Amidinoanthracyclines – a new group of potential anti-hepatitis C virus compounds

Krawczyk, Mariusz; Wasowska-Lukawska, Malgorzata; Oszczapowicz, Irena; Boguszewska-Chachulska, Anna M.

doi:10.1515/bc.2009.040

Cited by 21 publications

(23 citation statements)

References 30 publications

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“…There are only a few classes of helicase inhibitors that have been reported to slow HCV RNA replication in cell culture system of viral replication. HCV helicase inhibitors reported to act as antiviral include nucleoside mimics [29] triphenylmethanes [30], acridones [31], [32], amidinoanthracyclines [33], tropolones [34], symmetrical benzimidazoles [35]–[37] and primuline derivatives [38]. A very few studies have been reported targeting NS3 helicase by using flavonoid.…”

Section: Methodology and Principal Findingsmentioning

confidence: 99%

Docking Studies of Pakistani HCV NS3 Helicase: A Possible Antiviral Drug Target

Fatima

Mathew

Suhail³

et al. 2014

PLoS ONE

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The nonstructural protein 3 (NS3) of hepatitis C virus (HCV) helicase is believed to be essential for viral replication and has become an attractive target for the development of antiviral drugs. The study of helicase is useful for elucidating its involvement in positive sense single-stranded RNA virus replication and to serve as templates for the design of novel antiviral drugs. In recent years, several models have been proposed on the conformational change leading to protein movement and RNA unwinding. Some compounds have been recently reported to inhibit the helicase and these include small molecules, RNA aptamers and antibodies. The current study is designed to help gain insights for the consideration of potential inhibitors for Pakistani HCV NS3 helicase protein. We have cloned, expressed and purified HCV NS3 helicase from Pakistani HCV serum samples and determined its 3D structure and employed it further in computational docking analysis to identify inhibitors against HCV genotype 3a (GT3a),including six antiviral key molecules such as quercetin, beta-carotene, resveratrol, catechins, lycopene and lutein. The conformation obtained after docking showed good hydrogen bond (HBond) interactions with best docking energy for quercetin and catechins followed by resveratrol and lutein. These anti-helicase key molecules will offer an alternative attraction to target the viral helicase, due to the current limitation with the interferon resistance treatment and presences of high rate of resistance in anti-protease inhibitor classes.

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Section: Methodology and Principal Findingsmentioning

confidence: 99%

Docking Studies of Pakistani HCV NS3 Helicase: A Possible Antiviral Drug Target

Fatima

Mathew

Suhail³

et al. 2014

PLoS ONE

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“…Some anthracyclines, such as doxorubicin, daunomycin, epirubicin, and nogalamycin, as well as their derivatives, have been identified as NS3 helicase inhibitors [ 24 , 25 ]. Anthracyclines have a hydroxyanthraquinone moiety in their chemical structure, and mitoxantrone, which is also known to inhibit NS3 helicase, is an analogue of hydroxyanthraquinone [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Hydroxyanthraquinones as Novel Inhibitors of Hepatitis C Virus NS3 Helicase

Furuta

Tsubuki

Endoh

et al. 2015

IJMS

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Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. Some anthracyclines are known to be NS3 helicase inhibitors and have a hydroxyanthraquinone moiety in their structures; mitoxantrone, a hydroxyanthraquinone analogue, is also known to inhibit NS3 helicase. Therefore, we hypothesized that the hydroxyanthraquinone moiety alone could also inhibit NS3 helicase. Here, we performed a structure–activity relationship study on a series of hydroxyanthraquinones by using a fluorescence-based helicase assay. Hydroxyanthraquinones inhibited NS3 helicase with IC50 values in the micromolar range. The inhibitory activity varied depending on the number and position of the phenolic hydroxyl groups, and among different hydroxyanthraquinones examined, 1,4,5,8-tetrahydroxyanthraquinone strongly inhibited NS3 helicase with an IC50 value of 6 µM. Furthermore, hypericin and sennidin A, which both have two hydroxyanthraquinone-like moieties, were found to exert even stronger inhibition with IC50 values of 3 and 0.8 µM, respectively. These results indicate that the hydroxyanthraquinone moiety can inhibit NS3 helicase and suggest that several key chemical structures are important for the inhibition.

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“…To date, only a few classes of helicase inhibitors have been reported to slow HCV RNA replication in cells. HCV helicase inhibitors reported to act as antivirals include nucleoside mimics (13), triphenylmethanes (14), acridones (8,15), amidinoanthracyclines (16), tropolones (17), symmetrical benzimidazoles (18–20) and primuline derivatives (21). …”

Section: Introductionmentioning

confidence: 99%

Identification and analysis of hepatitis C virus NS3 helicase inhibitors using nucleic acid binding assays

Mukherjee

Hanson

Shadrick

et al. 2012

Nucleic Acids Research

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Typical assays used to discover and analyze small molecules that inhibit the hepatitis C virus (HCV) NS3 helicase yield few hits and are often confounded by compound interference. Oligonucleotide binding assays are examined here as an alternative. After comparing fluorescence polarization (FP), homogeneous time-resolved fluorescence (HTRF®; Cisbio) and AlphaScreen® (Perkin Elmer) assays, an FP-based assay was chosen to screen Sigma’s Library of Pharmacologically Active Compounds (LOPAC) for compounds that inhibit NS3-DNA complex formation. Four LOPAC compounds inhibited the FP-based assay: aurintricarboxylic acid (ATA) (IC 50 = 1.4 μM), suramin sodium salt (IC 50 = 3.6 μM), NF 023 hydrate (IC 50 = 6.2 μM) and tyrphostin AG 538 (IC 50 = 3.6 μM). All but AG 538 inhibited helicase-catalyzed strand separation, and all but NF 023 inhibited replication of subgenomic HCV replicons. A counterscreen using Escherichia coli single-stranded DNA binding protein (SSB) revealed that none of the new HCV helicase inhibitors were specific for NS3h. However, when the SSB-based assay was used to analyze derivatives of another non-specific helicase inhibitor, the main component of the dye primuline, it revealed that some primuline derivatives (e.g. PubChem CID50930730) are up to 30-fold more specific for HCV NS3h than similarly potent HCV helicase inhibitors.

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Amidinoanthracyclines – a new group of potential anti-hepatitis C virus compounds

Cited by 21 publications

References 30 publications

Docking Studies of Pakistani HCV NS3 Helicase: A Possible Antiviral Drug Target

Docking Studies of Pakistani HCV NS3 Helicase: A Possible Antiviral Drug Target

Identification of Hydroxyanthraquinones as Novel Inhibitors of Hepatitis C Virus NS3 Helicase

Identification and analysis of hepatitis C virus NS3 helicase inhibitors using nucleic acid binding assays

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