Oral Treatment of Murine Cytomegalovirus Infections with Ether Lipid Esters of Cidofovir

Abstract

To improve the oral bioavailability of cidofovir (CDV), a series of ether lipid ester prodrugs were synthesized and evaluated for activity against murine cytomegalovirus (MCMV) infection. Four of these analogs, hexadecyloxypropyl (HDP)-CDV, octadecyloxyethyl (ODE)-CDV, oleyloxyethyl (OLE)-CDV, and oleyloxypropyl (OLP)-CDV, were found to have greater activity than CDV against human CMV and MCMV in vitro. The efficacy of oral treatment with these compounds against MCMV infections in BALB/c mice was then determined. Treatment with HDP-CDV, ODE-CDV, OLE-CDV, or OLP-CDV at 2.0 to 6.7 mg/kg of body weight provided significant protection when daily treatments were initiated 24 to 48 h after viral inoculation. Additionally, HDP-CDV or ODE-CDV administered twice weekly or as a single dose of 1.25 to 10 mg/kg was effective in reducing mortality when treatment was initiated at 24 h, 48 h, or, in some cases, 72 h after viral inoculation. In animals treated daily with HDP-CDV or ODE-CDV, virus titers in lung, liver, spleen, kidney, pancreas, salivary gland, and blood were reduced 3 to 5 log 10 -fold, which was comparable to CDV given intraperitoneally. These results indicated that HDP-CDV or ODE-CDV given orally was as effective as parenteral CDV for the treatment of experimental MCMV infection and suggest that further evaluation for use in CMV infections in humans is warranted.Cytomegalovirus (CMV) infections continue to be a major cause of morbidity in solid organ (35) and stem cell recipients (10, 12). The management of these infections has generally been through the use of prophylaxis or prevention therapy with ganciclovir (GCV) (15) or acyclovir (ACV) (3); however, the lack of activity when they are administered orally has limited their use. While the availability of oral ACV (valacyclovir) (29) and GCV (valganciclovir) (32) has broadened the range of choices for treatment or prevention of CMV infections, a number of problems, including neutropenia, nephrotoxicity, and the selection of drug-resistant mutants, remain (6,8,13,27,28,39). Cidofovir (CDV) has greater activity against CMV in vitro and in vivo than any of the other licensed drugs (16,22,23,40) and retains activity against many of the GCV-and foscarnet (PFA)-resistant mutants (4). However, CDV does not have activity when given orally and may also cause severe nephrotoxicity (25, 37). One approach to overcoming the limitation of the lack of activity of CDV given orally has been to prepare prodrugs of CDV that are bioavailable when administered orally. The synthesis of alkylglycerol phosphate or alkylpropyl phosphate esters of ACV, penciclovir, or GCV provided prodrugs that were active when given orally in animal models of herpes simplex virus, murine CMV (MCMV), and woodchuck hepatitis virus infections (17-19). Using similar methodology, a series of ether lipid ester analogs of CDV or cyclic CDV were prepared and evaluated for activity against CMV and poxviruses (4, 24).It has been reported previously that this series of ether lipid ester prodrugs of CDV, partic...

Comparative Activities of Lipid Esters of Cidofovir and Cyclic Cidofovir against Replication of Herpesviruses In Vitro

“…orally as the parent, CDV, given parenterally (4,5,23,31). In addition to its lack of oral bioavailability, another limitation to the use of CDV is its nephrotoxicity (35).…”

“…The CDV and cCDV analogs were provided by Karl Hostetler, University of California at San Diego, La Jolla, CA, through the Antiviral Substance Program, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD. Their structure, synthesis, purification, and characterization have been published previously (3,21,23,38).…”

“…After 24 h of incubation, the medium was replaced with MEM containing 2% FBS, and drug was added to the first row and then diluted serially fivefold from 100 to 0.03 g/ml. The plates were incubated for 7 days, and the cells were stained with neutral red and incubated for 1 h. The plates were washed and shaken for 15 min, and the optical density was read at 540 nm (23). The concentration of drug that reduced cell viability by 50% (CC 50 ) was calculated as previously described (30).…”

“…We have reported previously that hexadecyloxypropyl cido-fovir (HDP-CDV), octadecyloxypropyl cidofovir (ODE-CDV), oleyloxyethyl cidofovir (OLE-CDV), and oleyloxypropyl cidofovir (OLP-CDV) may be good candidates for new antiviral agents (3,20,21,22,23,31). On the basis of the activities of these compounds, additional analogs of CDV and cyclic CDV (cCDV) were synthesized.…”

Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model

“…Its bioavailability and cellular uptake are significantly enhanced because of the lipid moiety, which is cleaved inside the cell by phospholipase to liberate cidofovir. This increased cellular uptake of CMX001 results in enhanced activity compared with cidofovir against multiple double-strand DNA viruses, including poxvirus (22)(23)(24) and CMV (25,26) infections. Furthermore, the drug is 5-to 200-fold more potent in vitro than cidofovir against species A (Ad31), B (Ad3, Ad7), C (Ad5), and D (Ad8) Ads (27).…”