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Mechanism of anti-H...
Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives
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Balzarini, J (author)
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- Karlsson, A (author)
- Karolinska Institutet
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Aquaro, S (author)
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Perno, CF (author)
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Cahard, D (author)
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Naesens, L (author)
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DeClercq, E (author)
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McGuigan, C (author)
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(creator_code:org_t)
- 1996-07-09
- 1996
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 93:14, s. 7295-7299
- Related links:
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http://www.pnas.org/...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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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 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.
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