Metabolism and anti-human immunodeficiency virus-1 activity of 2-halo-2',3'-dideoxyadenosine derivatives

T. Haertle, C. J. Carrera, D. B. Wasson, Lawrence Sowers, D. D. Richman, D. A. Carson

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Both 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine have been shown (Mitsuya, H., and Broder, S. (1987) Nature 325, 773-778) to have in vitro activity against the human immunodeficiency virus-1 (HIV). However, these dideoxynucleosides may be catabolized by human T cells, even when adenosine deaminase is inhibited by deoxycoformycin. To overcome this problem, we have synthesized the 2-fluoro-, 2-chloro-, and 2-bromo-derivatives of 2',3'-dideoxyadenosine. The metabolism and anti-HIV activity of the 2-halo-2',3'-dideoxyadenosine derivatives and of 2',3'-dideoxyadenosine were compared. The 2-halo-2',3'-dideoxyadenosine derivatives were not deaminated significantly by cultured CEM T lymphoblasts. Experiments with 2-chloro-2',3'-dideoxyadenosine showed that the T cells converted the dideoxynucleoside to the 5'-monophosphate, 5'-diphosphate, and 5'-triphosphate metabolites. At concentrations lower than those producing cytotoxicity in uninfected cells (3-10 μM), the 2-halo-2',3'-dideoxyadenosine derivatives inhibited the cytopathic effects of HIV toward MT-2 T lymphoblasts, and retarded viral replication in CEM T lymphoblasts. Experiments with a deoxycytidine kinase-deficient mutant CEM T cell line showed that this enzyme was necessary for the phosphorylation and anti-HIV activity of the 2-chloro-2',3'-dideoxyadenosine. In contrast, 2',3'-dideoxyadenosine was phosphorylated by the deoxycytidine kinase-deficient mutant and retained anti-HIV activity in this cell line. Thus, the 2-halo derivatives of 2',3'-dideoxyadenosine, in contrast to 2',3'-dideoxyadenosine itself, are not catabolized by T cells. Their anti-HIV and anti-proliferative activities are manifest only in cells expressing deoxycytidine kinase. The in vivo implications of these results for anti-HIV chemotherapy are discussed.

Original languageEnglish (US)
Pages (from-to)5870-5875
Number of pages6
JournalJournal of Biological Chemistry
Volume263
Issue number12
StatePublished - 1988
Externally publishedYes

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Dideoxyadenosine
Viruses
Metabolism
HIV-1
Derivatives
Deoxycytidine Kinase
T-cells
Dideoxynucleosides
T-Lymphocytes
Pentostatin
Didanosine
Cells
Cell Line
Adenosine Deaminase
Diphosphates
Phosphorylation
Chemotherapy
Cytotoxicity
Metabolites
Experiments

ASJC Scopus subject areas

  • Biochemistry

Cite this

Haertle, T., Carrera, C. J., Wasson, D. B., Sowers, L., Richman, D. D., & Carson, D. A. (1988). Metabolism and anti-human immunodeficiency virus-1 activity of 2-halo-2',3'-dideoxyadenosine derivatives. Journal of Biological Chemistry, 263(12), 5870-5875.

Metabolism and anti-human immunodeficiency virus-1 activity of 2-halo-2',3'-dideoxyadenosine derivatives. / Haertle, T.; Carrera, C. J.; Wasson, D. B.; Sowers, Lawrence; Richman, D. D.; Carson, D. A.

In: Journal of Biological Chemistry, Vol. 263, No. 12, 1988, p. 5870-5875.

Research output: Contribution to journalArticle

Haertle, T, Carrera, CJ, Wasson, DB, Sowers, L, Richman, DD & Carson, DA 1988, 'Metabolism and anti-human immunodeficiency virus-1 activity of 2-halo-2',3'-dideoxyadenosine derivatives', Journal of Biological Chemistry, vol. 263, no. 12, pp. 5870-5875.
Haertle, T. ; Carrera, C. J. ; Wasson, D. B. ; Sowers, Lawrence ; Richman, D. D. ; Carson, D. A. / Metabolism and anti-human immunodeficiency virus-1 activity of 2-halo-2',3'-dideoxyadenosine derivatives. In: Journal of Biological Chemistry. 1988 ; Vol. 263, No. 12. pp. 5870-5875.
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