Fluoroquinolones Inhibit HCV by Targeting its Helicase

Khan, Irfan; Siddiqui, Sammer; Rehmani, Sadiq; Kazmi, Shahana Urooj; Ali, Sajid

doi:10.3851/imp1943

Cited by 7 publications

(10 citation statements)

References 7 publications

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“…Huh7.5 cells were cultured in Dulbecco's modified Eagle medium (DMEM, pH 7–7.5) containing 10% fetal bovine serum (FBS) and 1% streptomycin–penicillin solution at 37°C with 5% CO 2 (Khan, Siddiqui, Rehmani, Kazmi, & Ali, 2012).…”

Section: Methodsmentioning

confidence: 99%

Rational drug discovery: Ellagic acid as a potent dual‐target inhibitor against hepatitis C virus genotype 3 (HCV G3) NS3 enzymes

et al. 2020

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Structure-based virtual screening (SBVS) has served as a popular strategy for rational drug discovery. In this study, we aimed to discover novel benzopyran-based inhibitors that targeted the NS3 enzymes (NS3/4A protease and NS3 helicase) of HCV G3 using a combination of in silico and in vitro approaches. With the aid of SBVS, six novel compounds were discovered to inhibit HCV G3 NS3/4A protease and two phytochemicals (ellagic acid and myricetin) were identified as dual-target inhibitors that inhibited both NS3/4A protease and NS3 helicase in vitro (IC 50 = 40.37 ± 5.47 nm and 6.58 ± 0.99 µm, respectively). Inhibitory activities against the replication of HCV G3 replicons were further assessed in a cell-based system with four compounds showed dose-dependent inhibition. Compound P8 was determined to be the most potent compound from the cell-based assay with an EC 50 of 19.05 µm. The dual-target inhibitor, ellagic acid, was determined as the second most potent (EC 50 = 32.37 µm) and the most selective in its inhibitory activity against the replication of HCV replicons, without severely affecting the viability of the host cells (selectivity index > 6.18).

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Section: Methodsmentioning

confidence: 99%

Rational drug discovery: Ellagic acid as a potent dual‐target inhibitor against hepatitis C virus genotype 3 (HCV G3) NS3 enzymes

et al. 2020

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“…Previously determined in vitro IC50 (µM) for each fluoroquinolone, except for Levofloxacin (shown as –) is also given. Ligand (top 10 poses) IC 50 (uM) 12 Genotype 1a (MolDock score) Genotype 1b (MolDock score) Genotype 2b (MolDock score) Genotype 3a (MolDock score) Balofloxacin 1.37 − 99 − 105 − 112 − 104 Ciprofloxacin 2.99 − 104 − 115 − 108 − 110 Enrofloxacin 1.15 − 101 − 102 − 107 − 122 Levofloxacin – − 90 − 116 − 106 − 102 Lomefloxacin 1.14 − 96 − 91 − 102 − 99 Ofloxacin 1.47 − 88 − 97 − 107 − 100 Pefloxacin 4.22 − 103 − 87 − 102 − 110 Sparfloxacin 1.22 − 92 − 88 − 104 − 92 …”

Section: Resultsmentioning

confidence: 99%

“…Previously reported studies from our group and others have demonstrated that fluoroquinolones actively inhibit HCV replication by targeting viral protein NS3helicase. Since bacterial gyrase and viral helicase are functionally homologous; it has been hypothesized that fluoroquinolones inhibit viral helicases in a similar fashion 12 – 15 . To explore how genotype-specific variations in HCV NS3 might affect the inhibition of its activity by fluoroquinolones, we have investigated the effect of active site residue variations in HCV genotype 1a, 1b, 2b and 3a on NS3-fluoroquinolone interactions.…”

Section: Introductionmentioning

confidence: 99%

An in silico approach to analyze HCV genotype-specific binding-site variation and its effect on drug–protein interaction

Khalid

Anwar

Raees

et al. 2020

Sci Rep

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Genotype variation in viruses can affect the response of antiviral treatment. Several studies have established approaches to determine genotype-specific variations; however, analyses to determine the effect of these variations on drug–protein interactions remain unraveled. We present an in-silico approach to explore genotype-specific variations and their effect on drug–protein interaction. We have used HCV NS3 helicase and fluoroquinolones as a model for drug–protein interaction and have investigated the effect of amino acid variations in HCV NS3 of genotype 1a, 1b, 2b and 3a on NS3-fluoroquinolone interaction. We retrieved 687, 667, 101 and 248 nucleotide sequences of HCV NS3 genotypes 1a, 1b, 2b, and 3a, respectively, and translated these into amino acid sequences and used for genotype variation analysis, and also to construct 3D protein models for 2b and 3a genotypes. For 1a and 1b, crystal structures were used. Drug–protein interactions were determined using molecular docking analyses. Our results revealed that individual genotype-specific HCV NS3 showed substantial sequence heterogeneity that resulted in variations in docking interactions. We believe that our approach can be extrapolated to include other viruses to study the clinical significance of genotype-specific variations in drug–protein interactions.

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“…Twelve fluoroquinolone derivatives were reported to inhibit HCV replication and HCV NS3 helicase activity in cultured cells. Among them, fleroxacin, difloxacin, ofloxacin, 8-quinolinol, enoxacin, lumifloxacin and flumiquine were reported to inhibit HCV with IC 50 of 3.8, 2.5, 2.4, 2.2, 1.0, 1.9 and 1.7 μM, respectively [49].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hepatitis C virus replication by chalepin and pseudane IX isolated from Ruta angustifolia leaves

et al. 2014

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Hepatitis C virus (HCV) infection is highly prevalent among global populations, with an estimated number of infected patients being 170 million. Approximately 70-80% of patients acutely infected with HCV will progress to chronic liver disease, such as liver cirrhosis and hepatocellular carcinoma, which is a substantial cause of morbidity and mortality worldwide. New therapies for HCV infection have been developed, however, the therapeutic efficacies still need to be improved. Medicinal plants are promising sources for antivirals against HCV. A variety of plants have been tested and proven to be beneficial as antiviral drug candidates against HCV. In this study, we examined extracts, their subfractions and isolated compounds of Ruta angustifolia leaves for antiviral activities against HCV in cell culture. We isolated six compounds, chalepin, scopoletin, γ-fagarine, arborinine, kokusaginine and pseudane IX. Among them, chalepin and pseudane IX showed strong anti-HCV activities with 50% inhibitory concentration (IC 50 ) of 1.7 ± 0.5 and 1.4 ± 0.2 μg/ml, respectively, without apparent cytotoxicity. Their anti-HCV activities were stronger than that of ribavirin (2.8 ± 0.4 μg/ml), which has been widely used for the treatment of HCV infection. Mode-of-action analyses revealed that chalepin and pseudane IX inhibited HCV at the post-entry step and decreased the levels of HCV RNA replication and viral protein synthesis. We also observed that arborinine, kokusaginine and γ-fagarine possessed moderate levels of anti-HCV activities with IC 50 values being 6.4 ± 0.7, 6.4 ± 1.6 and 20.4 ± 0.4 μg/ml, respectively, whereas scopoletin did not exert significant anti-HCV activities at 30 μg/ml.

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Fluoroquinolones Inhibit HCV by Targeting its Helicase

Cited by 7 publications

References 7 publications

Rational drug discovery: Ellagic acid as a potent dual‐target inhibitor against hepatitis C virus genotype 3 (HCV G3) NS3 enzymes

Rational drug discovery: Ellagic acid as a potent dual‐target inhibitor against hepatitis C virus genotype 3 (HCV G3) NS3 enzymes

An in silico approach to analyze HCV genotype-specific binding-site variation and its effect on drug–protein interaction

Inhibition of hepatitis C virus replication by chalepin and pseudane IX isolated from Ruta angustifolia leaves

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