title: In vitro anti-HIV-1 activity of sn-2-substituted 1-O-octadecyl-sn-glycero-3-phosphonoformate analogues and synergy with zidovudine.
abstract: Monoalkyl ether lipid analogues of foscarnet (phosphonoformate, PFA) exhibit substantially greater in vitro antiviral activity than unmodified PFA against human immunodeficiency virus type 1 (HIV-1). Our previous studies indicate that the length of the alkyl chain must be 14-22 carbons for optimal antiviral activity. To further evaluate the structure-activity relationship, we prepared 1-O-octadecyl-sn-glycerol analogues of PFA with various substitutions at the sn-2 position of glycerol and determined the effect of structure on in vitro antiviral activity and selectivity against HIV-1 in MT-2 and CD4-expressing HeLa cells (HT4-6C). We also studied combinations of zidovudine with PFA, 1-O-octadecyl-2-O-methyl-sn-glycero-3-PFA, or 1-O-octadecyl-sn-glycero-3-PFA and calculated their combination index values against HIV-1 in HT4-6C cells. Alkyl substitutions of one to four carbons at the sn-2 position of glycerol showed optimal antiviral activity. Both alkyl ether lipid analogues were strongly synergistic with zidovudine over a wide range of drug ratios and concentrations. 1-O-octadecyl-sn-glycerol analogues of PFA have selective antiviral properties and warrant further evaluation as potential antiretroviral drugs.
authors.affiliation: Department of Medicine, Veterans Affairs Medical Center and the University of California, San Diego, La Jolla, USA. khostetler@ucsd.edu
authors.forename: K Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: J L
authors.initials: JL
authors.lastname: Hammond
authors.forename: G D
authors.initials: GD
authors.lastname: Kini
authors.forename: S E
authors.initials: SE
authors.lastname: Hostetler
authors.forename: J R
authors.initials: JR
authors.lastname: Beadle
authors.forename: K A
authors.initials: KA
authors.lastname: Aldern
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: D D
authors.initials: DD
authors.lastname: Richman
authors.forename: J W
authors.initials: JW
authors.lastname: Mellors
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D004337:Drug Carriers; D004338:Drug Combinations; D004357:Drug Synergism; D017245:Foscarnet / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells / Q000821:virology; D006801:Humans; D008081:Liposomes; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D004337:Drug Carriers; D004338:Drug Combinations; D008081:Liposomes; D017245:Foscarnet; D015215:Zidovudine