Potent DNA chain termination activity and selective inhibition of human immunodeficiency virus reverse transcriptase by 2',3'-dideoxyuridine-5'-triphosphate.
2',3'-Dideoxyuridine (ddUrd) exhibits poor if any anti-human immunodeficiency virus (HIV) activity in ATH8 and MT-4 cells. This is in agreement with the failure of ddUrd to be efficiently anabolized intracellularly to its 5'-triphosphate metabolite. However, 2',3'-dideoxyuridine-5'-triphosphate (ddUTP) proved to be a potent and selective inhibitor of the reverse transcriptase of HIV (Ki, 0.05 microM) and avian myeloblastosis virus (Ki, 1.0 microM). Bacterial DNA polymerase I, mammalian DNA polymerase alpha, terminal deoxyribonucleotidyl transferase, and Moloney murine leukemia virus reverse transcriptase were resistant to ddUTP. ddUTP is incorporated into the growing DNA chain principally at dTTP sites and inhibits further elongation. The potential of ddUTP as an anti-HIV therapeutic agent merits further investigation. However, to achieve this goal, it will be necessary to resort to techniques capable of delivering preformed phosphorylated ddUrd to the susceptible cells.
Hao
Z
Z
Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cooney
D A
DA
Farquhar
D
D
Perno
C F
CF
Zhang
K
K
Masood
R
R
Wilson
Y
Y
Hartman
N R
NR
Balzarini
J
J
Johns
D G
DG
D000818:Animals; D000998:Antiviral Agents; D002460:Cell Line; D004253:DNA Nucleotidylexotransferase / Q000037:antagonists & inhibitors; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004261:DNA Replication / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000378:metabolism; D015224:Dideoxynucleosides / Q000378:metabolism / Q000494:pharmacology; D054306:Dideoxynucleotides; D006678:HIV / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D018894:Reverse Transcriptase Inhibitors; D013698:Templates, Genetic; D014500:Uracil Nucleotides / Q000378:metabolism / Q000494:pharmacology*
D000998:Antiviral Agents; D004277:DNA, Single-Stranded; D015224:Dideoxynucleosides; D054306:Dideoxynucleotides; D018894:Reverse Transcriptase Inhibitors; D014500:Uracil Nucleotides; C059513:2',3'-dideoxyuridine; C063034:2',3'-dideoxyuridine-5'-triphosphate; D004253:DNA Nucleotidylexotransferase; D004256:DNA Polymerase I; D004257:DNA Polymerase II