Comparative activities of lipid esters of cidofovir and cyclic cidofovir against replication of herpesviruses in vitro.
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 microM 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.
Williams-Aziz
Stephanie L
SL
University of Alabama School of Medicine, 1600 6th Ave. South, 128 Children's Harbor Bldg., Birmingham, AL 35233, USA.
Hartline
Caroll B
CB
Harden
Emma A
EA
Daily
Shannon L
SL
Prichard
Mark N
MN
Kushner
Nicole L
NL
Beadle
James R
JR
Wan
W Brad
WB
Hostetler
Karl Y
KY
Kern
Earl R
ER
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000077404:Cidofovir; D003500:Cyclization; D003587:Cytomegalovirus / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004952:Esters / Q000494:pharmacology; D005347:Fibroblasts / Q000821:virology; D005434:Flow Cytometry; D006564:Herpesviridae / Q000187:drug effects*; D006801:Humans; D017403:In Situ Hybridization; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004952:Esters; D063065:Organophosphonates; D013778:Tetrazolium Salts; D013844:Thiazoles; D003596:Cytosine; C022616:thiazolyl blue; D000077404:Cidofovir