Title: Metabolism and anti-HIV activity of phosphoramidate derivatives of D4T-MP with variations in the amino acid moiety
Authors: Naesens, Lieve
Cahard, D
Salgado, A
Bidois, L
De Clercq, Erik
McGuigan, C
Balzarini, Jan #
Issue Date: Jan-1998
Host Document: Advances in Experimental Medicine and Biology vol:431 pages:753-7
Conference: Proceedings of the 9th International/6th Eropean Joint Symposium on Purine & Pyrimidine Metabolism in Man location:Gmunden, Austria date:1-7 June 1997
Abstract: The metabolism of different phosphoramidate prodrugs of d4T-MP, in which the phosphate group is linked to a phenyl group and the alkyl ester of an amino acid was studied in crude CEM cell extracts. Significant (80-100%) conversion to the amino acyl d4T-MP metabolite was obtained with derivatives containing L-alanine or methyl-L-aspartic acid. A lower degree of conversion was seen with derivatives containing L-phenylalanine, L-methionine, methyl-L-glutamic acid or L-leucine. Derivatives containing D-alanine, beta-alanine, glycine, L-valine or L-lactate showed no conversion to the amino acyl d4T-MP metabolite. Overall, there was a close correlation between the anti-HIV activity of these prodrugs and their conversion rate to the amino acyl d4T-MP metabolite. Our data suggest that the enzymes involved in the formation of the amino acyl d4T-MP metabolite have a rather stringent specificity for L-alanine as the amino acid moiety. In addition, these enzymes were found to be markedly species-dependent, their activities being highest in mouse serum, followed by guinea pig serum, but only minimal in human serum. Mouse serum therefore appears to be the medium of choice to isolate and identify the enzymes that are involved in the metabolism of these phosphoramidate prodrugs.
ISSN: 0065-2598
Publication status: published
KU Leuven publication type: IC
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
# (joint) last author

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