%, and 14%, respectively). Testing of more than 20 clinical samples each for g1a, g1b, g2, and g3 resulted in successful detection of NS3, NS5a, and NS5b mutations that confer drug resistance. The design successfully permitted detection of relevant mutations known to date for all 11 drugs. The number of reportable mutations range from 20 ‒ 36, 9 ‒ 49, and 10 ‒ 29 for the NS3, NS5a, and NS5b inhibitors, respectively (Figure 1). Conclusion These assays provide the most comprehensive commercially available antiviral drug resistance information to date for mutations in HCV NS3, NS5A, and NS5B. This testing will assist physicians in deciding on the most appropriate treatment options for their patients. Disclosures J. Nutt, Viracor Eurofins Laboratories: Employee, Salary;  J. Grantham, Viracor Eurofins Laboratories: Employee, Salary; M. Smith, Viracor Eurofins Laboratories: Employee, Salary; E. Smith, Viracor Eurofins Laboratories: Employee, Salary; A. Wedin, Viracor Eurofins Laboratories: Employee, Salary;  A. Tyler, Viracor Eurofins Laboratories: Employee, Salary; M. Miralles, Viracor Eurofins Laboratories: Employee, Salary; S. Kleiboeker, Viracor Eurofins Laboratories: Employee, Salary; M. Wissel, Viracor Eurofins Laboratories: Employee, Salary

Estilos ABNT, Harvard, Vancouver, APA, etc.

22

Mousa, Mai H. A., Nermin S. Ahmed, Kai Schwedtmann, Efseveia Frakolaki, Niki Vassilaki, Grigoris Zoidis, Jan J. Weigand e Ashraf H. Abadi. "Design and Synthesis of Novel Symmetric Fluorene-2,7-Diamine Derivatives as Potent Hepatitis C Virus Inhibitors". Pharmaceuticals 14, n.º 4 (25 de março de 2021): 292. http://dx.doi.org/10.3390/ph14040292.

Texto completo da fonte

Resumo:

Hepatitis C virus (HCV) is an international challenge. Since the discovery of NS5A direct-acting antivirals, researchers turned their attention to pursue novel NS5A inhibitors with optimized design and structure. Herein we explore highly potent hepatitis C virus (HCV) NS5A inhibitors; the novel analogs share a common symmetrical prolinamide 2,7-diaminofluorene scaffold. Modification of the 2,7-diaminofluorene backbone included the use of (S)-prolinamide or its isostere (S,R)-piperidine-3-caboxamide, both bearing different amino acid residues with terminal carbamate groups. Compound 26 exhibited potent inhibitory activity against HCV genotype (GT) 1b (effective concentration (EC50) = 36 pM and a selectivity index of >2.78 × 106). Compound 26 showed high selectivity on GT 1b versus GT 4a. Interestingly, it showed a significant antiviral effect against GT 3a (EC50 = 1.2 nM). The structure-activity relationship (SAR) analysis revealed that picomolar inhibitory activity was attained with the use of S-prolinamide capped with R- isoleucine or R-phenylglycine residues bearing a terminal alkyl carbamate group.

Estilos ABNT, Harvard, Vancouver, APA, etc.

23

Ng, Teresa, Tami Pilot-Matias, Rakesh Tripathi, Gretja Schnell, Preethi Krishnan, Thomas Reisch, Jill Beyer et al. "Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection". Viruses 10, n.º 9 (28 de agosto de 2018): 462. http://dx.doi.org/10.3390/v10090462.

Texto completo da fonte

Resumo:

Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-infected patients receiving 3-day monotherapy of glecaprevir or pibrentasvir, respectively. None of the NS3 polymorphisms detected in the 47 baseline samples collected prior to glecaprevir monotherapy conferred reduced susceptibility to glecaprevir. The NS3 A156T substitution, which conferred resistance to glecaprevir but had low replication efficiency, emerged in one genotype 1a-infected patient among the 35 patients with available post-baseline sequence data. Baseline NS5A polymorphisms were detected in 12 of 40 patients prior to pibrentasvir monotherapy; most polymorphisms were single-position NS5A amino acid substitutions that did not confer resistance to pibrentasvir. Among the 19 patients with available post-baseline NS5A sequence data, 3 had treatment-emergent NS5A substitutions during pibrentasvir monotherapy. All treatment-emergent NS5A substitutions were linked multiple-position, almost exclusively double-position, substitutions that conferred resistance to pibrentasvir. Replicons engineered with these double-position substitutions had low replication efficiency. In conclusion, resistance-conferring substitutions emerged in a small number of genotype 1-infected patients during glecaprevir or pibrentasvir monotherapy; unlike other NS5A inhibitors, pibrentasvir did not select single-position NS5A substitutions during monotherapy.

Estilos ABNT, Harvard, Vancouver, APA, etc.

24

Quintavalle, Manuela, Sonia Sambucini, Chiara Di Pietro, Raffaele De Francesco e Petra Neddermann. "The α Isoform of Protein Kinase CKI Is Responsible for Hepatitis C Virus NS5A Hyperphosphorylation". Journal of Virology 80, n.º 22 (30 de agosto de 2006): 11305–12. http://dx.doi.org/10.1128/jvi.01465-06.

Texto completo da fonte

Resumo:

ABSTRACT Hepatitis C virus (HCV) has been the subject of intensive studies for nearly two decades. Nevertheless, some aspects of the virus life cycle are still a mystery. The HCV nonstructural protein 5A (NS5A) has been shown to be a modulator of cellular processes possibly required for the establishment of viral persistence. NS5A is heavily phosphorylated, and a switch between a basally phosphorylated form of NS5A (p56) and a hyperphosphorylated form of NS5A (p58) seems to play a pivotal role in regulating HCV replication. Using kinase inhibitors that specifically inhibit the formation of NS5A-p58 in cells, we identified the CKI kinase family as a target. NS5A-p58 increased upon overexpression of CKI-α, CKI-δ, and CKI-ε, whereas the RNA interference of only CKI-α reduced NS5A hyperphosphorylation. Rescue of inhibition of NS5A-p58 was achieved by CKI-α overexpression, and we demonstrated that the CKI-α isoform is targeted by NS5A hyperphosphorylation inhibitors in living cells. Finally, we showed that down-regulation of CKI-α attenuates HCV RNA replication.

Estilos ABNT, Harvard, Vancouver, APA, etc.

25

Abdel-Magid, Ahmed F. "Halting HCV Replication with NS5A Inhibitors and NS5B Polymerase Inhibitors: Effective New Treatments of HCV Infection". ACS Medicinal Chemistry Letters 5, n.º 3 (20 de novembro de 2013): 234–37. http://dx.doi.org/10.1021/ml400456r.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

26

Bagaglio, Sabrina, Emanuela Messina, Hamid Hasson, Andrea Galli, Caterina Uberti-Foppa e Giulia Morsica. "Geographic Distribution of HCV-GT3 Subtypes and Naturally Occurring Resistance Associated Substitutions". Viruses 11, n.º 2 (11 de fevereiro de 2019): 148. http://dx.doi.org/10.3390/v11020148.

Texto completo da fonte

Resumo:

Background: Little is known about the frequency or geographic distributions of naturally occurring resistance-associated substitutions (RASs) in the nonstructural protein 5A (NS5A) domain of hepatitis-C virus (HCV) genotype-3 (GT-3) different subtypes. We investigated naturally occurring GT-3 RASs that confer resistance to NS5A inhibitors. Methods: From a publicly accessible database, we retrieved 58 complete GT-3 genomes and an additional 731 worldwide NS5A sequences from patients infected with GT-3 that were naive to direct-acting antiviral treatment. Results: We performed a phylogenetic analysis of NS5A domains in complete HCV genomes to determine more precisely HCV-GT-3 subtypes, based on commonly used target regions (e.g., 5′untranslated region and NS5B partial domain). Among 789 NS5A sequences, GT-3nonA subtypes were more prevalent in Asia than in other geographic regions (P<0.0001). The A30K RAS was detected more frequently in HCV GT3nonA (84.6%) than in GT-3A subtypes (0.8%), and the amino acid change was polymorphic in isolates from Asia. Conclusions: These results provided information on the accuracy of HCV-3 subtyping with a phylogenetic analysis of the NS5A domain with data from the Los Alamos HCV genome database. This information and the worldwide geographic distribution of RASs according to HCV GT-3 subtypes are crucial steps in meeting the challenges of treating HCV GT-3.

Estilos ABNT, Harvard, Vancouver, APA, etc.

27

Gottwein, Judith M., Sanne B. Jensen, Yi-Ping Li, Lubna Ghanem, Troels K. H. Scheel, Stéphanie B. N. Serre, Lotte Mikkelsen e Jens Bukh. "Combination Treatment with Hepatitis C Virus Protease and NS5A Inhibitors Is Effective against Recombinant Genotype 1a, 2a, and 3a Viruses". Antimicrobial Agents and Chemotherapy 57, n.º 3 (28 de dezembro de 2012): 1291–303. http://dx.doi.org/10.1128/aac.02164-12.

Texto completo da fonte

Resumo:

ABSTRACTWith the development of directly acting antivirals, hepatitis C virus (HCV) therapy entered a new era. However, rapid selection of resistance mutations necessitates combination therapy. To study combination therapy in infectious culture systems, we aimed at developing HCV semi-full-length (semi-FL) recombinants relying only on the JFH1 NS3 helicase, NS5B, and the 3′ untranslated region. With identified adaptive mutations, semi-FL recombinants of genotypes(isolates) 1a(TN) and 3a(S52) produced supernatant infectivity titers of ∼4 log10focus-forming units/ml in Huh7.5 cells. Genotype 1a(TN) adaptive mutations allowed generation of 1a(H77) semi-FL virus. Concentration-response profiles revealed the higher efficacy of the NS3 protease inhibitor asunaprevir (BMS-650032) and the NS5A inhibitor daclatasvir (BMS-790052) against 1a(TN and H77) than 3a(S52) viruses. Asunaprevir had intermediate efficacy against previously developed 2a recombinants J6/JFH1 and J6cc. Daclatasvir had intermediate efficacy against J6/JFH1, while low sensitivity was confirmed against J6cc. Using a cross-titration scheme, infected cultures were treated until viral escape or on-treatment virologic suppression occurred. Compared to single-drug treatment, combination treatment with relatively low concentrations of asunaprevir and daclatasvir suppressed infection with all five recombinants. Escaped viruses primarily had substitutions at amino acids in the NS3 protease and NS5A domain I reported to be genotype 1 resistance mutations. Inhibitors showed synergism at drug concentrations reportedin vivo. In summary, semi-FL HCV recombinants, including the most advanced reported genotype 3a infectious culture system, permitted genotype-specific analysis of combination treatment in the context of the complete viral life cycle. Despite differential sensitivity to lead compound NS3 protease and NS5A inhibitors, genotype 1a, 2a, and 3a viruses were suppressed by combination treatment with relatively low concentrations.

Estilos ABNT, Harvard, Vancouver, APA, etc.

28

O'Boyle II, Donald R., Jin-Hua Sun, Peter T. Nower, Julie A. Lemm, Robert A. Fridell, Chunfu Wang, Jeffrey L. Romine et al. "Characterizations of HCV NS5A replication complex inhibitors". Virology 444, n.º 1-2 (setembro de 2013): 343–54. http://dx.doi.org/10.1016/j.virol.2013.06.032.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

29

Yu, Wensheng, Bancha Vibulbhan, Stuart B. Rosenblum, Gregory S. Martin, A. Samuel Vellekoop, Christian L. Holst, Craig A. Coburn et al. "Discovery of potent macrocyclic HCV NS5A inhibitors". Bioorganic & Medicinal Chemistry Letters 26, n.º 15 (agosto de 2016): 3793–99. http://dx.doi.org/10.1016/j.bmcl.2016.05.042.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

30

Gish, Robert G., e Nicholas A. Meanwell. "The NS5A Replication Complex Inhibitors: Difference Makers?" Clinics in Liver Disease 15, n.º 3 (agosto de 2011): 627–39. http://dx.doi.org/10.1016/j.cld.2011.05.010.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

31

Di Maio, V. C., V. Cento, D. Di Paolo, R. Campoli, K. Yu, A. Manunta, V. Micheli et al. "P1236 NS3, NS5A AND NS5B COEVOLUTION DURING TREATMENT WITH FIRST-GENERATION PROTEASE INHIBITORS". Journal of Hepatology 60, n.º 1 (abril de 2014): S501. http://dx.doi.org/10.1016/s0168-8278(14)61396-9.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

32

Esposito, Isabella, Sebastián Marciano, Leila Haddad, Omar Galdame, Alejandra Franco, Adrián Gadano, Diego Flichman e Julieta Trinks. "Prevalence and Factors Related to Natural Resistance-Associated Substitutions to Direct-Acting Antivirals in Patients with Genotype 1 Hepatitis C Virus Infection". Viruses 11, n.º 1 (21 de dezembro de 2018): 3. http://dx.doi.org/10.3390/v11010003.

Texto completo da fonte

Resumo:

This study aimed to assess the prevalence of natural resistance-associated substitutions (RASs) to NS3, NS5A and NS5B inhibitors in 86 genotype 1 Hepatitis C Virus (HCV)-infected patients from Buenos Aires, Argentina, and to determine their effect on therapy outcome. Additionally, virological, clinical and host genetic factors were explored as predictors of the presence of baseline RASs. NS3 RASs (39.2%) were more prevalent than NS5A RASs (25%) and NS5B RASs (8.9%). In the three regions, the frequencies of RASs were significantly higher in HCV-1b than in HCV-1a. The prevalence of Y93H, L159F and Q80K were 1.3%, 6.3% and 2.5%, respectively. IFNL3 CC genotype was identified as an independent predictor of the presence of baseline RASs in NS5A and NS3 genes (p = 0.0005 and p = 0.01, respectively). Sustained virologic response was achieved by 93.3% of the patients after receiving direct-acting antivirals (DAAs), although 48.7% of them showed baseline RASs related to the DAA-regimen. Notably, the prevalence of clinically relevant RASs in the three genes was lower than that observed around the world. The baseline presence of RASs in both subtypes did not appear to affect therapy outcome. These results support the need to evaluate resistance patterns in each particular country since RASs´ prevalence significantly vary worldwide.

Estilos ABNT, Harvard, Vancouver, APA, etc.

33

Sudo, Kenji, Kayo Yamaji, Kouich Kawamura, Tomoko Nishijima, Naoko Kojima, Kazuhiko Aibe, Kunitada Shimotohno e Yasuaki Shimizu. "High-Throughput Screening of Low Molecular Weight NS3-NS4A Protease Inhibitors Using a Fluorescence Resonance Energy Transfer Substrate". Antiviral Chemistry and Chemotherapy 16, n.º 6 (dezembro de 2005): 385–92. http://dx.doi.org/10.1177/095632020501600605.

Texto completo da fonte

Resumo:

Hepatitis C virus (HCV) NS3-NS4A protease is an attractive target for anti-HCV agents because of its important role in replication. An optimized fluorescence resonance energy transfer (FRET) substrate for NS3-NS4A protease, based on the sequence of the NS5A-5B cleavage site, was designed and synthesized. High-throughput screening of in-house compound libraries was performed using a FRET substrate FS10 (MOCAc-DKIVPC-SMSYK-Dnp) and MBP-NS3-NS4A fusion protein. Several hit compounds were found, including YZ-9577 (2-oxido-1,2,5-oxadiazole-3,4-diyl) bis (phenylmethanone) with potent inhibitory activity (IC50=1.6 μM) and good selectivity against other human serine proteases.

Estilos ABNT, Harvard, Vancouver, APA, etc.

34

Vallet-Pichard, Anaïs, e Stanislas Pol. "Grazoprevir/elbasvir combination therapy for HCV infection". Therapeutic Advances in Gastroenterology 10, n.º 1 (17 de outubro de 2016): 155–67. http://dx.doi.org/10.1177/1756283x16671293.

Texto completo da fonte

Resumo:

Interferon-free regimens combine different second-wave direct-acting antiviral agents (DAAs), which target the main viral proteins involved in the replication cycle of hepatitis C virus (HCV): NS3/4A protease inhibitors (simeprevir or paritaprevir boosted by ritonavir), NS5B nucleos(t)idic (sofosbuvir) and nonnucleos(t)idic (dasabuvir) polymerase inhibitors, NS5A replication complex inhibitors (daclatasvir, ledipasvir, elbasvir, velpatasvir). Combinations of two or three DAAs, given for 8–24 weeks reach sustained virology response (SVR) rates greater than 90% with good tolerance. SVR rates and safety are similar in clinical trials and in real life, usually higher than 95% in the per-protocol analysis. Next-generation DAAs are now expected. To be competitive, these new combinations need to prove their added value regarding the pill burden, the reduced duration of treatment, the drug–drug interaction profile and safety. Zepatier is a fixed-dose combination product coformulating MK-5172 [grazoprevir (GZR), 100 mg QD] and MK-8742 [elbasvir or (EBR) 50 mg QD]: it combines highly potent inhibitors of the HCV NS3/4A protease and NS5A replication complex, respectively. This review provides a summary of the main evidence available for the use of GZR/EBR and highlights the strength of this combination.

Estilos ABNT, Harvard, Vancouver, APA, etc.

35

Kichatova, V. S., A. A. Karlsen, O. V. Isaeva, S. A. Solonin, E. Yu Malinnikova, K. K. Kyuregyan e M. I. Mikhailov. "Drug resistant variants of hepatitis C virus genotype 1b in Russia: analysis of aminoacid substitutions in NS5a and core proteins". Journal Infectology 10, n.º 4 (30 de dezembro de 2018): 30–36. http://dx.doi.org/10.22625/2072-6732-2018-10-4-30-36.

Texto completo da fonte

Resumo:

Aim. To determine the prevalence of amino acid substitutions in hepatitis C virus NS5a and core proteins which areassociated with resistance to direct-acting antivirals and interferon in genotype 1b (HCV-1b) strains circulating in Russia. Materials and methods. Nucleotide sequences of NS5a (n=93) and core (n=30) of HCV-1b were obtained using direct sequencing of respective amplified genome fragments. The search for resistance associated substitutions was performed for amino acid positions 28, 29, 30, 31, 32, 58, 62, 92, 93 of NS5a, and 70 and 91 amino acid positions of core proteins, respectively. Results. The total proportion of HCV-1b strains carrying resistance associated substitutions in NS5a was 22,6% (21/93). The total detection rate of L31M and Y93H substitutions that are associated with resistance to the majority of NS5a inhibitors was 10,8%. Less clinically significant substitutions L28M, R30Q, P58S/T, A92T were detected too. The proportion of infections caused by HCV-1b strains that are potentially resistant both to interferon and NS5a inhibitors was 10% (10/30). Conclusion. Testing of HCV-1b infected patients for background resistance profile could be a useful tool to prevent the choosing of initially ineffective treatment regimen.

Estilos ABNT, Harvard, Vancouver, APA, etc.

36

Krishnan, Preethi, Jill Beyer, Neeta Mistry, Gennadiy Koev, Thomas Reisch, David DeGoey, Warren Kati et al. "In VitroandIn VivoAntiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A". Antimicrobial Agents and Chemotherapy 59, n.º 2 (1 de dezembro de 2014): 979–87. http://dx.doi.org/10.1128/aac.04226-14.

Texto completo da fonte

Resumo:

ABSTRACTOmbitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A.In vitroresistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluatedin vivoin a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.)

Estilos ABNT, Harvard, Vancouver, APA, etc.

37

Yau, Alan Hoi Lun, e Eric M. Yoshida. "Hepatitis C Drugs: The End of the Pegylated Interferon Era and the Emergence of All-Oral, Interferon-Free Antiviral Regimens: A Concise Review". Canadian Journal of Gastroenterology and Hepatology 28, n.º 8 (2014): 445–51. http://dx.doi.org/10.1155/2014/549624.

Texto completo da fonte

Resumo:

Between 2001 and 2011, the standard of care for chronic hepatitis C virus (HCV) infection was a combination of pegylated interferon (PEGIFN) and ribavirin (RBV). In May 2011, boceprevir and telaprevir, two first-generation NS3/4A protease inhibitors, were approved in combination with PEG-IFN and RBV for 24 to 48 weeks in hepatitis C virus genotype 1 infections. In December 2013, simeprevir, a second-generation NS3/4A protease inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotype 1, while sofosbuvir, a NS5B nucleotide polymerase inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotypes 1 and 4, as well as with RBV alone for 12 weeks in genotype 2 and for 24 weeks in genotype 3. Sofosbuvir combined with simeprevir or an NS5A replication complex inhibitor (ledipasvir or daclatasvir) with or without RBV for 12 weeks in genotype 1 resulted in a sustained virological response >90%, irrespective of previous treatment history or presence of cirrhosis. Similarly impressive sustained virological response rates have been shown with ABT-450/r (ritonavir-boosted NS3/4A protease inhibitor)-based regimens in combination with other direct-acting antiviral agent(s) with or without RBV for 12 weeks in genotype 1. The optimal all-oral interferon-free antiviral regimen likely entails a combination of an NS5B nucleotide polymerase inhibitor with either a second-generation NS3/4A protease inhibitor or an NS5A replication complex inhibitor with or without RBV. Further research is needed to determine the role of resistance testing, clarify the optimal follow-up duration post-treatment, and evaluate the antiviral efficacy and safety in difficult-to-cure patient populations.

Estilos ABNT, Harvard, Vancouver, APA, etc.

38

Neddermann, Petra, Manuela Quintavalle, Chiara Di Pietro, Angelica Clementi, Mauro Cerretani, Sergio Altamura, Linda Bartholomew e Raffaele De Francesco. "Reduction of Hepatitis C Virus NS5A Hyperphosphorylation by Selective Inhibition of Cellular Kinases Activates Viral RNA Replication in Cell Culture". Journal of Virology 78, n.º 23 (1 de dezembro de 2004): 13306–14. http://dx.doi.org/10.1128/jvi.78.23.13306-13314.2004.

Texto completo da fonte

Resumo:

ABSTRACT Efficient replication of hepatitis C virus (HCV) subgenomic RNA in cell culture requires the introduction of adaptive mutations. In this report we describe a system which enables efficient replication of the Con1 subgenomic replicon in Huh7 cells without the introduction of adaptive mutations. The starting hypothesis was that high amounts of the NS5A hyperphosphorylated form, p58, inhibit replication and that reduction of p58 by inhibition of specific kinase(s) below a certain threshold enables HCV replication. Upon screening of a panel of kinase inhibitors, we selected three compounds which inhibited NS5A phosphorylation in vitro and the formation of NS5A p58 in cell culture. Cells, transfected with the HCV Con1 wild-type sequence, support HCV RNA replication upon addition of any of the three compounds. The effect of the kinase inhibitors was found to be synergistic with coadaptive mutations in NS3. This is the first direct demonstration that the presence of high amounts of NS5A-p58 causes inhibition of HCV RNA replication in cell culture and that this inhibition can be relieved by kinase inhibitors.

Estilos ABNT, Harvard, Vancouver, APA, etc.

39

Welzel, Tania M., e Stefan Zeuzem. "NS5A inhibitors to treat hepatitis C virus infection". Lancet Infectious Diseases 12, n.º 9 (setembro de 2012): 648–49. http://dx.doi.org/10.1016/s1473-3099(12)70145-7.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

40

Brazeau, Jean-Francois, e Gerard Rosse. "Inhibitors of NS5A for Treatment of HCV Infection". ACS Medicinal Chemistry Letters 5, n.º 3 (24 de setembro de 2013): 224. http://dx.doi.org/10.1021/ml4003716.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

41

Pawlotsky, Jean-Michel. "NS5A inhibitors in the treatment of hepatitis C". Journal of Hepatology 59, n.º 2 (agosto de 2013): 375–82. http://dx.doi.org/10.1016/j.jhep.2013.03.030.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

42

Tamori, Akihiro, Masaru Enomoto e Norifumi Kawada. "Recent Advances in Antiviral Therapy for Chronic Hepatitis C". Mediators of Inflammation 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/6841628.

Texto completo da fonte

Resumo:

Hepatitis C virus (HCV) infection is a major worldwide health problem. Chronic infection induces continuous inflammation in the liver, progression of hepatic fibrosis, eventual cirrhosis, and possible hepatocellular carcinoma. Eradication of the virus is one of the most important treatment aims. A number of promising new direct-acting antivirals (DAAs) have been developed over the past 10 years. Due to their increased efficacy, safety, and tolerability, interferon-free oral therapies with DAAs have been approved for patients with HCV, including those with cirrhosis. This review introduces the characteristics and results of recent clinical trials of several DAAs: NS3/4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors. DAA treatment failure and prognosis after DAA therapy are also discussed.

Estilos ABNT, Harvard, Vancouver, APA, etc.

43

Cheng, Du, Lei Zhao, Leiliang Zhang, Yongfang Jiang, Yi Tian, Xinqiang Xiao e Guozhong Gong. "p53 controls hepatitis C virus non-structural protein 5A-mediated downregulation of GADD45α expression via the NF-κB and PI3K–Akt pathways". Journal of General Virology 94, n.º 2 (1 de fevereiro de 2013): 326–35. http://dx.doi.org/10.1099/vir.0.046052-0.

Texto completo da fonte

Resumo:

Growth arrest and DNA-damage-inducible gene 45-α (GADD45α) protein has been shown to be a tumour suppressor and is implicated in cell-cycle arrest and suppression of cell growth. The hepatitis C virus (HCV) non-structural 5A (NS5A) protein plays an important role in cell survival and is linked to the development of hepatocellular carcinoma (HCC). However, the role of HCV NS5A in the development of HCC remains to be clarified. This study sought to determine whether GADD45α mediates HCV NS5A-induced cellular survival and to elucidate the molecular mechanism of GADD45α expression regulated by HCV NS5A. It was found that HCV NS5A downregulated GADD45α expression at the transcriptional level by decreasing promoter activity, mRNA transcription and protein levels. Knockdown of p53 resulted in a similar decrease in GADD45α expression to that caused by HCV NS5A, whilst overexpression of p53 reversed the HCV NS5A-mediated downregulation of GADD45α. HCV NS5A repressed p53 expression, which was followed by a subsequent decrease in GADD45α expression. Further evidence was provided showing that HCV NS5A led to increases of phosphorylated nuclear factor-κB and Akt levels. Inhibition of these pathways using pharmacological inhibitors or specific small interfering RNAs rescued HCV NS5A-mediated downregulation of p53 and GADD45α. It was also found that HCV NS5A protein and depletion of GADD45α increased cell growth, whereas ectopic expression of GADD45α eliminated HCV NS5A-induced cell proliferation. These results indicated that HCV NS5A downregulates GADD45α expression and subsequently triggers cellular proliferation. These findings provide new insights suggesting that HCV NS5A could contribute to the occurrence of HCV-related HCC.

Estilos ABNT, Harvard, Vancouver, APA, etc.

44

QADRI, Ishtiaq, Mieko IWAHASHI, Juan M. CAPASSO, Matthew W. HOPKEN, Sonia FLORES, Jerome SCHAACK e Francis R. SIMON. "Induced oxidative stress and activated expression of manganese superoxide dismutase during hepatitis C virus replication: role of JNK, p38 MAPK and AP-1". Biochemical Journal 378, n.º 3 (15 de março de 2004): 919–28. http://dx.doi.org/10.1042/bj20031587.

Texto completo da fonte

Resumo:

Activation of cellular kinases and transcription factors mediates the early phase of the cellular response to chemically or biologically induced stress. In the present study we investigated the oxidant/antioxidant balance in Huh-7 cells expressing the HCV (hepatitis C virus) subgenomic replicon, and observed a 5-fold increase in oxidative stress during HCV replication. We used MnSOD (manganese-superoxide dismutase) as an indicator of the cellular antioxidant response, and found that its activity, protein levels and promoter activity were significantly increased, whereas Cu/ZnSOD was not affected. The oxidative stress-induced protein kinases p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) were activated in the HCV repliconcontaining cells and in Huh-7 cells transduced with Ad-NS5A [a recombinant adenovirus encoding NS5A (non-structural protein 5A)], coupled with a 4–5-fold increase in AP-1 (activator protein-1) DNA binding. Ava.1 cells, which encode a replication-defective HCV replicon, showed no significant changes in MnSOD, p38 MAPK or JNK activity. The AP-1 inhibitors dithiothreitol and N-acetylcysteine, as well as a dominant negative AP-1 mutant, significantly reduced AP-1 activation, demonstrating that this activation is oxidative stress-related. Exogenous NS5A had no effect on AP-1 activation in vitro, suggesting that NS5A acts at the upstream targets of AP-1 involving p38 MAPK and JNK signalling cascades. AP-1-dependent gene expression was increased in HCV subgenomic replicon-expressing Huh-7 cells. MnSOD activation was blocked by inhibitors of JNK (JNKI1) and p38 MAPK (SB203580), but not by an ERK (extracellular-signal-regulated kinase) inhibitor (U0126), in HCV-replicating and Ad-NS5A-transduced cells. Our results demonstrate that cellular responses to oxidative stress in HCV subgenomic replicon-expressing and Ad-NS5A-transduced cells are regulated by two distinct signalling pathways involving p38 MAPK and JNK via AP-1 that is linked to increased oxidative stress and therefore to an increased antioxidant MnSOD response.

Estilos ABNT, Harvard, Vancouver, APA, etc.

45

Bhattacharya, Dipankar, Israrul H. Ansari, Robert Hamatake, Jill Walker, Wieslaw M. Kazmierski e Rob Striker. "Pharmacological disruption of hepatitis C NS5A protein intra- and intermolecular conformations". Journal of General Virology 95, n.º 2 (1 de fevereiro de 2014): 363–72. http://dx.doi.org/10.1099/vir.0.054569-0.

Texto completo da fonte

Resumo:

Non-structural 5A protein (NS5A) has emerged as an important pharmacological target for hepatitis C virus (HCV). However, little is known about the conformation of NS5A intracellularly or how NS5A inhibitors achieve the picomolar (pM) inhibition of virus replication. Here, we have presented two structurally related small molecules, one that potently inhibits HCV replication and selects for resistance in NS5A, and another that is inactive. Resistance to this antiviral was greater in genotype 1a than in genotype 1b replicons and mapped to domain 1 of NS5A. Using a novel cell-based assay that measures the intracellular proximity of fluorescent tags covalently attached to NS5A, we showed that only the active antiviral specifically disrupted the close proximity of inter- and intramolecular positions of NS5A. The active antiviral, termed compound 1, caused a repositioning of both the N and C termini of NS5A, including disruption of the close approximation of the N termini of two different NS5A molecules in a multimolecular complex. These data provide the first study of how antivirals that select resistance in domain 1 of NS5A alter the cellular conformation of NS5A. This class of antiviral disrupts the close proximity of the N termini of domain 1 in a NS5A complex but also alters the conformation of domain 3, and leads to large aggregates of NS5A. Current models predict that a multicomponent cocktail of antivirals is needed to treat HCV infection, so a mechanistic understanding of what each component does to the viral machinery will be important.

Estilos ABNT, Harvard, Vancouver, APA, etc.

46

Lawitz, Eric J., William D. O'Riordan, Armen Asatryan, Bradley L. Freilich, Terry D. Box, J. Scott Overcash, Sandra Lovell et al. "Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection". Antimicrobial Agents and Chemotherapy 60, n.º 3 (28 de dezembro de 2015): 1546–55. http://dx.doi.org/10.1128/aac.02264-15.

Texto completo da fonte

Resumo:

ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistancein vitro. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log10IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.)

Estilos ABNT, Harvard, Vancouver, APA, etc.

47

Li, Jiayu, Wenyue Tian, Diaohui Gao, Yuying Li, Yiqun Chang, Jun Xu, Junxia Zheng e Pinghua Sun. "QSAR Studies on Thiazole Derivatives as HCV NS5A Inhibitors via CoMFA and CoMSIA Methods". Letters in Drug Design & Discovery 16, n.º 4 (8 de março de 2019): 453–60. http://dx.doi.org/10.2174/1570180815666180702153529.

Texto completo da fonte

Resumo:

Background: Hepatitis C Virus (HCV) infection is the major cause of hepatitis after transfusion. And HCV Nonstructural Protein 5A (NS5A) inhibitors have become a new hotspot in the study of HCV inhibitors due to their strong antiviral activity, rapid speed of viral removing and broad antiviral spectrum. Methods: Forty-five NS5A inhibitors were chosen to process three-dimensional quantitative structure- activity relationship (3D-QSAR) by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. A training set consisting of 30 compounds was applied to establish the models and a test set consisting of 15 compounds was applied to do the external validation. Results: The CoMFA model predicted a q2 value of 0.607 and an r2 value of 0.934. And the CoMSIA model predicted a q2 value of 0.516 and an r2 value of 0.960 established on the effects of steric, electrostatic, hydrophobic and hydrogen-bond acceptor. 0.713 and 0.939 were the predictive correlation co-efficients (r2pred) of CoMFA and CoMSIA models, respectively. Conclusion: These conclusions provide a theoretical basis for drug design and screening of HCV NS5A complex inhibitors.

Estilos ABNT, Harvard, Vancouver, APA, etc.

48

Bobardt, Michael, Christina M. Ramirez, Marc M. Baum, Daren Ure, Robert Foster e Philippe A. Gallay. "The combination of the NS5A and cyclophilin inhibitors results in an additive anti-HCV inhibition in humanized mice without development of resistance". PLOS ONE 16, n.º 5 (20 de maio de 2021): e0251934. http://dx.doi.org/10.1371/journal.pone.0251934.

Texto completo da fonte

Resumo:

We and others previously reported that the direct-acting agents (DAA) NS5A inhibitors (NS5Ai) and the host-targeting agents cyclophilin inhibitors (CypIs) inhibit HCV replication in vitro. In this study, we investigated whether the combination of NS5Ai and CypI offers a potent anti-HCV effect in vivo. A single administration of NS5Ai or CypI alone to HCV-infected humanized-mice inhibits HCV replication. The combination of NS5Ai with CypI suppresses HCV (GT1a, GT2a, GT3a and GT4a) replication in an additive manner. NS5Ai/CypI combinations provide a statistically more profound anti-HCV inhibition for GT2a and GT3a than GT1a and GT4a, leading to a fastest and deepest inhibition of GT2a and GT3a replications. Combining CypI with NS5Ai prevents the viral rebound normally observed in mice treated with NS5Ai alone. Results were confirmed in mice implanted with human hepatocytes from different donors. Therefore, the combination of NS5Ai with CypI may serve as a regimen for the treatment of HCV patients with specific genotypes and disorder conditions, which diminish sustain viral response levels to DAA, such as GT3a infection, cirrhosis, and DAA resistance associated with the selection of resistance-associated substitutions present at baseline or are acquired during treatment.

Estilos ABNT, Harvard, Vancouver, APA, etc.

49

Nakamoto, Shingo. "Hepatitis C virus NS5A inhibitors and drug resistance mutations". World Journal of Gastroenterology 20, n.º 11 (2014): 2902. http://dx.doi.org/10.3748/wjg.v20.i11.2902.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

50

A. Ivanenkov, Yan, Mark S. Veselov, Vladimir A. Aladinskiy, Artem G. Shakhbazyan, Sofya M. Yartseva, Alexander G. Majouga, Anastasia V. Aladinskaya et al. "In Silico Approaches to the Design of NS5A Inhibitors". Current Topics in Medicinal Chemistry 16, n.º 12 (3 de março de 2016): 1383–91. http://dx.doi.org/10.2174/1568026616666151120113705.

Texto completo da fonte

Estilos ABNT, Harvard, Vancouver, APA, etc.

Artigos de revistas sobre o tema "NS5A inhibitors"

Crie uma referência precisa em APA, MLA, Chicago, Harvard, e outros estilos