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 GEM, 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 thymidine 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 approximate to 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.

Balzarini, J., Karlsson, A., Aquaro, S., Perno, C.f., Cahard, D., Naesens, L., et al. (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, 93(14), 7295-7299 [10.1073/pnas.93.14.7295].

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

AQUARO, STEFANO;PERNO, CARLO FEDERICO;
1996-01-01

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 GEM, 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 thymidine 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 approximate to 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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07 - Microbiologia e Microbiologia Clinica
English
Con Impact Factor ISI
2',3' dideoxy 2',3' didehydrothymidine 5' monophosphate; antivirus agent; drug metabolite; phosphoramidic acid derivative; so 324; stavudine; tritium; unclassified drug; antiviral activity; article; drug mechanism; human; human cell; human immunodeficiency virus; isotope labeling; lymphocyte culture; methylation; nonhuman; priority journal; retrovirus; virus inhibition; virus replication; Alanine; Antiviral Agents; Biotransformation; Cell Line; HIV-1; HIV-2; Humans; Indicators and Reagents; Lymphocytes; Macrophages; Molecular Structure; Monocytes; Phosphorylation; Prodrugs; T-Lymphocytes, Helper-Inducer; Thymidine Monophosphate; Tritium
Balzarini, J., Karlsson, A., Aquaro, S., Perno, C.f., Cahard, D., Naesens, L., et al. (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, 93(14), 7295-7299 [10.1073/pnas.93.14.7295].
Balzarini, J; Karlsson, A; Aquaro, S; Perno, Cf; Cahard, D; Naesens, L; De Clercq, E; Mcguigan, C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/51560
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