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) exhibi t substantially greater in vitro antiviral activity than unmodified PFA aga inst human immunodeficiency virus type 1 (HIV-1). Our previous studies indi cate that the length of the alkyl chain must be 14-22 carbons for optimal a ntiviral activity. To further evaluate the structure-activity relationship, we prepared 1-O-octadecyl-sn-glycerol analogues of PFA with various substi tutions at the sn-2 position of glycerol and determined the effect of struc ture on in vitro antiviral activity and selectivity against HIV-1 in MT-2 a nd CD4-expressing HeLa cells (HT4-6C). We also studied combinations of zido vudine 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 li pid analogues were strongly synergistic with zidovudine over a wide range o f drug ratios and concentrations. 1-O-octadecyl-sn-glycerol analogues of PF A have selective antiviral properties and warrant further evaluation as pot ential antiretroviral drugs.