title: Soraphen A: A broad-spectrum antiviral natural product with potent anti-hepatitis C virus activity.
abstract: OBJECTIVE
  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.
authors.affiliation: Molecular Virology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: George
authors.initials: G
authors.lastname: Koutsoudakis
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Inés
authors.initials: I
authors.lastname: Romero-Brey
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Berger
authors.affiliation: Molecular Virology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Pérez-Vilaró
authors.affiliation: 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.
authors.forename: Paula
authors.initials: P
authors.lastname: Monteiro Perin
authors.affiliation: 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.
authors.forename: Florian Wolfgang Rudolf
authors.initials: FW
authors.lastname: Vondran
authors.affiliation: Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kalesse
authors.affiliation: Helmholtz Institut für Pharmazeutische Forschung Saarland, Saarbrücken, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harmrolfs
authors.affiliation: Helmholtz Institut für Pharmazeutische Forschung Saarland, Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Javier P
authors.initials: JP
authors.lastname: Martinez
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; German Centre for Infection Research (DZIF), partner site Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Brönstrup
authors.affiliation: Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyerhans
authors.affiliation: Molecular Virology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: juana.diez@upf.edu.
authors.forename: Juana
authors.initials: J
authors.lastname: Díez
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects* / Q000648:ultrastructure / Q000821:virology; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008854:Microscopy, Electron; D012367:RNA, Viral / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D018942:Macrolides; D012367:RNA, Viral; C086151:soraphen A
keywords: Broad-spectrum antiviral; HCV replication inhibitor; HCV/HIV co-infection; Lipid metabolism; Natural product