Amino acid phosphoramidates of antiviral 3-deazaadenosine analogs exhibit high potency and low cytotoxicity

E. J. McIntee, C. R. Wagner, V. Giordano, K. T. Jeang, P. K. Chiang

Research output: Contribution to journalArticle

Abstract

Currently, nucleoside based reverse transcriptaseinhibitors are being successfully employed as potent antiviral agents. Although the mechanism of action is unknown, the 3-deazaadenosine analogs, 3-deazaadenosine (DZA), 3-deaza-(±)-aristeromycin (DZAri), 3-deazaneplanocin A (DZNep) have been found to have significant antiviral activity against AZT sensitive and resistant clinical isolates of HIV-1. Recently, we have demonstrated that amino acid phosphoramidates of AZT and d4T exhibit significant antiviral activity with considerably reduced cytotoxicity. Consequently, in order to examine the generality of this approach, we have constructed phenylalanine and tryptophan phosphoramidates of DZA, DZAri and DZAra-A. Preliminary results have demonstrated that the tryptophan phosphoramidate is nearly 40-fold more active than DZA, while the phenylalanine derivative is nearly 10-fold more active than DZA. As was observed for AZT-phosphoramidates, the DZA phosphoramidates exhibited no detectable cytotoxicity to PBMCs at concentrations as high as 10 μM. Unlike DZA itself, the phosphoramidates of DZA did not exhibit activity against AZT resistant HIV-1. Additionally, both DZA phosphoramidates were also effective against HIV-1 in MT4 cells.

Original languageEnglish (US)
JournalFASEB Journal
Volume12
Issue number5
StatePublished - Mar 20 1998

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Cytotoxicity
Human immunodeficiency virus 1
Antiviral Agents
cytotoxicity
Amino Acids
phenylalanine
tryptophan
amino acids
antiviral agents
nucleosides
mononuclear leukocytes
HIV-1
mechanism of action
chemical derivatives
Phenylalanine
Tryptophan
phosphoramidic acid
3-deazaadenosine
cells
Nucleosides

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Amino acid phosphoramidates of antiviral 3-deazaadenosine analogs exhibit high potency and low cytotoxicity. / McIntee, E. J.; Wagner, C. R.; Giordano, V.; Jeang, K. T.; Chiang, P. K.

In: FASEB Journal, Vol. 12, No. 5, 20.03.1998.

Research output: Contribution to journalArticle

McIntee, E. J. ; Wagner, C. R. ; Giordano, V. ; Jeang, K. T. ; Chiang, P. K. / Amino acid phosphoramidates of antiviral 3-deazaadenosine analogs exhibit high potency and low cytotoxicity. In: FASEB Journal. 1998 ; Vol. 12, No. 5.
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AU - Wagner, C. R.

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AU - Chiang, P. K.

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