title: Therapeutic potential of furin inhibitors for the chronic infection of hepatitis B virus.
abstract: OBJECTIVE
  Hepatitis B e antigen (HBeAg) is essential for the development of chronic hepatitis B virus (HBV) infection. Furin, a proprotein convertase, plays a key role in processing of HBeAg precursor into maturated HBeAg. For these reasons, the therapeutic potential of furin inhibition for chronic HBV infection was studied.
  
  
  METHODS
  The effects of furin inhibitor I (decanoyl-RVKR-chloromethylketone, CMK) and furin inhibitor II (hexa-D-arginine, D6R) on HBeAg secretion, the destination of unprocessed precursor and cellular secretory functions were comparatively investigated.
  
  
  RESULTS
  CMK and D6R significantly decreased the supernatant level of HBeAg and increased the intracellular level of HBeAg precursor in HepG2.2.15 cells in vitro. The accumulated HBeAg precursor was not found to be retro-transported into the cytosol to inhibit HBV replication as expected, but was found to be expressed on the cell surface, where it may be more convenient to mediate host immune responses. Furthermore, these inhibitors at effective concentrations were not found to interfere with the maturations of albumin and prothrombin. Compared with CMK, D6R was suboptimal in effectiveness; however, D6R neither enhanced HBV replication through the accumulation of cytosolic HBcAg nor did it cause severe cell damage in an elongated safety analyses.
  
  
  CONCLUSIONS
  Furin inhibitors CMK and D6R reduce HBeAg secretion and increase cell surface expression of the HBeAg precursor in HepG2.2.15 cells. Novel furin inhibitors or modified forms of D6R may promote the reduction of immune tolerance and the elimination of infected hepatocytes in patients with chronic HBV infection.
authors.affiliation: Hepatology Laboratory, The Hospital for Liver Disease, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yan J
authors.initials: YJ
authors.lastname: Pang
authors.forename: Xiao J
authors.initials: XJ
authors.lastname: Tan
authors.forename: Dong M
authors.initials: DM
authors.lastname: Li
authors.forename: Zi H
authors.initials: ZH
authors.lastname: Zheng
authors.forename: Rui X
authors.initials: RX
authors.lastname: Lei
authors.forename: Xiao M
authors.initials: XM
authors.lastname: Peng
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology* / Q000633:toxicity; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D045683:Furin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology* / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D011516:Prothrombin / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D000075462:Serum Albumin, Human; D014162:Transfection
chemical_list: C422455:ALB protein, human; D000590:Amino Acid Chloromethyl Ketones; D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D009842:Oligopeptides; D012709:Serum Albumin; C460143:decanoylRVKRchloromethylketone; D011516:Prothrombin; D045683:Furin; D046988:Proteasome Endopeptidase Complex; D000075462:Serum Albumin, Human
keywords: Hepatitis B virus; chronic hepatitis B; furin; hepatitis B e antigen; maturation; proprotein convertase; protease inhibitor