scholarly journals Exploration of acetanilide derivatives of 1-(ω-phenoxyalkyl)uracils as novel inhibitors of Hepatitis C Virus replication

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Andrea Magri ◽  
Alexander A. Ozerov ◽  
Vera L. Tunitskaya ◽  
Vladimir T. Valuev-Elliston ◽  
Ahmed Wahid ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
De Novo ◽  
Antiviral Agents ◽  
Public Health Problem ◽  
Pyrimidine Ring ◽  
Major Public Health Problem ◽  
Virus Genotype ◽  
Biochemical Assays

Abstract Hepatitis C Virus (HCV) is a major public health problem worldwide. While highly efficacious directly-acting antiviral agents have been developed in recent years, their high costs and relative inaccessibility make their use limited. Here, we describe new 1-(ω-phenoxyalkyl)uracils bearing acetanilide fragment in 3 position of pyrimidine ring as potential antiviral drugs against HCV. Using a combination of various biochemical assays and in vitro virus infection and replication models, we show that our compounds are able to significantly reduce viral genomic replication, independently of virus genotype, with their IC50 values in the nanomolar range. We also demonstrate that our compounds can block de novo RNA synthesis and that effect is dependent on a chemical structure of the compounds. A detailed structure-activity relationship revealed that the most active compounds were the N3-substituted uracil derivatives containing 6-(4-bromophenoxy)hexyl or 8-(4-bromophenoxy)octyl fragment at N1 position.

scholarly journals Hepatitis C Virus Genotype 5a Subgenomic Replicons for Evaluation of Direct-Acting Antiviral Agents

2014 ◽  
Vol 58 (9) ◽  
pp. 5386-5394 ◽  
Author(s):  
Constance N. Wose Kinge ◽  
Christine Espiritu ◽  
Nishi Prabdial-Sing ◽  
Nomathamsaqa Patricia Sithebe ◽  
Mohsan Saeed ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonstructural Protein ◽  
Antiviral Agents ◽  
Rna Replication ◽  
Firefly Luciferase ◽  
Hcv Rna ◽  
Virus Genotype ◽  
Subgenomic Replicon

ABSTRACTHepatitis C virus (HCV) exists as six major genotypes that differ in geographical distribution, pathogenesis, and response to antiviral therapy.In vitroreplication systems for all HCV genotypes except genotype 5 have been reported. In this study, we recovered genotype 5a full-length genomes from four infected voluntary blood donors in South Africa and established a G418-selectable subgenomic replicon system using one of these strains. The replicon derived from the wild-type sequence failed to replicate in Huh-7.5 cells. However, the inclusion of the S2205I amino acid substitution, a cell culture-adaptive change originally described for a genotype 1b replicon, resulted in a small number of G418-resistant cell colonies. HCV RNA replication in these cells was confirmed by quantification of viral RNA and detection of the nonstructural protein NS5A. Sequence analysis of the viral RNAs isolated from multiple independent cell clones revealed the presence of several nonsynonymous mutations, which were localized mainly in the NS3 protein. These mutations, when introduced back into the parental backbone, significantly increased colony formation. To facilitate convenient monitoring of HCV RNA replication levels, the mutant with the highest replication level was further modified to express a fusion protein of firefly luciferase and neomycin phosphotransferase. Using such replicons from genotypes 1a, 1b, 2a, 3a, 4a, and 5a, we compared the effects of various HCV inhibitors on their replication. In conclusion, we have established anin vitroreplication system for HCV genotype 5a, which will be useful for the development of pan-genotype anti-HCV compounds.

scholarly journals Impact of Preexisting Hepatitis C Virus Genotype 6 NS3, NS5A, and NS5B Polymorphisms on theIn VitroPotency of Direct-Acting Antiviral Agents

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Fiona McPhee ◽  
Joseph Ueland ◽  
Vincent Vellucci ◽  
Scott Bowden ◽  
William Sievert ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Virologic Response ◽  
Virus Genotype ◽  
Direct Acting Antiviral ◽  
East And Southeast Asia ◽  
Direct Acting ◽  
Ns3 Protease

ABSTRACTHCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAAin vitropotency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (<4%). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S).In vitrosusceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90% effective concentration [EC90] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC90range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC90[L28A-R30S] of ≥720 nM or EC90[L28T-R30S] of ≥128 nM against tested DAAs) or as L28T-L31I (EC90[tested DAAs] of >5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.

scholarly journals In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Ernest Asante-Appiah ◽  
Rong Liu ◽  
Stephanie Curry ◽  
Patricia McMonagle ◽  
Sony Agrawal ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
De Novo ◽  
Antiviral Agents ◽  
Cross Resistance ◽  
Hcv Rna ◽  
Direct Acting Antiviral ◽  
Direct Acting

ABSTRACT Inhibition of NS5A has emerged as an attractive strategy to intervene in hepatitis C virus (HCV) replication. Ruzasvir (formerly MK-8408) was developed as a novel NS5A inhibitor to improve upon the potency and barrier to resistance of early compounds. Ruzasvir inhibited HCV RNA replication with 50% effective concentrations (EC50s) of 1 to 4 pM in Huh7 or Huh7.5 cells bearing replicons for HCV genotype 1 (GT1) to GT7. The antiviral activity was modestly (10-fold) reduced in the presence of 40% normal human serum. The picomolar potency in replicon cells extended to sequences of clinical isolates available in public databases that were synthesized and tested as replicons. In GT1a, ruzasvir inhibited common NS5A resistance-associated substitutions (RASs), with the exception of M28G. De novo resistance selection studies identified pathways with certain amino acid substitutions at residues 28, 30, 31, and 93 across genotypes. Substitutions at position 93 were more common in GT1 to -4, while changes at position 31 emerged frequently in GT5 and -6. With the exception of GT4, the reintroduction of selected RASs conferred a ≥100-fold potency reduction in the antiviral activity of ruzasvir. Common RASs from other classes of direct-acting antiviral agents (DAAs) did not confer cross-resistance to ruzasvir. The interaction of ruzasvir with an NS3/4A protease inhibitor (grazoprevir) and an NS5B polymerase prodrug (uprifosbuvir) was additive to synergistic, with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.

scholarly journals In Vitro Activity and Preclinical Profile of TMC435350, a Potent Hepatitis C Virus Protease Inhibitor

2009 ◽  
Vol 53 (4) ◽  
pp. 1377-1385 ◽  
Author(s):  
Tse-I Lin ◽  
Oliver Lenz ◽  
Gregory Fanning ◽  
Thierry Verbinnen ◽  
Frédéric Delouvroy ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Intestinal Tract ◽  
Pharmacokinetic Profile ◽  
Absolute Bioavailability ◽  
Time Curve ◽  
Biochemical Assays ◽  
Single Oral Administration ◽  
Half Maximal Effective Concentration

ABSTRACT The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.5 and 0.4 nM, respectively, were determined. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC50) of 8 nM and a selectivity index of 5,875. The compound was synergistic with alpha interferon and an NS5B inhibitor in the replicon model and additive with ribavirin. In rats, TMC435350 was extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability was 44% after a single oral administration. Compound concentrations detected in both plasma and liver at 8 h postdosing were above the EC99 value measured in the replicon. In conclusion, given the selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and the favorable pharmacokinetic profile, TMC435350 has been selected for clinical development.

scholarly journals Treatment of hepatitis C virus genotype 3 infection with direct-acting antiviral agents

2016 ◽  
Vol 49 (11) ◽  
Author(s):  
L.P. Zanaga ◽  
N. Miotto ◽  
L.C. Mendes ◽  
R.S.B. Stucchi ◽  
A.G. Vigani
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Genotype 3 ◽  
Virus Genotype ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

scholarly journals Cross-Genotypic Examination of Hepatitis C Virus Polymerase Inhibitors Reveals a Novel Mechanism of Action for Thumb Binders

2014 ◽  
Vol 58 (12) ◽  
pp. 7215-7224 ◽  
Author(s):  
Auda A. Eltahla ◽  
Enoch Tay ◽  
Mark W. Douglas ◽  
Peter A. White
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
De Novo ◽  
Hcv Rna ◽  
Amino Acid Residues ◽  
Recombinant Enzymes ◽  
Polymerase Inhibitors ◽  
Binding Pockets ◽  
Direct Acting

ABSTRACTDirect-acting antivirals (DAAs) targeting proteins encoded by the hepatitis C virus (HCV) genome have great potential for the treatment of HCV infections. However, the efficacy of DAAs designed to target genotype 1 (G1) HCV against non-G1 viruses has not been characterized fully. In this study, we investigated the inhibitory activities of nonnucleoside inhibitors (NNIs) against the HCV RNA-dependent RNA polymerase (RdRp). We examined the ability of six NNIs to inhibit G1b, G2a, and G3a subgenomic replicons in cell culture, as well asin vitrotranscription by G1b and G3a recombinant RdRps. Of the six G1 NNIs, only the palm II binder nesbuvir demonstrated activity against G1, G2, and G3 HCV, in both replicon and recombinant enzyme models. The thumb I binder JTK-109 also inhibited G1b and G3a replicons and recombinant enzymes but was 41-fold less active against the G2a replicon. The four other NNIs, which included a palm I binder (setrobuvir), two thumb II binders (lomibuvir and filibuvir), and a palm β-hairpin binder (tegobuvir), all showed at least 40-fold decreases in potency against G2a and G3a replicons and the G3a enzyme. This antiviral resistance was largely conferred by naturally occurring amino acid residues in the G2a and G3a RdRps that are associated with G1 resistance. Lomibuvir and filibuvir (thumb II binders) inhibited primer-dependent but notde novoactivity of the G1b polymerase. Surprisingly, these compounds instead specifically enhanced thede novoactivity at concentrations of ≥100 nM. These findings highlight a potential differential mode of RdRp inhibition for HCV NNIs, depending on their prospective binding pockets, and also demonstrate a surprising enhancement ofde novoactivity for thumb RdRp binders. These results also provide a better understanding of the antiviral coverage for these polymerase inhibitors, which will likely be used in future combinational interferon-free therapies.

scholarly journals In VitroandIn VivoAntiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

2014 ◽  
Vol 59 (2) ◽  
pp. 988-997 ◽  
Author(s):  
Tami Pilot-Matias ◽  
Rakesh Tripathi ◽  
Daniel Cohen ◽  
Isabelle Gaultier ◽  
Tatyana Dekhtyar ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Cross Resistance ◽  
Hcv Rna ◽  
Genotype 1 ◽  
Common Amino Acid ◽  
Direct Acting Antiviral ◽  
Genotype 1A

ABSTRACTThe development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively.In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.)

Hepatitis C virus resistance to interferon therapy: an alarming situation

2014 ◽  
Vol 9 (12) ◽  
pp. 1155-1167
Author(s):  
Sobia Kanwal ◽  
Tariq Mahmood
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Social Factors ◽  
Molecular Mechanisms ◽  
Public Health Problem ◽  
Pegylated Interferon ◽  
Host Factors ◽  
Interferon Α ◽  
Major Public Health Problem ◽  
Choice Of Treatment

AbstractHepatitis C virus is presently a major public health problem across the globe. The main objective in treating hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). Interferon-α (IFN-α) and pegylated interferon (PegIFN) in combination with Ribavirin (RBV) are the choice of treatment nowadays against chronic hepatitis C. There are several mechanisms evolved by the hepatitis C virus that facilitate the persistence of virus and further lead the patient’s status as non responder. Various factors involved in patient’s lack ofresponse to the therapy include: (1) viral factors, (2) host factors, (3) molecular mechanisms related to the lack of response and (4) social factors. Herein we have made an attempt to summarize all the related predictors of drug resistance in one article so that the future polices can be planned to overcome this obstacle and potential therapies can be designed by considering these factors.

Prevalence and Distribution of Hepatitis C Virus in Iranian Drug User: Systematic Review and Meta-Analysis Study

2020 ◽  
Author(s):  
Alireza Najimi-Varzaneh ◽  
Mohammad Gholami-Fesharaki
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug User ◽  
Drug Users ◽  
Meta Analysis ◽  
Scientific Information ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Analysis Study ◽  
Hcv Prevalence

Context: Hepatitis C, as a major public health problem, has serious complications and drug users are the highest risk group for it.Objectives: As the importance of this subject, the current study has been done to estimate the pooled prevalence  and distribution of hepatitis c virus in Iranian Drug User.Evidence Acquisition: Articles were identified through international searching databases including PubMed, Scopus, Elsevier, Google Scholar and Web of Science and Iranian scientific information database (SID), Health. barakatkns, IranDoc, Civilica and MagIran. We reviewed systematically all studies reporting the prevalence of HCV Iranian Drug User.Results: 227 records were identified by the electronic search, of which 62 studies were identified as relevant  papers which were meta-analyzed for the pooled HCV prevalence. Overall, prevalence of HCV  was 42.01 %( 36.83%-47.20%) in Iranian drug user.Conclusion: Our meta-analysis study showed that HCV prevalence is high in drug users in Iran. With respect to the high prevalence of Hepatitis C among Drug User, ongoing preventive actions for this group are recommended.

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