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Antimicrobial Agents and Chemotherapy, March 2005, p. 1039-1045, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1039-1045.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vitro Activity and Mechanism of Action of Methylenecyclopropane Analogs of Nucleosides against Herpesvirus Replication

The University of Alabama School of Medicine, Birmingham, Alabama,¹ Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan²

Received 8 June 2004/ Returned for modification 8 September 2004/ Accepted 11 November 2004

We have reported previously that methylenecyclopropane analogs of nucleosides have excellent activity against certain members of the herpesvirus family. A second generation, the 2,2-bis-hydroxymethyl derivatives, were synthesized, and 18 compounds were tested for activity in vitro against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human and murine cytomegalovirus (HCMV and MCMV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). Selected analogs were also evaluated against human herpesvirus type 6 (HHV-6) and HHV-8. None of the 18 compounds had activity against HSV-1 or HSV-2, but four were active against VZV by plaque reduction (PR) assay at 50% effective concentration (EC₅₀) levels of 50 µM. Six of the 18 compounds were active against HCMV by cytopathic effect or PR assays with EC₅₀s of 0.5 to 44 µM, and all were active against MCMV by PR (0.3 to 54 µM). Four of the compounds were active against EBV by enzyme-linked immunosorbent assay (<0.3 to 4.4 µM). Four compounds with CMV activity were also active against HHV-6A and HHV-6B (0.7 to 28 µM), and three compounds were active against HHV-8 (5.5 to 16 µM). One of these, ZSM-I-62, had particularly good activity against CMV, HHV-6, and HHV-8, with EC₅₀s of 0.7 to 8 µM. Toxicity was evaluated in adherent and nonadherent cells, and minimal cytotoxicity was observed. Mechanism of action studies with HCMV suggested that these compounds are phosphorylated by the ppUL97 phosphotransferase and are potent inhibitors of viral DNA synthesis. These results indicate that at least one of these compounds may have potential for use in treating CMV and other herpesvirus infections in humans.

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