title: Amphipathic DNA polymers are candidate vaginal microbicides and block herpes simplex virus binding, entry and viral gene expression.
abstract: BACKGROUND
  Amphipathic DNA polymers are promising therapies for the prevention of HIV and genital herpes infections. Recent studies on a panel of such compounds indicated potent activity against HIV binding and entry. This current study was conducted to explore the anti-herpes simplex virus (HSV) activity of the same panel of compounds and to determine their mechanism of activity.
  
  
  METHODS
  The anti-HSV activity of a 40-nucleotide degenerate polymer (REP 9), a 40-nucleotide polycytidine amphipathic DNA polymer (REP 9C) and an analogue lacking amphipathic activity (Randomer 3) were compared in plaque reduction assays in the absence or presence of human genital tract secretions; the mechanisms of anti-HSV activity were explored.
  
  
  RESULTS
  REP 9 inhibited HSV infection 10,000-fold, whereas Randomer 3 displayed no anti-HSV activity. The antiviral activity was independent of sequence but was dependent on size: the most potent activity was observed for analogues of 40 nucleotides in length. Mechanistic studies indicated that REP 9 and REP 9C blocked HSV-2 binding and entry, were active when added post-entry, inhibited viral gene expression and blocked HSV-induced apoptosis. Confocal microscopy studies showed rapid delivery of fluorescently tagged REP 9 and REP 9C into human epithelial cells, and delivery was significantly greater in infected cells as compared with uninfected cells. REP 9 exhibited no cytotoxicity and retained anti-HSV activity in the presence of cervicovaginal secretions and when virus was introduced in seminal plasma.
  
  
  CONCLUSIONS
  REP 9 and REP 9C represent a novel class of antiviral agents that act by multiple mechanisms. These compounds warrant further development for systemic or topical delivery for the prevention and treatment of HIV and HSV.
authors.affiliation: Department of Pediatrics and Medicine, Mount Sinai School of Medicine, New York, USA.
authors.forename: Esmeralda M
authors.initials: EM
authors.lastname: Guzman
authors.forename: Natalia
authors.initials: N
authors.lastname: Cheshenko
authors.forename: Vikas
authors.initials: V
authors.lastname: Shende
authors.forename: Marla J
authors.initials: MJ
authors.lastname: Keller
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goyette
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Juteau
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
authors.forename: Andrew
authors.initials: A
authors.lastname: Vaillant
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Herold
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001685:Biological Factors / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002584:Cervix Uteri / Q000378:metabolism; D002522:Chlorocebus aethiops; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D054735:Phosphorothioate Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D012661:Semen; D018139:Simplexvirus / Q000187:drug effects* / Q000502:physiology; D014621:Vagina / Q000378:metabolism; D014709:Vero Cells; D010948:Viral Plaque Assay; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D001685:Biological Factors; D054735:Phosphorothioate Oligonucleotides; D011108:Polymers