Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives

J. Balzarini, A. Karlsson, S. Aquaro, C. F. Perno, D. Cahard, L. Naesens, E. De Clercq, C. Mcguigan

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So324 is a 2',3'-dideoxy-2',3'-didehydrothymidine-5'-monophosphate (d4T- MP) prodrug containing at the phosphate moiety a phenyl group and the methylester of alanine linked to the phosphate through a phosphoramidate linkage. So324 has anti-HIV activity in human CEM, MT4, and monocyte/macrophage cells that is superior to that of d4T. In contrast to d4T, So324 is also able to inhibit HIV replication in thyroidine kinase- deficient CEM cells. After uptake of So324 by intact human lymphocytes, d4T- MP is released and subsequently converted intracellularly to d4T-TP. In addition, accumulation of substantial amounts of a novel d4T derivative has been found. This d4T metabolite has been characterized as alaninyl d4T- MP. The latter metabolite accumulates at ≃13- to 200-fold higher levels than d4T-TP depending the experimental conditions. Alaninyl d4T-MP should be considered as an intra- and/or extracellular depot form of d4T and/or d4T- MP. These findings may explain the superior anti-retroviral activity of So324 over d4T in cell culture.

Original languageEnglish
Pages (from-to)7295-7299
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
Publication statusPublished - Jul 9 1996

ASJC Scopus subject areas

  • Genetics
  • General


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