Title : Prodrugs of gamma-Alkyl-modified Nucleoside Triphosphates - improved Inhibition of HIV Reverse Transcriptase - Meier_2020_Angew.Chem.Int.Ed.Engl__ |
Author(s) : Meier C , Zhao C , Weber S , Schols D , Balzarini J |
Ref : Angew Chem Int Ed Engl , : , 2020 |
Abstract :
The development of nucleoside triphosphate prodrugs is one option to apply nucleoside reverse transcriptase inhibitors. Here, we report on the synthesis and evaluation of of d4TTP analogues in which the gamma-phosphate was modified covalently by lipophilic alkyl residues and on acyloxybenzyl-prodrugs of such gamma-alkyl-modified d4TTPs . Thus, the intracellular delivery of gamma-alkyl-d4TTP was aimed. . Selective formation of gamma-alkyl-d4TTP was proven with esterase and in CD4+-cell extracts. In contrast to d4TTP, gamma-alkyl-d4TTPs proved highly stable against dephosphorylation. Primer extension assays with HIV-RT and DNA-polymerases alpha, beta or gamma showed that gamma-alkyl-d4TTPs were substrates for 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 gamma-alkyl-NTPs may potentially lead to a higher selectivity of NTPs towards the viral polymerase to act in virus-infected cells. |
PubMedSearch : Meier_2020_Angew.Chem.Int.Ed.Engl__ |
PubMedID: 32379948 |
Meier C, Zhao C, Weber S, Schols D, Balzarini J (2020)
Prodrugs of gamma-Alkyl-modified Nucleoside Triphosphates - improved Inhibition of HIV Reverse Transcriptase
Angew Chem Int Ed Engl
:
Meier C, Zhao C, Weber S, Schols D, Balzarini J (2020)
Angew Chem Int Ed Engl
: