LIPID PRODRUGS OF PHOSPHONOACIDS - GREATLY ENHANCED ANTIVIRAL ACTIVITY OF 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHONOFORMATE IN HIV-1, HSV-1 AND HCMV-INFECTED CELLS, IN-VITRO

Phosphonoformate (PFA) effectively inhibits viral polymerases but is r elatively ineffective in virus-infected cells in tissue culture. A lip id prodrug of phosphonoformate was synthesized by coupling the phospho nate residue of phosphonoformate to the sn-3 hydroxyl of 1-O-octadecyl -sn-glycerol. This prodrug, 1-O-octadecyl-sn-glycero-3-phosphonoformat e (ODG-PFA), was 93-fold more active than phosphonoformate in cells in fected with the AD169 strain of cytomegalovirus (CMV), and 111-147-fol d more active in cells infected with three human clinical isolates of CMV. The compound was also 44-fold more active in human immunodeficien cy virus-1 (HIV-1) infected cells and 43-fold more active in cells inf ected with herpes simplex virus (HSV). Studies of the mechanisms of in creased antiviral activity indicate that 1-O-octadecyl-sn-glycero-3-[C -14]phosphonoformate is taken up more extensively than the free drug b y the host MRC-5 human lung fibroblasts. Intracellular enzymes convert 1-O-octadecyl-sn-glycero-3-phosphonoformate to phosphonoformate. This conversion does not occur in the tissue culture medium containing fet al bovine serum (FBS) or in MRC-5-conditioned medium. In view of its g reatly increased in vitro potency and selectivity, 1-O-octadecyl-sn-gl ycero-3-phosphonoformate may be useful in treating viral diseases.