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Antimicrobial Agents and Chemotherapy, July 2003, p. 2193-2198, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2193-2198.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication

Kathy A. Keith,1 Michael J. M. Hitchcock,2 William A. Lee,2 Antonin Holy,3 and Earl R. Kern1*

University of Alabama School of Medicine, Birmingham, Alabama,1 Gilead Sciences, Inc., Foster City, California,2 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic3

Received 16 December 2002/ Returned for modification 10 March 2003/ Accepted 7 April 2003

In the event of a bioterrorism attack using smallpox virus, there currently is no approved drug for the treatment of infections with this virus. We have reported previously that (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC) (also known as cidofovir [CDV]) has good activity against poxvirus infections; however, a major limitation is the requirement for intravenous administration. Two related acyclic nucleoside phosphonates (ANPs), adefovir (PMEA) and tenofovir (PMPA), are active against human immunodeficiency virus or hepatitis B virus but do not have activity against the orthopoxviruses. Therefore, we have evaluated a number of analogs and potential oral prodrugs of these three compounds for their ability to inhibit the replication of vaccinia virus or cowpox virus in tissue culture cells. The most-active compounds within the CDV series were (S)-HPMPA and (butyl L-alaninyl) cyclic HPMPC, with 50% effective concentrations (EC50s) from 4 to 8 µM, compared with 33 to 43 µM for CDV. Although PMEA itself was not active, adefovir dipivoxil {bis[(pivaloyl)oxymethyl] PMEA} and bis(butyl L-alaninyl) PMEA were active against both viruses, and bis(butyl L-alaninyl) PME-N6-(cyclopropyl)DAP and (isopropyl L-alaninyl)phenyl PME-N6-(cyclopropyl)DAP were the most active compounds tested, with EC50s of 0.1 to 2.6 µM. In the PMPA series, none of the analogs tested had significantly better activity than PMPA itself. These data indicate that a number of these ANP derivatives have activity against vaccinia virus and cowpox virus in vitro and should be evaluated for their efficacies in animal models.

* Corresponding author. Mailing address: University of Alabama School of Medicine, Department of Pediatrics, 1600 6th Ave. S., 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. 2193-2198, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2193-2198.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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