title: Targeting the non-structural proteins of hepatitis C virus: beyond hepatitis C virus protease and polymerase.
abstract: BACKGROUND
  Chronic hepatitis C virus (HCV) infection is a main cause of cirrhosis of the liver and hepatocellular carcinoma. The standard of care is a combination of pegylated interferon with ribavirin, a regimen that has undesirable side effects and is frequently ineffective. Compounds targeting HCV protease and polymerase are in late-stage clinical trials and have been extensively reviewed elsewhere.
  
  
  OBJECTIVE
  To review and evaluate the progress towards finding novel HCV antivirals targeting HCV proteins beyond the already precedented NS3 protease and NS5B polymerase.
  
  
  METHODS
  Searches of CAplus and Medline databases were combined with information from key conferences. This review focuses on NS2/3 serine protease, NS3 helicase activity and the non-structural proteins 4A, 4B and 5A.
  
  
  CONCLUSIONS
  Use of the replicon model of HCV replication and biochemical assays of specific targets has allowed screening of vast libraries of compounds, but resulted in clinical candidates from only NS4A and NS5A. The field is hindered by a lack of good chemical matter that inhibits the remaining enzymes from HCV, and a lack of understanding of the functions of non-structural proteins 4A, 4B and 5A in the replication of HCV.
authors.affiliation: Associate Research Fellow Pfizer Global Research and Development, Antiviral Biology, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK +44 130 464 6387 ; +44 130 465 1819 ; tod.holler@pfizer.com.
authors.forename: Tod P
authors.initials: TP
authors.lastname: Holler
authors.forename: Tanya
authors.initials: T
authors.lastname: Parkinson
authors.forename: David C
authors.initials: DC
authors.lastname: Pryde