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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), &lt;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 &lt; 0.001), while a lower dose (100 mg/ml) protected 100% of the mice (P &lt; 0.001). The acid stable REP 9C formulation also provided protection at 30 min (83%, P &lt; 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.

Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo