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J Hepatol. 2015 Oct;63(4):813-21. doi: 10.1016/j.jhep.2015.06.002. Epub 2015 Jun 10.

Soraphen A: A broad-spectrum antiviral natural product with potent anti-hepatitis C virus activity.

Author information

1
Molecular Virology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
2
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
3
TWINCORE - Institute of Experimental Virology, Centre for Experimental and Clinical Infection Research, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany.
4
German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany; ReMediES, Department of General, Visceral and Transplantation Surgery, German Centre for Infection Research Hannover Medical School, Hannover, Germany.
5
Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6
Helmholtz Institut für Pharmazeutische Forschung Saarland, Saarbrücken, Germany.
7
Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
8
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; German Centre for Infection Research (DZIF), partner site Heidelberg, Germany.
9
Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
10
Molecular Virology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: juana.diez@upf.edu.

Abstract

BACKGROUND & AIMS:

Soraphen A (SorA) is a myxobacterial metabolite that inhibits the acetyl-CoA carboxylase, a key enzyme in lipid biosynthesis. We have previously identified SorA to efficiently inhibit the human immunodeficiency virus (HIV). The aim of the present study was to evaluate the capacity of SorA and analogues to inhibit hepatitis C virus (HCV) infection.

METHODS:

SorA inhibition capacity was evaluated in vitro using cell culture derived HCV, HCV pseudoparticles and subgenomic replicons. Infection studies were performed in the hepatoma cell line HuH7/Scr and in primary human hepatocytes. The effects of SorA on membranous web formation were analysed by electron microscopy.

RESULTS:

SorA potently inhibits HCV infection at nanomolar concentrations. Obtained EC50 values were 0.70 nM with a HCV reporter genome, 2.30 nM with wild-type HCV and 2.52 nM with subgenomic HCV replicons. SorA neither inhibited HCV RNA translation nor HCV entry, as demonstrated with subgenomic HCV replicons and HCV pseudoparticles, suggesting an effect on HCV replication. Consistent with this, evidence was obtained that SorA interferes with formation of the membranous web, the site of HCV replication. Finally, a series of natural and synthetic SorA analogues helped to establish a first structure-activity relationship.

CONCLUSIONS:

SorA has a very potent anti-HCV activity. Since it also interferes with the membranous web formation, SorA is an excellent tool to unravel the mechanism of HCV replication.

KEYWORDS:

Broad-spectrum antiviral; HCV replication inhibitor; HCV/HIV co-infection; Lipid metabolism; Natural product

PMID:
26070407
DOI:
10.1016/j.jhep.2015.06.002
[Indexed for MEDLINE]

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