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

ABSTRACT: 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 ?-phosphate of the NTP aiming to achieve the metabolic bypass. Thus, ?-non-symmetrically dimasked TriPPPro-compounds (?-(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.

SUBMITTER: Zhao C 

PROVIDER: S-EPMC7894357 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature