title: 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.
abstract: Phosphonoformate (PFA) effectively inhibits viral polymerases but is relatively ineffective in virus-infected cells in tissue culture. A lipid prodrug of phosphonoformate was synthesized by coupling the phosphonate residue of phosphonoformate to the sn-3 hydroxyl of 1-O-octadecyl-sn-glycerol. This prodrug, 1-O-octadecyl-sn-glycero-3-phosphonoformate (ODG-PFA), was 93-fold more active than phosphonoformate in cells infected with the AD169 strain of cytomegalovirus (CMV), and 111-147-fold more active in cells infected with three human clinical isolates of CMV. The compound was also 44-fold more active in human immunodeficiency virus-1 (HIV-1) infected cells and 43-fold more active in cells infected with herpes simplex virus (HSV). Studies of the mechanisms of increased antiviral activity indicate that 1-O-octadecyl-sn-glycero-3-[14C]phosphonoformate is taken up more extensively than the free drug by 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 fetal bovine serum (FBS) or in MRC-5-conditioned medium. In view of its greatly increased in vitro potency and selectivity, 1-O-octadecyl-sn-glycero-3-phosphonoformate may be useful in treating viral diseases.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla 92093-0676, USA. KHostetl@ucsd.edu
authors.forename: K Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: G D
authors.initials: GD
authors.lastname: Kini
authors.forename: J R
authors.initials: JR
authors.lastname: Beadle
authors.forename: K A
authors.initials: KA
authors.lastname: Aldern
authors.forename: M F
authors.initials: MF
authors.lastname: Gardner
authors.forename: R
authors.initials: R
authors.lastname: Border
authors.forename: R
authors.initials: R
authors.lastname: Kumar
authors.forename: L
authors.initials: L
authors.lastname: Barshak
authors.forename: C N
authors.initials: CN
authors.lastname: Sridhar
authors.forename: C J
authors.initials: CJ
authors.lastname: Wheeler
authors.forename: D D
authors.initials: DD
authors.lastname: Richman
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics; D004279:DNA, Viral / Q000096:biosynthesis; D017245:Foscarnet / Q000031:analogs & derivatives*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008055:Lipids; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives*; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D004279:DNA, Viral; D008055:Lipids; D011355:Prodrugs; D017245:Foscarnet; D010746:Phosphonoacetic Acid