Patients infected with human immunodeficiency virus (HIV) often suffer from
herpesvirus infections as a result of immunosuppression. These
infections can occur while patients are receiving antiretroviral
therapy, and additional drugs required to treat their
infection can adversely affect compliance. It would be useful to have
antivirals with a broader spectrum of activity that included both HIV and the herpesviruses. We reported previously that alkoxyalkyl
ester prodrugs of
cidofovir are up to 3 orders of magnitude more active against herpesvirus replication and may be less toxic than the unmodified
drug. To determine if this strategy would be effective for certain phosphonomethoxyethyl
nucleoside phosphonates which are also active against
HIV infections, the hexadecyloxypropyl (HDP)
esters of 1-(phosphonomethoxyethyl)-cytosine, 1-(phosphonomethoxyethyl)-5-bromo-cytosine (PME-5BrC), 1-(phosphonomethoxyethyl)-5-fluoro-cytosine, 9-(phosphonomethoxyethyl)-2,6-diaminopurine (PME-DAP), and 9-(phosphonomethoxyethyl)-2-amino-6-cyclopropylaminopurine (PME-cPrDAP) were evaluated for activity against herpesvirus replication. The HDP
esters were substantially more active than the unmodified acyclic
nucleoside phosphonates, indicating that esterification with alkoxyalkyl groups increases the
antiviral activity of many acyclic
nucleoside phosphonates. The most interesting compounds included HDP-PME-cPrDAP and HDP-PME-DAP, which were 12- to 43-fold more active than the parent
nucleoside phosphonates against herpes simplex virus and cytomegalovirus, and HDP-PME-cPrDAP and HDP-PME-5BrC which were especially active against Epstein-Barr virus. The results presented here indicate that HDP-esterified acyclic
nucleoside phosphonates with
antiviral activity against HIV also inhibit the replication of some herpesviruses and can extend the spectrum of activity for these compounds.