Inhibition of herpesvirus replication by hexadecyloxypropyl esters of purine- and pyrimidine-based phosphonomethoxyethyl nucleoside phosphonates.
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.
Prichard
Mark N
MN
Department of Pediatrics, University of Alabama School of Medicine, 128 Children's Harbor Building, 1600 6th Ave. South, Birmingham, AL 35233, USA. mprichard@peds.uab.edu
Hartline
Caroll B
CB
Harden
Emma A
EA
Daily
Shannon L
SL
Beadle
James R
JR
Valiaeva
Nadejda
N
Kern
Earl R
ER
Hostetler
Karl Y
KY
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D006564:Herpesviridae / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D011684:Purine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004952:Esters; D063065:Organophosphonates; D011684:Purine Nucleosides; D011741:Pyrimidine Nucleosides