Potent DNA chain termination activity and selective inhibition of human immunodeficiency virus reverse transcriptase by 2′,3′-dideoxyuridine-5′-triphosphate

Zhang Hao, David A. Cooney, David Farquhar, Carlo F. Perno, K. Zhang, R. Masood, Yvonne Wilson, Neil R. Hartman, Jan Balzarini, David G. Johns

Research output: Contribution to journalArticle

Abstract

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 μM) and avian myeloblastosis virus (Ki, 1.0 μM). Bacterial DNA polymerase I, mammalian DNA polymerase α, 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.

Original languageEnglish
Pages (from-to)157-163
Number of pages7
JournalMolecular Pharmacology
Volume37
Issue number2
Publication statusPublished - Feb 1990

Fingerprint

DNA
Avian Myeloblastosis Virus
HIV
Moloney murine leukemia virus
HIV Reverse Transcriptase
Bacterial DNA
DNA Polymerase I
DNA Nucleotidylexotransferase
RNA-Directed DNA Polymerase
DNA-Directed DNA Polymerase
Human immunodeficiency virus 2 reverse transcriptase
triphosphoric acid
Therapeutics
thymidine 5'-triphosphate

ASJC Scopus subject areas

  • Pharmacology

Cite this

Potent DNA chain termination activity and selective inhibition of human immunodeficiency virus reverse transcriptase by 2′,3′-dideoxyuridine-5′-triphosphate. / Hao, Zhang; Cooney, David A.; Farquhar, David; Perno, Carlo F.; Zhang, K.; Masood, R.; Wilson, Yvonne; Hartman, Neil R.; Balzarini, Jan; Johns, David G.

In: Molecular Pharmacology, Vol. 37, No. 2, 02.1990, p. 157-163.

Research output: Contribution to journalArticle

Hao, Z, Cooney, DA, Farquhar, D, Perno, CF, Zhang, K, Masood, R, Wilson, Y, Hartman, NR, Balzarini, J & Johns, DG 1990, 'Potent DNA chain termination activity and selective inhibition of human immunodeficiency virus reverse transcriptase by 2′,3′-dideoxyuridine-5′-triphosphate', Molecular Pharmacology, vol. 37, no. 2, pp. 157-163.
Hao, Zhang ; Cooney, David A. ; Farquhar, David ; Perno, Carlo F. ; Zhang, K. ; Masood, R. ; Wilson, Yvonne ; Hartman, Neil R. ; Balzarini, Jan ; Johns, David G. / Potent DNA chain termination activity and selective inhibition of human immunodeficiency virus reverse transcriptase by 2′,3′-dideoxyuridine-5′-triphosphate. In: Molecular Pharmacology. 1990 ; Vol. 37, No. 2. pp. 157-163.
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AB - 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 μM) and avian myeloblastosis virus (Ki, 1.0 μM). Bacterial DNA polymerase I, mammalian DNA polymerase α, 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.

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