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

Research output: Contribution to journalArticle

Abstract

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
Volume93
Issue number14
DOIs
Publication statusPublished - Jul 9 1996

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HIV
Phosphates
Prodrugs
Human Activities
Alanine
2',3'-dideoxy-2',3'-didehydrothymidine monophosphate
Monocytes
Phosphotransferases
Cell Culture Techniques
Macrophages
So 324
Lymphocytes

ASJC Scopus subject areas

  • Genetics
  • General

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Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives. / Balzarini, J.; Karlsson, A.; Aquaro, S.; Perno, C. F.; Cahard, D.; Naesens, L.; De Clercq, E.; Mcguigan, C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 14, 09.07.1996, p. 7295-7299.

Research output: Contribution to journalArticle

Balzarini, J, Karlsson, A, Aquaro, S, Perno, CF, Cahard, D, Naesens, L, De Clercq, E & Mcguigan, C 1996, 'Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives', Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 14, pp. 7295-7299. https://doi.org/10.1073/pnas.93.14.7295
Balzarini, J. ; Karlsson, A. ; Aquaro, S. ; Perno, C. F. ; Cahard, D. ; Naesens, L. ; De Clercq, E. ; Mcguigan, C. / Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives. In: Proceedings of the National Academy of Sciences of the United States of America. 1996 ; Vol. 93, No. 14. pp. 7295-7299.
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