Novel Membrane-Interactive Ether Lipid Analogs That Inhibit Infectious HIV-1 Production and Induce Defective Virus Formation

Abstract

A new class of membrane-active ether lipid (EL) analogs of platelet-activating factor were studied for in vitro anti-HIV-1 activity. Human T-cell (CEM-ss) monolayers or suspension cultures were used to determine effects of structural modifications of Type A phosphorus-containing and Type B nonphosphorus EL analogs on (a) the inhibitory concentration50 (IC50) for HIV-1 syncytial plaque formation and cell growth, and, (b) virus budding at the cell plasma membrane. Results indicate that representative Type A and Type B EL inhibit HIV-1 but not herpes simplex virus type 2 plaque formation when added before or up to 2 days after viral infection. Anti-HIV-1 activity does not involve direct inactivation of virus infectivity. Type A EL (IC50 range = 0.2-1.4 microM) with alkyoxy, alkylthio, or alkyamido substitution at glycerol position 1 and ethoxy or methoxy substitution at position 2, and Type B compounds (IC50 range = 0.33-0.63 microM) with an inverse choline or nitrogen heterocyclic substitution at position 3 have selective activity against HIV-1-infected T-cells. EL treatment of HIV-1-infected cells is associated with subsequent release of reverse transcriptase activity, but infectious virus production is inhibited with time after infection. Electron microscopic examination of HIV-1-infected and EL-treated cells revealed absence of detectable budding virus at the plasma membrane but presence of intracytoplasmic vacuolar virus particles. In summary, these data suggest that EL analogs are a novel class of agents that induce defective intracytoplasmic vacuolar HIV-1 formation in T-cells. Being membrane interactive, EL are ideally suited for combination chemotherapy with DNA-interactive anti-HIV nucleoside analogs.

Boronic Acid Derivatives Targeting HIV-1

“…The rationale for the synthesis of 3 was based on its facile conversion to the hypoxanthine analogue (6) and its decreased polarity compared with analogues 4-6. Thus, the lack of activity of the latter compounds may be due either to their polar Boronic Acid Derivatives Targeting HIV-1 111 TdR for 6 hrs to measure total DNA synthesis in treated and untreated cell cultures and calculate the IC so as previously described (Kucera et al, 1990). The IC 5 0 value for AZT, the control antiviral compound, was 5.1 ± 3.0 J.IM as previously reported (Piantadosi et al, 1991).…”

“…After 5 days incubation, the numbers of HIV-1 syncytial plaques in treated and untreated cell monolayers were counted to calculate the EC so as previously described (Kucera et al, 1990). The EC so value for AZT, the control antiviral compound, was 0.004 ± 0.002 J.IM as previously reported (Piantadosi et al, 1991).…”

“…The boronic acid derivatives (2-8) were screened for their cell cytotoxicity and anti-HIV-1 activity by utilizing sH-TdR incorporation into total DNA and an HIV plaque reduction assay (Kucera et al, 1990). In this series, only two compounds (3 and 7) showed appreciable in-vitro activity.…”

Membrane-interactive lipids as experimental anticancer drugs

“…These additive or supra-additive effects are currently under further investigation. Interestingly, some of these membrane-active ether lipid structures inhibit infectious HIV-1 production and induce defective virus formation in T-cells (Kucera et al, 1990). This effect is currently under study for combination chemotherapy with DNA-interactive anti-HIV nucleoside analogs.…”

In vitro Anti-HIV-1 Activity of sn-2-Substituted 1-O-Octadecyl-sn-Glycero-3-Phosphonoformate Analogues and Synergy with Zidovudine

“…A series of phosphatidylcholines having -alkoxy, -alkylthio, or -alkylamido substitution at the sn-1 position of glycerol and -ethoxy or -methoxy at the sn-2 hydroxyl of glycerol have been reported to have anti-HIV-1 activity in CEM-ss cells (Kucera et al, 1990, Meyer et al, 1998. Because our analogues of PFA also have alkyl groups at the sn-1 and -2 positions of glycerol, we evaluated the effect of 1-O-octadecyl-sn-glycerol and 1-O-octadecyl-2-Omethyl-sn-glycerol on HIV replication using liposomes identical to those used for the drug assays but containing the alkyl glycerol controls.…”