Bibliografias temáticas / NS5A inhibitors

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Literatura científica selecionada sobre o tema "NS5A inhibitors"

Autor: Grafiati

Publicado: 4 de junho de 2021

Última modificação: 17 de fevereiro de 2022

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Artigos de revistas sobre o assunto "NS5A inhibitors"

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.

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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.

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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.

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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, n.º 3 (28 de dezembro de 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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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.

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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, n.º 11 (1 de novembro de 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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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.

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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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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.

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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.

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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.

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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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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.

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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.

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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.

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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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Teses / dissertações sobre o assunto "NS5A inhibitors"

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 e 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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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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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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Milhas, Sabine. "Développement d'outils pour l'étude des interactions protéine-protéine". Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4020.

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Au cours de ma thèse je me suis intéressée aux interactions protéine-protéine (PPI’s). Les PPI’s jouent un rôle majeur dans une grande diversité de processus cellulaires et sont maintenant considérées comme une cible majeure dans le but de développer de nouveaux médicaments. Cependant, cibler ce type d’interactions requiert le développement de chimiothèques dédiées, permettant d’accélérer la découverte de molécules « touches ». Pour surmonter ce problème, une chimiothèque orientée PPI (2P2I3D) a été conçu au laboratoire. Dans un premier temps, j’ai donc évalué cette chimiothèque sur différents complexes possédant des interfaces variées. Les résultats obtenus ont révélé des taux de touches supérieurs à ceux obtenus avec des chimiothèques non orientées, de 0,2 à 1,6% contre 0,01 à 0,1%, respectivement. Cette étude a permis d’établir une preuve de concept de la faisabilité de créer une chimiothèque orientée PPI, permettant ainsi une accélération de la découverte de composés biologiquement actifs.Dans un deuxième temps, je me suis intéressée à l’interaction entre deux protéines majeures du virus de la dengue : les protéines NS3 et NS5. J’ai tout d’abord identifié et caractérisé un nouveau site d’interaction, ce qui m’a permis de mettre en évidence que cette interaction avait pour conséquence d’augmenter l’activité enzymatique du domaine hélicase. J’ai par la suite recherché et identifié des petites molécules chimiques capable d’inhiber cette interaction. Les différentes caractérisations effectuées ont permis de mettre en évidence un effet antiviral. Ces inhibiteurs constituent un excellent point de départ afin d’étudier plus en détail le rôle biologique de ce complexe
In my thesis I became interested in protein-protein interactions (PPI's). PPI's play a major role in a variety of cellular processes and are now considered a major target in order to develop new drugs. However, targeting such interactions requires the development of dedicated libraries, to accelerate the discovery of “hits”molecules .To overcome this issue, a focused chemical library PPI (2P2I3D) was designed in the laboratory.At first, I evaluated this chemical library on different complexes with diverse interfaces. The results showed higher hit rate to those obtained with non-oriented libraries, from 0.2 to 1.6% against 0.01 to 0.1%, respectively. This study has established a proof of concept of the feasibility of creating a focused chemical library PPI, thus accelerating the discovery of biologically active compounds.Secondly, I am interested in the interaction between two major proteins of dengue virus: the NS3 and NS5 proteins. I initially identified and characterized a novel interaction site, which allowed me to demonstrate that this interaction had the effect of increasing the enzymatic activity of the helicase domain. I searched and identified small molecules able to inhibit this interaction. The different characterizations helped to highlight an antiviral effect. These inhibitors are an excellent starting point to further explore the biological role of this complex

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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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Zlatev, Ivan. "Synthèse et étude d'analogues de dinucléosides phosphoramidates - inhibiteurs de la polymérase NS5B du Virus de l’Hépatite C". Montpellier 2, 2008. http://www.theses.fr/2008MON20129.

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Avec plus de 3 % de la population mondiale actuellement infectée, l'hépatite C est une des plus graves maladies infectieuses. La recherche et la mise au point de nouvelles molécules, capables de traiter ou de conduire à l'éradication de cette maladie, sont donc d'une grande importance. Nous présentons dans ce manuscrit le développement et la synthèse de deux séries de dinucléosides phosphoramidates de type 2'-O-méthylguanosin-3'-yl-cytidin-5'-yle et de type 2'-O-méthylguanosin-3'-yl-3'-désoxycytidin-5'-yle, utilisés comme inhibiteurs de la polymérase NS5B du VHC. Ces composés ont été évalués in vitro sur une polymérase purifiée et en culture cellulaire contenant un réplicon sub-génomique du virus. Ils ont montré un modeste caractère inhibiteur de la réplication du VHC
With more than 3% of the world's population chronically infected, hepatitis C is nowadays one of the leading infectious diseases. The research and development of novel antiviral molecules is hence of great importance. We describe in this manuscript the development and the synthesis of two major series of phosphoramidate dinucleosides 2'-O-methylguanosin-3'-yl-cytidin-5'-yle and 2'-O-methylguanosin-3'-yl-3'-désoxycytidin-5'-yle, used as HCV polymerase inhibitors. The target compounds were evaluated in vitro on a purified recombinant NS5B polymerase and in cells containing a HCV sub-genomic replica. Tested compounds exhibited modest inhibitory activity towards HCV replication

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Roche, Gilles. "Synthèse d’inhibiteurs de la protéase NS3-NS4A du VHC.Matériaux organiques et hybrides auto-organisés pour les transistors à effet de champ". Thesis, Montpellier, Ecole nationale supérieure de chimie, 2017. http://www.theses.fr/2017ENCM0007.

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Les travaux présentés dans ce manuscrit relatent les recherches les plus significatives de mon parcours professionnel au cours des onze dernières années. Dans un premier temps, nous montrons comment il est possible de prospecter de nouvelles molécules actives contre l’hépatite C en développant de nouveaux acides aminés non naturels innovants. Cette étude a été assistée par le logiciel de docking GenMol pour le design des divers composés. Nous y détaillons l’évolution des structures produites en fonctions des propriétés recherchées et des dernières avancées du domaine. Les synthèses énantio convergeantes, appuyées par la chimie des peptides, ont pu aboutir à cinq molécules finales qui ont montré différents potentiels antiviraux. Ensuite, la synthèse et l’étude structurale du composé BHH-BTT sont abordées. Nous y décrivons les propriétés physico-chimiques de l’empilement des molécules et comment celles-ci finissent par influer les propriétés de transport des charges. Nous avons ainsi élaboré des OFETs performants qui montrent de bonnes perspectives en termes de futurs détecteurs. Enfin nous rapportons la première intégration de matériaux semi-conducteurs organiques (BTBT) au sein de matériaux hybrides organique-silice. Cette démarche impliquait la réalisation d’un précurseur sol-gel optimisé bis(triéthoxysilane) qui nous permettait de contrôler l’organisation des cœurs π conjugués lors de la création des matériaux. Nous avons, grâce à des suivis spectroscopiques détaillés, démontré une agrégation de type J lors de la formation des films minces et une réorganisation des cœurs π-conjuguées en agrégation de type H lors l’application du procédé sol-gel. Après une mise au point au niveau de l’interface semi-conducteur/électrodes, nous avons alors réalisé des transistors hybrides organique-silice à effet de champs entièrement réticulés dont la robustesse face à une grande diversité de solvants organique a été démontrée
The different works presented in this manuscript relate the most relevant investigations representing my career evolution along this last eleven years. First, we show how it is possible to explore new active molecules by developing innovating non-natural amino-acids. This investigation was supported by the docking software GenMol. We show here the structures evolution of the produced molecules according to desired properties and to last advances in the field. The enantio convergent synthesis supported by peptide chemistry allowed us to reach five final molecules with diverse antiviral potentials. Then, synthesis and structural investigation of the compound BHH-BTBT was broached. We describe here physicochemical properties of the packing and how they affect charge transport properties. So then, we achieved OFET with good performance that show interesting perspective for future sensors. Finally we reported the first integration of a semi-conducting material (BTBT) in a hybrid organo-silica material. This approach involved the conception of an informed sol-gel bis(triethoxysilane) precursor that allowed us to control the π-conjugated cores organisation during the creation of the material. With detailed spectroscopic monitoring we demonstrated a J-aggregation during the thin film formation and a reorganisation to a H-aggregation during the sol-gel process. After optimisation of the semiconductor/electrode interface, we obtained hybrid organo-silica field effect transistors entirely reticulated showing a high resilience to a large diversity of organic solvent

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Capítulos de livros sobre o assunto "NS5A inhibitors"

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

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Watkins, William J. "Evolution of HCV NS5B Non-nucleoside Inhibitors". In 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". In 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, Shawn K. Pack e Nicholas A. Meanwell. "Daclatasvir (Daklinza): The First-in-Class HCV NS5A Replication Complex Inhibitor". In 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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Schinazi, Raymond F., Junxing Shi e Tony Whitaker. "Sofosbuvir (Sovaldi): The First-in-Class HCV NS5B Nucleotide Polymerase Inhibitor". In 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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Meanwell, Nicholas A., e Makonen Belema. "The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex". In 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®". In Topics in Medicinal Chemistry, 57–80. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/7355_2019_66.

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Beaulieu, Pierre L. "CHAPTER 8. Design and Development of NS5B Polymerase Non‐nucleoside Inhibitors for the Treatment of Hepatitis C Virus Infection". In Drug Discovery, 248–94. Cambridge: Royal Society of Chemistry, 2013. http://dx.doi.org/10.1039/9781849737814-00248.

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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". In Translational Research in Biomedicine, 63–93. Basel: KARGER, 2008. http://dx.doi.org/10.1159/000140936.

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Tsantrizos, Youla S. "Synthetic Challenges in the Assembly of Macrocyclic HCV NS3/NS4A Protease Inhibitors: The Case of BILN 2061 and Its Analogs". In Topics in Heterocyclic Chemistry, 89–112. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/7081_2015_184.

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Trabalhos de conferências sobre o assunto "NS5A inhibitors"

Rupp, C., T. Hippchen, P. Sauer, J. Pfeiffenberger, W. Stremmel, P. Schemmer, DN Gotthardt, A. Mehrabi e KH Weiss. "High SVR12 rates with combination of NS5A- and NS5B- inhibitors for 24 weeks in liver transplanted patients". In 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 e U. S. F. Tambunan. "Computational screening of flavonoid based inhibitor targeting DENV NS5 methyltransferase". In 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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Sulistyawati, Indah, Sulistyo Dwi K. P. e Mochammad Ichsan. "Inhibitor candidates’s identification of HCV’s RNA polymerase NS5B using virtual screening against iPPI-library". In 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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Wong, Yu Jun, Rajneesh Kumar, Chen Hua Liu, Jia Horng Kao, Vicky Wing-Ki Hui, Grace Wong e 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". In 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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Stephanie, Filia, Mutiara Saragih, Ahmad Husein Alkaff, Mochammad Arfin Fardiansyah Nasution e Usman Sumo Friend Tambunan. "Screening of Potential Northern African Natural Product Compounds as Dengue Virus NS5 Methyltransferase Inhibitor: An in Silico Approach". In 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 e Usman Sumo Friend Tambunan. "Identification of natural product compounds as NS5 RDRP inhibitor for dengue virus serotype 1-4 through in silico analysis". In THE 14TH JOINT CONFERENCE ON CHEMISTRY 2019. AIP Publishing, 2020. http://dx.doi.org/10.1063/5.0005236.

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