title: Inhibition of proprotein convertase 5/6 activity: potential for nonhormonal women-centered contraception.
abstract: BACKGROUND
  Proprotein convertase 5/6 (PC6) is critical for endometrial epithelial receptivity and stromal cell decidualization for embryo implantation in women. We hypothesized that inhibiting PC6 could block implantation for contraception. The aim of this study was to prove this concept using human cell models and rabbits.
  
  
  METHODS
  A potential PC6 inhibitor, C1239-PEG-Poly R, was biochemically confirmed to be a potent PC6 inhibitor. The potential contraceptive action of the inhibitor was then tested in decidualization of primary human endometrial stromal cells in a human trophoblast spheroid attachment model and in vivo in rabbits.
  
  
  RESULTS
  The PC6 inhibitor C1239-PEG-Poly R inhibited in a dose-dependent manner both decidualization and spheroid attachment. Vaginal delivery of 200 μL of the inhibitor at a final concentration of 5 mM to rabbits over a 3-day period starting 6 days after mating resulted in a 60% decrease in implantation and, hence, pregnancy.
  
  
  CONCLUSIONS
  This study presents proof of concept that PC6 inhibition has the potential to block embryo implantation, providing nonhormonal contraception for women.
authors.affiliation: Prince Henry's Institute of Medical Research, Clayton VIC, Australia. Mo.aljofan@monash.edu
authors.forename: Mohamad
authors.initials: M
authors.lastname: Aljofan
authors.forename: Harmeet
authors.initials: H
authors.lastname: Singh
authors.forename: Huiting
authors.initials: H
authors.lastname: Ho
authors.forename: Shuwu
authors.initials: S
authors.lastname: Xie
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Zhaogui
authors.initials: Z
authors.lastname: Sun
authors.forename: Xiangjie
authors.initials: X
authors.lastname: Guo
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Guiying
authors.initials: G
authors.lastname: Nie
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D003271:Contraceptive Agents, Female / Q000008:administration & dosage*; D003656:Decidua / Q000187:drug effects / Q000502:physiology; D010064:Embryo Implantation / Q000187:drug effects; D004717:Endometrium / Q000166:cytology; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D009842:Oligopeptides / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011247:Pregnancy; D045702:Proprotein Convertase 5 / Q000037:antagonists & inhibitors*; D011817:Rabbits; D017154:Stromal Cells / Q000187:drug effects; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism
chemical_list: C574695:C1239-PEG-Poly R; D003271:Contraceptive Agents, Female; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D011092:Polyethylene Glycols; D045702:Proprotein Convertase 5