Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-human immunodeficiency virus compounds.
3'-Azido-2',3'-dideoxythymidine (AZT) and 2',3'-didehydro-2',3'-dideoxythymidine (D4T) are potent and selective inhibitors of human immunodeficiency virus replication in MT-4 and ATH8 cells. They are also inhibitory to the replication of murine retroviruses, i.e. Moloney murine sarcoma virus-induced transformation of C3H cells. In MT-4 cells AZT is readily phosphorylated to its 5'-monophosphate, while the 5'-di- and 5'-triphosphates are generated to a 200-600-fold lower extent than the 5'-monophosphate. D4T is phosphorylated in MT-4 cells to its 5'-monophosphate at a 300-600-fold lower extent than AZT. The phosphorylation of AZT in the thymidine kinase-deficient cell line (Raji/TK-) is severely depressed, while D4T phosphorylation is only slightly diminished in Raji/TK- as compared to Raji/0 cells. D4T has a 10-fold lower affinity for phosphorylation by crude MT-4 cell extracts than AZT (Km, 142 and 14 microM, respectively), and the Vmax for phosphorylation of D4T is only 5% that of AZT. D4T is phosphorylated by MT-4 cell extracts about 180-fold less efficiently than AZT (Vmax/Km, 0.06 for D4T, as compared to 11 for AZT), and this is consistent with the differences found in the amounts of phosphorylated products of D4T and AZT formed in intact MT-4 cells. The 5'-triphosphates of AZT and D4T are equipotent in their inhibitory effects on the reverse transcriptases from human immunodeficiency virus and Moloney murine leukemia virus.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Herdewijn
P
P
De Clercq
E
E
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000494:pharmacology; D003854:Deoxyribonucleotides / Q000378:metabolism; D015224:Dideoxynucleosides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D009053:Sarcoma Viruses, Murine / Q000187:drug effects; D012995:Solubility; D018119:Stavudine; D013936:Thymidine / Q000494:pharmacology; D015215:Zidovudine / Q000378:metabolism*
D000998:Antiviral Agents; D003854:Deoxyribonucleotides; D015224:Dideoxynucleosides; D003841:Deoxycytidine; D015215:Zidovudine; D018119:Stavudine; D013936:Thymidine