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. and McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X 1996. Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives. Proceedings of the National Academy of Sciences 93 (14) , pp. 7295-7299.

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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 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 approximately 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Pharmacy Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RS Pharmacy and materia medica
Publisher:	National Academy of Sciences
ISSN:	1091-6490
Last Modified:	24 Oct 2022 11:12
URI:	https://orca.cardiff.ac.uk/id/eprint/47273

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