Phosphoramidate derivatives of d4T with improved anti-HIV efficacy retain full activity in thymidine kinase-deficient cells

McGuigan, Christopher; Cahard, Dominique; Sheeka, Hendrika M.; Clercq, Erik De; Balzarini, Jan

doi:10.1016/0960-894x(96)00195-3

Cited by 56 publications

(22 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The antiviral activities of compounds 1, 2, 3, 4a-c, 5a-f and the recently-prepared analogue 6 (McGuigan et al, 1996) were evaluated in two cell lines (human lymphocyte CEM/O and its thymidine kinase deficient CEMITK-counterpart) versus HIV-1 and HIV-2, with the resulting data shown in Table2. Thus, the previously reported amino acid-derived analogues 2 and 6 were again found to be very potent inhibitors of viral replication.…”

Section: Discussionmentioning

confidence: 99%

Phosphoramidates as Potent Prodrugs of anti-HIV Nucleotides: Studies in the Amino Region

McGuigan

Cahard

Salgado

et al. 1996

Antivir Chem Chemother

View full text Add to dashboard Cite

SummaryNovel phosphoramidate derivatives of the anti-HIV nucleoside analogues AZT and d4T have been prepared by phosphorochloridate chemistry. These materials are designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. All compounds were fully characterised by a range of methods and were subjected to evaluation in vitro of their anti-HIV efficacy. A notable feature of the current study was that any attempt to replace the amino acid moiety of the phosphoramidate with a simple amine lead to a marked, virtually total loss of activity. Such simple phenyl alkylamino phosphate derivatives of either d4T or AZT inhibit HIV replication at cytotoxic concentrations and have no detectable antiviral selectivity. This clearly highlights the Vital role played by the amino acid in the antiviral efficacy of the blocked phosphoramidates.

show abstract

Section: Discussionmentioning

confidence: 99%

Phosphoramidates as Potent Prodrugs of anti-HIV Nucleotides: Studies in the Amino Region

McGuigan

Cahard

Salgado

et al. 1996

Antivir Chem Chemother

View full text Add to dashboard Cite

show abstract

“…Part of the reason for continued interest in phosphoramidates has been their demonstrated utility as prodrugs of antiviral and anticancer nucleoside monophosphates or as pronucleo-tides (21)(22)(23)(24)(25). Typically, therapeutic nucleosides must be converted to the corresponding mono-, di-, and triphosphates before exhibiting biological activity.…”

mentioning

confidence: 99%

31P NMR and Genetic Analysis Establish hinT as the Only Escherchia coli Purine Nucleoside Phosphoramidase and as Essential for Growth under High Salt Conditions

Chou

Bieganowski

Shilinski

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Eukaryotic cells encode AMP-lysine (AMP-N-⑀-(N-␣acetyl lysine methyl ester) 5-phosphoramidate) hydrolases related to the rabbit histidine triad nucleotidebinding protein 1 (Hint1) sequence. Bacterial and archaeal cells have Hint homologs annotated in a variety of ways, but the enzymes have not been characterized, nor have phenotypes been described due to loss of enzymatic activity. We developed a quantitative 31 P NMR assay to determine whether Escherichia coli possesses an adenosine phosphoramidase activity. Indeed, soluble lysates prepared from wild-type laboratory E. coli exhibited activity on the model substrate adenosine 5-monophosphoramidate (AMP-NH 2 ). The E. coli Hint homolog, which had been comprehensively designated ycfF and is here named hinT, was cloned, overexpressed, purified, and characterized with respect to purine nucleoside phosphoramidate substrates. Bacterial hinT was several times more active than human or rabbit Hint1 on five model substrates. In addition, bacterial and mammalian enzymes preferred guanosine versus adenosine phosphoramidates as substrates. Analysis of the lysates from a constructed hinT knock-out strain of E. coli demonstrated that all of the cellular purine nucleoside phosphoramidase activity is due to hinT. Physiological analysis of this mutant revealed that the loss of hinT results in failure to grow in media containing 0.75 M KCl, 0.9 M NaCl, 0.5 M NaOAc, or 10 mM MnCl 2 . Thus, cation-resistant bacterial cell growth may be dependent on the hydrolysis of adenylylated and/or guanylylated phosphoramidate substrates by hinT.

show abstract

“…The rate-limiting step for the generation of the bioactive STV metabolite STV-triphosphate is the conversion of STV to its monophosphate derivative (1)(2)(3)(8)(9)(10). In an attempt to overcome the dependence of STV on intracellular nucleoside kinase activation, we prepared STV-5Ј-(p-bromophenyl methoxyalaninyl phosphate) (stampidine [STAMP]), a novel aryl phosphate derivative of STV, and structurally similar derivatives of STV, zidovudine (ZDV), and lamivudine (19).…”

mentioning

confidence: 99%

Stampidine Is a Potent Inhibitor of Zidovudine- and Nucleoside Analog Reverse Transcriptase Inhibitor-Resistant Primary Clinical Human Immunodeficiency Virus Type 1 Isolates with Thymidine Analog Mutations

Uckun

Pendergrass

Venkatachalam

et al. 2002

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Phosphoramidate derivatives of d4T with improved anti-HIV efficacy retain full activity in thymidine kinase-deficient cells

Cited by 56 publications

References 13 publications

Phosphoramidates as Potent Prodrugs of anti-HIV Nucleotides: Studies in the Amino Region

Phosphoramidates as Potent Prodrugs of anti-HIV Nucleotides: Studies in the Amino Region

31P NMR and Genetic Analysis Establish hinT as the Only Escherchia coli Purine Nucleoside Phosphoramidase and as Essential for Growth under High Salt Conditions

Stampidine Is a Potent Inhibitor of Zidovudine- and Nucleoside Analog Reverse Transcriptase Inhibitor-Resistant Primary Clinical Human Immunodeficiency Virus Type 1 Isolates with Thymidine Analog Mutations

Contact Info

Product

Resources

About