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Antimicrobial Agents and Chemotherapy, July 2003, p. 2186-2192, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2186-2192.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of Benzimidazole D- and L-Ribonucleosides against Herpesviruses

Stephanie L. Williams,1 Caroll B. Hartline,1 Nicole L. Kushner,1 Emma A. Harden,1 Deborah J. Bidanset,1 John C. Drach,2 Leroy B. Townsend,2 Mark R. Underwood,3 Karen K. Biron,3 and Earl R. Kern1*

University of Alabama School of Medicine, Birmingham, Alabama,1 University of Michigan, Ann Arbor, Michigan,2 GlaxoSmithKline, Inc., Research Triangle Park, North Carolina3

Received 20 November 2002/ Returned for modification 10 March 2003/ Accepted 24 April 2003

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and human herpesvirus 8 (HHV-8) are responsible for a number of clinical manifestations in both normal and immunocompromised individuals. The parent benzimidazole ribonucleosides evaluated in this series, 2-bromo-5,6-dichloro-1-(ß-D-ribofuranosyl)benzimidazole (BDCRB) and maribavir (1263W94), are potent and selective inhibitors of human CMV replication. These nucleosides act by two different mechanisms. BDCRB blocks the processing and maturation of viral DNA, whereas 1263W94 inhibits the viral enzyme pUL97 and interferes with DNA synthesis. In the present study, we have evaluated the in vitro antiviral activity of BDCRB, an analog, GW275175X (175X), and 1263W94 against the replication of HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, and HHV-8. By using various methodologies, significant activity was observed against human CMV and EBV but not against HSV-1, HSV-2, VZV, HHV-6, or HHV-8. Plaque reduction assays performed on a variety of laboratory and clinical isolates of human CMV indicated that all strains, including those resistant to ganciclovir (GCV) and foscarnet, were sensitive to all three benzimidazole ribonucleosides, with mean 50% effective concentration values of about 1 to 5 µM compared to that of GCV at 6 µM. The toxicity of these compounds in tissue culture cells appeared to be similar to that observed with GCV. These results demonstrate that the benzimidazole ribonucleosides are active against human CMV and EBV and suggest that they may be useful for the treatment of infections caused by these herpesviruses.

* Corresponding author. Mailing address: University of Alabama School of Medicine, 1600 6th Ave. South, CHB 128, Birmingham, AL 35233. Phone: (205) 934-1990. Fax: (205) 975-1992. E-mail: kern{at}uab.edu.

Antimicrobial Agents and Chemotherapy, July 2003, p. 2186-2192, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2186-2192.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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