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

Abstract

ABSTRACT 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 (EC 50 s) 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 EC 50 s 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.