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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

David I. Bernstein,^1* Nathalie Goyette,² Rhonda Cardin,¹ Earl R. Kern,³ Guy Boivin,² James Ireland,¹ Jean-Marc Juteau,⁴ and Andrew Vaillant^4*

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.

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* Corresponding author. Mailing address for D. I. Bernstein: Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., ML 6014, Cincinnati, OH 45229. Phone: (513) 636-7625. Fax: (513) 636-7682. E-mail: david.bernstein{at}cchmc.org. Mailing address for A. Vaillant: REPLICor, Inc., Laval, Quebec, Canada. Phone: (450) 688-6068, ext. 3. Fax: (450) 688-3138. E-mail: availlant{at}replicor.com

Published ahead of print on 27 May 2008.

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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.