Synthesis and targeted delivery of an azidothymidine homodinucleotide conferring protection to macrophages against retroviral infection.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

Synthesis and targeted delivery of an azidothymidine homodinucleotide conferring protection to macrophages against retroviral infection.

Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4403-8. Unique Identifier : AIDSLINE MED/96210656
Magnani M; Casabianca A; Fraternale A; Brandi G; Gessani S; Williams R; Giovine M; Damonte G; De Flora A; Benatti U; Institute of Biochemistry Giorgio Fomaini, Urbino, Italy.

Abstract: The infectivity and replication of human (HIV-1), feline (FIV), and murine (LP-BM5) immunodeficiency viruses are all inhibited by several nucleoside analogues after intracellular conversion to their triphosphorylated derivatives. At the cellular level, the main problems in the use of these drugs concern their limited phosphorylation in some cells (e.g., macrophages) and the cytotoxic side effects of nucleoside analogue triphosphates. To overcome these limitations a new nucleoside analogue homodinucleotide, di(thymidine-3'-azido-2',3'-dideoxy-D-riboside)-5'-5'-p1-p2-pyrop- hosphat e (AZTp2AZT), was designed and synthesized. AZTp2AZT was a poor in vitro inhibitor of HIV reverse transcriptase, although it showed antiviral and cytotoxic activities comparable to those of the parent AZT when added to cultures of a HTLV-1 transformed cell line. AZTp2AZT encapsulated into erythrocytes was remarkably stable. Induction of erythrocyte-membrane protein clusterization and subsequent phagocytosis of AZTp2AZT-loaded cells allowed the targeted delivery of this impermeant drug to macrophages where its metabolic activation occurs. The addition of AZTp2AZT-loaded erythrocytes to human, feline, and murine macrophages afforded almost complete in vitro protection of these cells from infection by HIVBa-L, FIV, and LP-BM5, respectively. Therefore, AZTp2AZT, unlike the membrane-diffusing azidothymidine, acts as a very efficient antiretroviral prodrug following selective targeting to macrophages by means of loaded erythrocytes.

Keywords: Animal Antiviral Agents/CHEMICAL SYNTHESIS/*PHARMACOLOGY Base Sequence Cats Cells, Cultured DNA Primers Erythrocytes/CYTOLOGY/DRUG EFFECTS/VIROLOGY Human HIV-1/*DRUG EFFECTS/PHYSIOLOGY/PATHOGENICITY Immunodeficiency Virus, Feline/*DRUG EFFECTS/PHYSIOLOGY/ PATHOGENICITY Kinetics Macrophages/CYTOLOGY/DRUG EFFECTS/*VIROLOGY Mice Mice, Inbred C57BL Molecular Sequence Data Molecular Structure Phagocytosis/DRUG EFFECTS Polymerase Chain Reaction Prodrugs/CHEMICAL SYNTHESIS/*PHARMACOLOGY Support, Non-U.S. Gov't Thymine Nucleotides/CHEMICAL SYNTHESIS/*PHARMACOLOGY Virus Replication/*DRUG EFFECTS JOURNAL ARTICLE
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M9690885

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