Potent Anti‐HIV Activity of Alkyl‐Modified DiPPro‐Nucleotides

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Erscheinungsjahr:
2023
Medientyp:
Text
Beschreibung:
  • Two convergent approaches for synthesizing a new class of nucleoside diphosphate prodrugs bearing different nucleoside analogs are reported herein. The DiPPro-nucleotides comprise an acyloxybenzyl group in combination with a lipophilic alkyl residue at the β-phosphate or β-phosphonate group, respectively. They are selectively cleaved to form their corresponding β-alkylated nucleoside diphosphate derivatives in chemical and biological hydrolysis studies. In contrast, there is a selective but slow cleavage observed in the hydrolysis of the DiPPro-compounds bearing two different, nonbioreversible alkyl moieties in human CD4+ T-lymphocyte CEM/0 cell extracts. In these studies, the delivery of nucleoside monophosphates rather than nucleoside diphosphates is being observed, most likely due to a pure chemical phosphoranhydride cleavage of the β-phosph(on)ate moiety. The antiviral evaluation of these two types of prodrugs reveals that these compounds exhibit marked anti-HIV efficacy in HIV-2-infected thymidine kinase-deficient CD4+ CEM T-cells (CEM/TK), with significantly better activities (up to 6700-fold) against HIV-2 replication than the parent nucleosides. Primer extension assays demonstrate that the β-dialkylphosphate-modified nucleoside derivatives, β-monoalkylated-diphosphates, and nucleoside diphosphates serve as substrates for HIV reverse transcriptase for the viral DNA elongation.
Lizenz:
  • info:eu-repo/semantics/openAccess
Quellsystem:
Forschungsinformationssystem der UHH

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oai:www.edit.fis.uni-hamburg.de:publications/3ffdbb50-de01-4f94-8cf5-2b3a1a8967c4