Anti-HIV action possessing a dual mechanism of masked alaninyl d4T-MP derivatives.
Int Conf AIDS 1996 Jul 7-12; 11:57 (abstract no. Mo.A.1012) Balzarini J, Egberink H, Hartmann K, Karlsson A, Perno CF, Cahard D, Vahlenkamp T, Thormar H, De Clercq E, McGuigan C; Rega Institute for Medical Research, Leuven, Belgium. Fax: 32-16-33.73.40.
Masked nucleoside phosphoramidate derivatives of stavudine (d4T) such as So324 were found to show a marked anti-HIV activity in cell culture. So324 proved more inhibitory to HIV replication in thymidine kinase-deficient CEM/TK- cells than in wild-type cells, whereas under similar experimental conditions d4T showed a 50- to 100-fold reduction in antiviral potency in the CEM/TK- cells. So324 represents the 5'-monophosphate derivative of d4T (d4T-MP), its phosphate moiety being esterified by a phenyl group and linked through a phosphoramidate linkage to the methyl ester of L-alanine. So324 releases intracellularly both d4T-MP and alaninyl d4T-MP. d4T-MP is further metabolized to its 5'-triphosphate form (d4T-TP), which is a potent inhibitor of HIV reverse transcriptase. Alaninyl d4T-MP accumulates inside the target cells to much higher levels than d4T-TP. Alaninyl d4T-MP was found to accumulate in all cell types examined (human lymphocytes, epithelial cells and monocyte/macrophages, and simian, feline, caprine and murine lymphocyte and fibroblast cells), and should be considered as a depot form for the intracellular release of d4T and d4T-MP. The masked nucleoside phosphoramidate derivative of d4T opens new perspectives in the design of novel prodrugs of nucleoside analogues.
Keywords: AEGIS, Stavudine, HIV, Thymidine Monophosphate, Anti-HIV Agents, Reverse Transcriptase Inhibitors, Prodrugs, Nucleosides, Alanine, HIV-1 Reverse Transcriptase, Monocytes, Macrophages, Lymphocytes, Thymidine Kinase, RNA-Directed DNA Polymerase, 2',3'-dideoxy-2',3'-didehydrothymidine monophosphate, So 324, Animal, Cats, Human, ICA11
