Lipophilic Triphosphate Prodrugs of Various Nucleoside Analogues

The
antiviral efficacy of many nucleoside analogues is strongly
dependent on their intracellular activation by host cellular kinases
to yield ultimately the bioactive nucleoside analogue triphosphates
(NTP). The metabolic conversion of nucleoside analogues into their
triphosphates often proceeds insufficiently. We developed a nucleoside
triphosphate (NTP) delivery system (the TriPPPro
approach), in which the γ-phosphate is covalently modified by
two different biodegradable masking units, one is the acyloxybenzyl
(AB) moiety and the other is the alkoxycarbonyloxybenzyl (ACB) group.
Such compounds formed NTPs with high selectivity by an enzyme-triggered
mechanism in human T-lymphocyte CEM cell extracts loosing first the
AB moiety, followed by the ACB group. This enables the bypass of all
steps of the intracellular phosphorylation. This approach was applied
here to convert some modestly active or even inactive nucleoside analogues
into powerful biologically active metabolites. Potent antiviral activity
profiles were obtained depending on the lipophilicity of the TriPPPro-NTP prodrugs against HIV-1 and HIV-2 replication in
cultures of infected wild-type CD4+ CEM T-cells and more
importantly in thymidine kinase-deficient CD4+ T-cells
(CEM/TK–). This TriPPPro strategy
offers high potential for future antiviral and antitumoral chemotherapies.