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Antimicrobial Agents and Chemotherapy, October 2004, p. 3918-3927, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3918-3927.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Human Cytomegalovirus Replication by Benzimidazole Nucleosides Involves Three Distinct Mechanisms

David L. Evers,^1,2 Gloria Komazin,^1,2 Roger G. Ptak,^1,2, Dongjin Shin,¹ Brian T. Emmer, Leroy B. Townsend,² and John C. Drach^1,2*

Department of Biologic and Materials Sciences, School of Dentistry,¹ Interdepartmental Graduate Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan²

Received 3 December 2003/ Returned for modification 8 January 2004/ Accepted 19 April 2004

The benzimidazole nucleosides 2-bromo-5,6-dichloro-1-(ß-D-ribofuranosyl)benzimidazole (BDCRB) and 2-isopropylamino-5,6-dichloro-1-(ß-L-ribofuranosyl)benzimidazole (1263W94, or maribavir) are potent and selective inhibitors of human cytomegalovirus (HCMV) replication. These inhibitors act by two different mechanisms: BDCRB blocks the processing and maturation of viral DNA, whereas maribavir prevents viral DNA synthesis and capsid nuclear egress. In order to determine by which of these two mechanisms other benzimidazole nucleosides acted, we performed time-of-addition studies and other experiments with selected new analogs. We found that the erythrofuranosyl analog and the -lyxofuranosyl analog acted late in the viral replication cycle, similar to BDCRB. In marked contrast, the -5'-deoxylyxofuranosyl analog of 2,5,6-trichloro-1-(ß-D-ribofuranosyl)benzimidazole (compound UMJD1311) acted early in the replication cycle, too early to be consistent with either mechanism. Similar to other reports on early acting inhibitors of herpesviruses, compound 1311 was multiplicity of infection dependent, an observation that could not be reproduced with UV-inactivated virus. HCMV isolates resistant to BDCRB and maribavir were sensitive to compound 1311, as were viruses resistant to ganciclovir, cidofovir, and foscarnet. The preincubation of host cells with compound 1311 and removal prior to the addition of HCMV did not produce an antiviral cellular response. We conclude that this newly discovered early mode of action occurs at a stage of viral replication after entry to cells but prior to viral DNA synthesis, thereby strongly suggesting that the trisubstituted benzimidazole nucleoside series possesses three distinct biochemical modes of action for inhibition of HCMV replication.

Present address: Southern Research Institute, Frederick, MD 21701.

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