title: Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.
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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: A
authors.initials: A
authors.lastname: Karlsson
authors.forename: S
authors.initials: S
authors.lastname: Aquaro
authors.forename: C F
authors.initials: CF
authors.lastname: Perno
authors.forename: D
authors.initials: D
authors.lastname: Cahard
authors.forename: L
authors.initials: L
authors.lastname: Naesens
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: C
authors.initials: C
authors.lastname: McGuigan
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D007202:Indicators and Reagents; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages; D015394:Molecular Structure; D009000:Monocytes; D010766:Phosphorylation; D011355:Prodrugs; D006377:T-Lymphocytes, Helper-Inducer; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
chemical_list: D000998:Antiviral Agents; D007202:Indicators and Reagents; D011355:Prodrugs; C100595:So 324; D014316:Tritium; D013938:Thymidine Monophosphate; D000409:Alanine