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Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals.

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 ?-phosphate of NTPs is bioreversibly modified. A series of TriPPPro-compounds bearing two lipophilic masking units at the ?-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.

SUBMITTER: Gollnest T

PROVIDER: S-EPMC4640093 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals.

Gollnest Tristan T de Oliveira Thiago Dinis TD Schols Dominique D Balzarini Jan J Meier Chris C

Nature communications 20151027

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 w ...[more]

PMID: 26503889

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