title: Amphipathic DNA polymers exhibit antiherpetic activity in vitro and in vivo.
abstract: Phosphorothioated oligonucleotides have a sequence-independent antiviral activity as amphipathic polymers (APs). The activity of these agents against herpesvirus infections in vitro and in vivo was investigated. The previously established sequence-independent, phosphorothioation-dependent antiviral activity of APs was confirmed in vitro by showing that a variety of equivalently sized homo- and heteropolymeric AP sequences were similarly active against herpes simplex virus type 1 (HSV-1) infection in vitro compared to the 40mer degenerate parent compound (REP 9), while the absence of phosphorothioation resulted in the loss of antiviral activity. In addition, REP 9 demonstrated in vitro activity against a broad spectrum of other herpesviruses: HSV-2 (50% effective concentration [EC(50)], 0.02 to 0.06 microM), human cytomegalovirus (EC(50), 0.02 to 0.13 microM), varicella zoster virus (EC(50), <0.02 microM), Epstein-Barr virus (EC(50), 14.7 microM) and human herpesvirus types 6A/B (EC(50), 2.9 to 10.2 microM). The murine microbicide model of genital HSV-2 was then used to evaluate in vivo activity. REP 9 (275 mg/ml) protected 75% of animals from disease and infection when provided 5 or 30 min prior to vaginal challenge. When an acid-stable analog (REP 9C) was used, 75% of mice were protected when treated with 240 mg/ml 5 min prior to infection (P < 0.001), while a lower dose (100 mg/ml) protected 100% of the mice (P < 0.001). The acid stable REP 9C formulation also provided protection at 30 min (83%, P < 0.001) and 60 min (50%, P = 0.07) against disease. These observations suggest that APs may have microbicidal activity and potential as broad-spectrum antiherpetic agents and represent a novel class of agents that should be studied further.
authors.affiliation: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA. david.bernstein@cchmc.org
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goyette
authors.forename: Rhonda
authors.initials: R
authors.lastname: Cardin
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
authors.forename: James
authors.initials: J
authors.lastname: Ireland
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Juteau
authors.forename: Andrew
authors.initials: A
authors.lastname: Vaillant
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000187:drug effects; D004247:DNA / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004355:Drug Stability; D005260:Female; D006558:Herpes Genitalis / Q000517:prevention & control* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D004247:DNA