γ-Non-Symmetrically Dimasked TriPPPro Prodrugs as Potential Antiviral Agents against HIV

Nucleoside analogue reverse transcriptase inhibitors (NRTI) and nucleoside analogue monophosphate prodrugs are used in combination antiretroviral therapy (cART). The design of antivirally active nucleoside triphosphate prodrugs is a recent and an important advancement in the field of nucleoside analogue drug development. Here, we report on TriPPPro-derivatives of nucleoside analogue triphosphates (NTPs) that comprised two different acyloxybenzyl-masks at the γ-phosphate of the NTP aiming to achieve the metabolic bypass. Thus, γ-non-symmetrically dimasked TriPPPro-compounds (γ-(AB,ab)-d4TTPs) were synthesized and they proved to be active against HIV-1 and HIV-2 in cultures of infected wild-type human CD4⁺ T-lymphocyte (CEM/0) cells and more importantly also in thymidine kinase-deficient CD4⁺ T-cells (CEM/TK-). From hydrolysis studies both in phosphate buffer (PB, pH 7.3) and CEM cell extracts, there was surprisingly no differentiation in the cleavage of the two acyloxybenzyl prodrug-masks. However, if within one of the two acyloxybenzyl groups a short PEG-type methoxytriglycol group was introduced, the "standard" acyloxybenzyl-mask was cleaved with high preference.