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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

12 Issues per year


IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

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ISSN
1437-4315
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Volume 390, Issue 4

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

Mariusz Krawczyk / Malgorzata Wasowska-Lukawska / Irena Oszczapowicz / Anna M. Boguszewska-Chachulska
  • 4Institute of Biochemistry and Biophysics PAS, Pawinskiego 5a, 02-106 Warsaw, Poland and Genomed Ltd. Poland, Chelmska 30/34, 00-725 Warsaw, Poland
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Published Online: 2009-02-07 | DOI: https://doi.org/10.1515/BC.2009.040

Abstract

Hepatitis C virus (HCV) infections represent one of the major and still unresolved health problems because current therapy is effective in only 50–80% of cases, depending on viral genotype. A large group of amidinoanthracyclines, with decreased acute toxicity and cardiotoxicity compared to the parent antibiotics, was tested in a high-throughput fluorometric HCV helicase assay. Here, we report the selection of more than 50 potent inhibitors of helicase activity that inhibit the enzyme with IC50 values in the range of 0.03–10 μm; four of these compounds are the most potent inhibitors of helicase activity described in the literature. The activity of these inhibitors is highly dependent on their chemical structure, mainly on the substituent at the amidino carbon atom and on the orientation of the hydroxyl group at the 4′ position of the daunosamine moiety. The most effective compounds act not solely via intercalation into the double-stranded DNA substrate, but also compete with the enzyme for access to the substrate, impeding formation of the active helicase complex. Selected amidinoanthracyclines were tested in the subgenomic HCV replicon system. These experiments confirmed the antiviral activity of two selected inhibitors (EC50 values below 0.2 μm with selectivity indices of 19 and 33) and proved that they may be considered as potential anti-HCV drugs.

Keywords: amidinoanthracyclines; anthracycline derivatives; anti-HCV; hepatitis C virus; NS3 helicase; subgenomic HCV replicon

About the article

Corresponding author


Received: 2008-08-26

Accepted: 2009-01-26

Published Online: 2009-02-07

Published in Print: 2009-04-01


Citation Information: Biological Chemistry, Volume 390, Issue 4, Pages 351–360, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2009.040.

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