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Antimicrobial Agents and Chemotherapy, September 2005, p. 3724-3733, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3724-3733.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Comparative Activities of Lipid Esters of Cidofovir and Cyclic Cidofovir against Replication of Herpesviruses In Vitro

Stephanie L. Williams-Aziz,1 Caroll B. Hartline,1 Emma A. Harden,1 Shannon L. Daily,1 Mark N. Prichard,1 Nicole L. Kushner,1 James R. Beadle,2 W. Brad Wan,2 Karl Y. Hostetler,2 and Earl R. Kern1*

University of Alabama School of Medicine, Birmingham, Alabama,1 VA San Diego Healthcare System and University of California, San Diego, La Jolla, California2

Received 3 March 2005/ Returned for modification 26 May 2005/ Accepted 22 June 2005

Cidofovir (CDV) is an effective therapy for certain human cytomegalovirus (HCMV) infections in immunocompromised patients that are resistant to other antiviral drugs, but the compound is not active orally. To improve oral bioavailability, a series of lipid analogs of CDV and cyclic CDV (cCDV), including hexadecyloxypropyl-CDV and -cCDV and octadecyloxyethyl-CDV and -cCDV, were synthesized and found to have multiple-log-unit enhanced activity against HCMV in vitro. On the basis of the activity observed with these analogs, additional lipid esters were synthesized and evaluated for their activity against herpes simplex virus (HSV) types 1 and 2, human cytomegalovirus, murine cytomegalovirus, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and HHV-8. Using several different in vitro assays, concentrations of drug as low as 0.001 µM reduced herpesvirus replication by 50% (EC50) with the CDV analogs, whereas the cCDV compounds were generally less active. In most of the assays performed, the EC50 values of the lipid esters were at least 100-fold lower than the EC50 values for unmodified CDV or cCDV. The lipid analogs were also active against isolates that were resistant to CDV, ganciclovir, or foscarnet. These results indicate that the lipid ester analogs are considerably more active than CDV itself against HSV, VZV, CMV, EBV, HHV-6, and HHV-8 in vitro, suggesting that they may have potential for the treatment of infections caused by a variety of herpesviruses.

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

Antimicrobial Agents and Chemotherapy, September 2005, p. 3724-3733, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3724-3733.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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