Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals

Tristan Gollnest, Thiago Dinis de Oliveira, Dominique Schols, Jan Balzarini and Chris Meier ()
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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

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9716

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