title: Amphipathic DNA polymers exhibit antiviral activity against systemic murine Cytomegalovirus infection.
abstract: BACKGROUND
  Phosphorothioated oligonucleotides (PS-ONs) have a sequence-independent, broad spectrum antiviral activity as amphipathic polymers (APs) and exhibit potent in vitro antiviral activity against a broad spectrum of herpesviruses: HSV-1, HSV-2, HCMV, VZV, EBV, and HHV-6A/B, and in vivo activity in a murine microbiocide model of genital HSV-2 infection. The activity of these agents against animal cytomegalovirus (CMV) infections in vitro and in vivo was therefore investigated.
  
  
  RESULTS
  In vitro, a 40 mer degenerate AP (REP 9) inhibited both murine CMV (MCMV) and guinea pig CMV (GPCMV) with an IC50 of 0.045 microM and 0.16 microM, respectively, and a 40 mer poly C AP (REP 9C) inhibited MCMV with an IC50 of 0.05 microM. Addition of REP 9 to plaque assays during the first two hours of infection inhibited 78% of plaque formation whereas addition of REP 9 after 10 hours of infection did not significantly reduce the number of plaques, indicating that REP 9 antiviral activity against MCMV occurs at early times after infection. In a murine model of CMV infection, systemic treatment for 5 days significantly reduced virus replication in the spleens and livers of infected mice compared to saline-treated control mice. REP 9 and REP 9C were administered intraperitoneally for 5 consecutive days at 10 mg/kg, starting 2 days prior to MCMV infection. Splenomegaly was observed in infected mice treated with REP 9 but not in control mice or in REP 9 treated, uninfected mice, consistent with mild CpG-like activity. When REP 9C (which lacks CpG motifs) was compared to REP 9, it exhibited comparable antiviral activity as REP 9 but was not associated with splenomegaly. This suggests that the direct antiviral activity of APs is the predominant therapeutic mechanism in vivo. Moreover, REP 9C, which is acid stable, was effective when administered orally in combination with known permeation enhancers.
  
  
  CONCLUSIONS
  These studies indicate that APs exhibit potent, well tolerated antiviral activity against CMV infection in vivo and represent a new class of broad spectrum anti-herpetic agents.
authors: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. rhonda.cardin@cchmc.org
authors: Rhonda D
authors: RD
authors: Cardin
authors: Fernando J
authors: FJ
authors: Bravo
authors: Andrea P
authors: AP
authors: Sewell
authors: James
authors: J
authors: Cummins
authors: Louis
authors: L
authors: Flamand
authors: Jean-Marc
authors: JM
authors: Juteau
authors: David I
authors: DI
authors: Bernstein
authors: Andrew
authors: A
authors: Vaillant
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D002478:Cells, Cultured; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000187:drug effects*; D011066:Poly C / Q000737:chemistry; D011119:Polynucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D011119:Polynucleotides; D011066:Poly C; D004247:DNA