Cytidine diphosphate diglyceride analogs of antiretroviral dideoxynucleosides: evidence for release of dideoxynucleoside-monophosphates by phospholipid biosynthetic enzymes in rat liver subcellular fractions.

Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.

Biochim Biophys Acta. 1991 Oct 15;1086(1):99-105. Unique Identifier : AIDSLINE MED/92062726
van Wijk GM; Hostetler KY; Schlame M; van den Bosch H; Centre for Biomembranes and Lipid Enzymology, University of; Utrecht, The Netherlands.

Abstract: We recently synthesized phospholipid analogs with antiviral nucleosides in the polar headgroup and demonstrated their antiretroviral activity in vitro in human immunodeficiency virus-infected cells (Hostetler, K.Y., Stuhmiller, L.M., Lenting, H.B.M., van den Bosch, H. and Richman, D.D. (1990) J. Biol. Chem. 265, 6112-6117). Dideoxynucleoside analogs of cytidine diphosphate diglyceride (CDP-DG) represent one class of such phospholipid prodrugs from which the antiviral active principle may be released through established pathways of cellular phospholipid metabolism. We now demonstrate that the liponucleotides of dideoxycytidine, 3'-deoxythymidine and 3'-azido-3'-deoxythymidine (AZT, Zidovudine) can substitute to varying extents for CDP-DG in the biosynthesis of phosphatidylinositol, phosphatidylglycerol or diphosphatidylglycerol by rat liver subcellular fractions. In all three biosynthetic pathways dideoxycytidine diphosphate diglyceride was the most active donor of the phosphatidyl unit. The nearly stoichiometric formation of dideoxycytidine-5'-monophosphate during phosphatidylinositol biosynthesis supports the rationale that the antiretroviral liponucleotides may provide cells with a depot form from which the antiviral drug can be released in 5'-monophosphorylated form, thus bypassing the initial phosphorylation of free dideoxynucleosides.

Keywords: Animal Cardiolipins/METABOLISM Cytidine Diphosphate Diglycerides/*METABOLISM Deoxycytosine Nucleotides/METABOLISM Dideoxynucleosides/*METABOLISM Diglycerides/METABOLISM In Vitro Microsomes, Liver/*METABOLISM Mitochondria, Liver/*METABOLISM Phosphatidylglycerols/METABOLISM Phosphatidylinositols/METABOLISM Prodrugs/*METABOLISM Rats Support, Non-U.S. Gov't Support, U.S. Gov't, Non-P.H.S. Support, U.S. Gov't, P.H.S. Thymine Nucleotides/METABOLISM JOURNAL ARTICLE

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