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Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals

Author

Listed:
  • Tristan Gollnest

    (Institute of Organic Chemistry, Faculty of Sciences, University of Hamburg)

  • Thiago Dinis de Oliveira

    (Institute of Organic Chemistry, Faculty of Sciences, University of Hamburg)

  • Dominique Schols

    (Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven)

  • Jan Balzarini

    (Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven)

  • Chris Meier

    (Institute of Organic Chemistry, Faculty of Sciences, University of Hamburg)

Abstract

The antiviral activity of nucleoside reverse transcriptase inhibitors is often limited by ineffective phosphorylation. We report on a nucleoside triphosphate (NTP) prodrug approach in which the γ-phosphate of NTPs is bioreversibly modified. A series of TriPPPro-compounds bearing two lipophilic masking units at the γ-phosphate and d4T as a nucleoside analogue are synthesized. Successful delivery of d4TTP is demonstrated in human CD4+ T-lymphocyte cell extracts by an enzyme-triggered mechanism with high selectivity. In antiviral assays, the compounds are potent inhibitors of HIV-1 and HIV-2 in CD4+ T-cell (CEM) cultures. Highly lipophilic acyl residues lead to higher membrane permeability that results in intracellular delivery of phosphorylated metabolites in thymidine kinase-deficient CEM/TK− cells with higher antiviral activity than the parent nucleoside.

Suggested Citation

  • Tristan Gollnest & Thiago Dinis de Oliveira & Dominique Schols & Jan Balzarini & Chris Meier, 2015. "Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals," Nature Communications, Nature, vol. 6(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9716
    DOI: 10.1038/ncomms9716
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    1. Sarah Krukenberg & Franziska Möckl & Mariella Weiß & Patrick Dekiert & Melanie Hofmann & Fynn Gerlach & Kai J. Winterberg & Dejan Kovacevic & Imrankhan Khansahib & Berit Troost & Macarena Hinrichs & V, 2024. "MASTER-NAADP: a membrane permeable precursor of the Ca2+ mobilizing second messenger NAADP," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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