In vitro anti-HIV-1 activity of sn-2-substituted 1-O-octadecyl-sn-glycero-3-phosphonoformate analogues and synergy with zidovudine.
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.
Hostetler
K Y
KY
Department of Medicine, Veterans Affairs Medical Center and the University of California, San Diego, La Jolla, USA. khostetler@ucsd.edu
Hammond
J L
JL
Kini
G D
GD
Hostetler
S E
SE
Beadle
J R
JR
Aldern
K A
KA
Chou
T C
TC
Richman
D D
DD
Mellors
J W
JW
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*
D000998:Antiviral Agents; D004337:Drug Carriers; D004338:Drug Combinations; D008081:Liposomes; D017245:Foscarnet; D015215:Zidovudine