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Antimicrobial Agents and Chemotherapy, August 2008, p. 2727-2733, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00279-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo

Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio,¹ Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Québec City, Québec, Canada,² Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama,³ REPLICor, Inc., Laval, Quebec, Canada⁴

Received 28 February 2008/ Returned for modification 2 April 2008/ Accepted 17 May 2008

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 [EC₅₀], 0.02 to 0.06 µM), human cytomegalovirus (EC₅₀, 0.02 to 0.13 µM), varicella zoster virus (EC₅₀, <0.02 µM), Epstein-Barr virus (EC₅₀, 14.7 µM) and human herpesvirus types 6A/B (EC₅₀, 2.9 to 10.2 µM). 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.

Published ahead of print on 27 May 2008.