J. Biol. Chem., Vol. 265, Issue 11, 6112-6117, Apr, 1990
Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides
KY Hostetler, LM Stuhmiller, HB Lenting, H van den Bosch and DD Richman
Vical Incorporated, San Diego, California 92121.
Treatment of acquired immunodeficiency syndrome with azidothymidine (AZT,
zidovudine) reduces p24 antigenemia, increases CD4 lymphocyte counts,
reduces the frequency and severity of opportunistic infections and prolongs
life. However, AZT and other dideoxynucleosides do not diminish the ability
to isolate human immunodeficiency virus (HIV) from peripheral blood
mononuclear cells. Failure to clear infectious virus may be due to
inadequate inhibition of virus production by macrophages, a major reservoir
of HIV infection. Cells of the macrophage lineage take up large amounts of
parenterally administered liposomal material. To direct larger proportions
of antiretroviral nucleosides to this important HIV reservoir, we
synthesized phosphatidylAZT, AZT diphosphate dipalmitin, phosphatidylddC
and phosphatidylddT, novel phospholipid prodrugs which are readily
incorporated into phospholipid bilayers. These liposomal liponucleotides
were shown to have antiretroviral activity in HIV-infected U937 and CEM
cells. In vivo, it is anticipated that liposomes containing the
antiretroviral liponucleotides will be taken up in large proportion by
macrophages. This property would appear to make phosphatidylAZT and the
related compounds promising candidate agents with a special potential to
target drug to the macrophage reservoir of HIV infection, thereby reducing
the toxicity of the antiviral nucleosides to other cells.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
