Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals.
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.
Institute of Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
Tristan
T
Gollnest
Institute of Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
Thiago Dinis
TD
de Oliveira
Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Dominique
D
Schols
Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Jan
J
Balzarini
Institute of Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
Chris
C
Meier
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000821:virology; D013942:Thymine Nucleotides / Q000737:chemistry / Q000494:pharmacology*
D019380:Anti-HIV Agents; D011355:Prodrugs; D013942:Thymine Nucleotides; C024157:thymidine 5'-triphosphate