title: A novel small-molecule inhibitor of hepatitis C virus replication acts by suppressing signal transducer and activator of transcription 3.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) infects hepatocytes and causes liver damage. The aim of this study was to identify new classes of host-targeting anti-HCV compounds that may provide novel approaches for antiviral treatment regimens.
  
  
  METHODS
  Cell culture-derived HCV (HCVcc), replicons and pseudoparticles were used in combination with high-throughput screening, reporter gene assays and cytotoxicity and signalling pathway analyses.
  
  
  RESULTS
  A small-molecule inhibitor of HCV, N-(cyclopropyl(phenyl)methyl)thieno[2,3-d]pyrimidin-4-amine, designated IB-32, was identified by screening a compound library with a Jc1-luc HCVcc assay. By using various virus models, HCV replication was identified as the predominant step of IB-32's action. IB-32 inhibited HCVcc (genotype 2a) and HCV replicons (genotype 1b) at low nanomolar ranges (with IC50s of 40 ± 8 and 100 ± 15 nM, respectively). IB-32 was found to be non-toxic when tested against a panel of human cell lines in vitro at the effective antiviral dose. Mechanistically, IB-32 strongly inhibited STAT3 (Tyr705) phosphorylation, a necessary cellular factor for HCV replication and a pivotal therapeutic target for multiple cancers. Furthermore, the inhibition of HCV replication by IB-32 was augmented in cells with STAT3 knockdown. In contrast, the inhibitory effect of IB-32 was attenuated in cells overexpressing a constitutively active form of STAT3.
  
  
  CONCLUSIONS
  The results presented here identify a promising STAT3-targeting anti-HCV therapeutic candidate. This novel small molecule could be further optimized and developed for use as both an antiviral and an anti-cancer drug.
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Yuqiang
authors: Y
authors: Niu
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Youhui
authors: Y
authors: Si
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Yan
authors: Y
authors: Li
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Xiaojing
authors: X
authors: Chi
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Xiang
authors: X
authors: Li
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Xiuying
authors: X
authors: Liu
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Duan
authors: D
authors: Li
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Min
authors: M
authors: Cheng
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Jingjing
authors: J
authors: Fan
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Shuyi
authors: S
authors: Si
authors: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China wyang@ipb.pumc.edu.cn.
authors: Wei
authors: W
authors: Yang
mesh_terms: D000998:Antiviral Agents / Q000302:isolation & purification* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D050796:STAT3 Transcription Factor
keywords: Hepatitis C virus; IB-32; N-(cyclopropyl(phenyl)methyl)thieno[2,3-d]pyrimidin-4-amine; STAT3; inhibitor