title: Inhibition of hepatitis C virus replication by semi-synthetic derivatives of glycopeptide antibiotics.
abstract: OBJECTIVE
  Some semi-synthetic derivatives of glycopeptide antibiotics have been shown to exert in vitro antiviral activity against HIV and coronaviruses. Here we report and characterize the in vitro anti-hepatitis C virus (HCV) activity of several semi-synthetic derivatives of teicoplanin aglycone.
  
  
  METHODS
  Anti-HCV activity was analysed in: (i) three different subgenomic HCV replicon systems using a luciferase or quantitative RT-PCR (qRT-PCR) assay; and (ii) an infectious HCV cell culture system by means of qRT-PCR and immunofluorescence assays.
  
  
  RESULTS
  Several teicoplanin aglycone derivatives elicited selective anti-HCV activity in replicons as well as infectious cell culture systems, with LCTA-949 being the most potent derivative. LCTA-949 proved, in contrast to several directly acting antivirals for HCV, efficient in clearing cells of their replicons. When LCTA-949 was combined with HCV protease or polymerase inhibitors an overall additive effect was observed. Likewise, LCTA-949 was equipotent against wild-type replicons as well as against replicons resistant to polymerase and protease inhibitors. Following up to 4 months of selective pressure, no drug-resistant replicons were selected. When combined with the HCV NS3 protease inhibitor VX-950, LCTA-949 prevented the development of VX-950-resistant variants.
  
  
  CONCLUSIONS
  Semi-synthetic derivatives of teicoplanin aglycone constitute a novel class of HCV replication inhibitors that are not cross-resistant with various HCV protease and polymerase inhibitors and in particular are potent in clearing hepatoma cells of their replicons. This class of molecules also provides a good tool to obtain novel insights into the replication cycle of HCV and into cellular factors/processes that are crucial for viral replication.
authors: Rega Institute for Medical Research, K.U. Leuven, B-3000 Leuven, Belgium.
authors: Susan
authors: S
authors: Obeid
authors: Svetlana S
authors: SS
authors: Printsevskaya
authors: Eugenia N
authors: EN
authors: Olsufyeva
authors: Kai
authors: K
authors: Dallmeier
authors: David
authors: D
authors: Durantel
authors: Fabien
authors: F
authors: Zoulim
authors: Maria N
authors: MN
authors: Preobrazhenskaya
authors: Johan
authors: J
authors: Neyts
authors: Jan
authors: J
authors: Paeshuyse
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter / Q000235:genetics; D006020:Glycopeptides / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008826:Microbial Sensitivity Tests / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013194:Staining and Labeling / Q000379:methods; D017334:Teicoplanin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014776:Virus Cultivation; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D006020:Glycopeptides; D017334:Teicoplanin; C063101:teicoplanin aglycone; D008156:Luciferases