Prodrugs of ?-Alkyl-Modified Nucleoside Triphosphates: Improved Inhibition of HIV Reverse Transcriptase.

ABSTRACT: The development of nucleoside triphosphate prodrugs is one option to apply nucleoside reverse transcriptase inhibitors. Herein, we report the synthesis and evaluation of d4TTP analogues, in which the ?-phosphate was modified covalently by lipophilic alkyl residues, and acyloxybenzyl prodrugs of these ?-alkyl-modified d4TTPs, with the aim of delivering of ?-alkyl-d4TTP into cells. Selective formation of ?-alkyl-d4TTP was proven with esterase and in CD4⁺ -cell extracts. In contrast to d4TTP, ?-alkyl-d4TTPs proved highly stable against dephosphorylation. Primer extension assays with HIV reverse transcriptase (RT) and DNA-polymerases ?, ? or ? showed that ?-alkyl-d4TTPs were substrates for HIV-RT only. In antiviral assays, compounds were highly potent inhibitors of HIV-1 and HIV-2 also in thymidine-kinase-deficient T-cell cultures (CEM/TK^- ). Thus, the intracellular delivery of such ?-alkyl-nucleoside triphosphates may potentially lead to nucleoside triphosphates with a higher selectivity towards the viral polymerase that can act in virus-infected cells.

SUBMITTER: Zhao C 

PROVIDER: S-EPMC7756582 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature