The development of nucleoside triphosphate prodrugs is one option to apply nucleoside reverse transcriptase inhibitors.H erein, we report the synthesis and evaluation of d4TTP analogues,i nw hich the g-phosphate was modified covalently by lipophilic alkylr esidues,a nd acyloxybenzyl prodrugs of these g-alkyl-modified d4TTPs,w ith the aim of delivering of g-alkyl-d4TTP into cells.S elective formation of g-alkyl-d4TTP was proven with esterase and in CD4 +-cell extracts.I nc ontrast to d4TTP, g-alkyl-d4TTPs proved highly stable against dephosphorylation. Primer extension assays with HIV reverse transcriptase (RT) and DNA-polymerases a, b or g showed that g-alkyl-d4TTPs were substrates for HIV-RT only.I na ntiviral assays,c ompounds were highly potent inhibitors of HIV-1 and HIV-2 also in thymidine-kinasedeficient T-cell cultures (CEM/TK À). Thus,t he intracellular delivery of such g-alkyl-nucleoside triphosphates mayp otentially lead to nucleoside triphosphates with ahigher selectivity towards the viral polymerase that can act in virus-infected cells.
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.
Background Fowl adenovirus is of major concern to the poultry industry worldwidely. In order to monitor the prevalent status of Fowl adenovirus in China, a total of 1920 clinical samples from apparently healthy birds in the 25 sites of poultry flocks, Slaughterhouse and living bird markets from 8 provinces in eastern China were collected and detected by PCR, sequencing, and phylogenetic analysis. Results The epidemiological survey showed that Fowl adenoviruses were detected in living bird markets, and circulating in a variety of fowl species, including chickens, ducks, goose and pigeons. Among the 1920 clinical samples, 166 samples (8.65%) were positive in the fowl adenovirus PCR detection. In this study, totally all the 12 serotypes (serotypes of 1, 2, 3, 4, 5, 6, 7, 8A, 8B, 9, 10 and 11) fowl adenoviruses were detected, the most prevalent serotype was serotype 1. Phylogenetic analysis indicated that 166 FAdVs of 12 serotypes were divided into 5 fowl adenovirus species (Fowl aviadenovirus A, B, C, D, E). Conclusions In the epidemiological survey, 8.65% of the clinical samples from apparently healthy birds were positive in the fowl adenovirus PCR detection. Totally all the 12 serotypes fowl adenoviruses were detected in a variety of fowl species, which provided abundant resources for the research of fowl adenoviruses in China. The newly prevalent FAdV serotypes provides valuable information for the development of an effective control strategy for FAdV infections in fowls.
The development of nucleoside triphosphate prodrugs is one option to apply nucleoside reverse transcriptase inhibitors.H erein, we report the synthesis and evaluation of d4TTP analogues,i nw hich the g-phosphate was modified covalently by lipophilic alkylr esidues,a nd acyloxybenzyl prodrugs of these g-alkyl-modified d4TTPs,w ith the aim of delivering of g-alkyl-d4TTP into cells.S elective formation of g-alkyl-d4TTP was proven with esterase and in CD4 +-cell extracts.I nc ontrast to d4TTP, g-alkyl-d4TTPs proved highly stable against dephosphorylation. Primer extension assays with HIV reverse transcriptase (RT) and DNA-polymerases a, b or g showed that g-alkyl-d4TTPs were substrates for HIV-RT only.I na ntiviral assays,c ompounds were highly potent inhibitors of HIV-1 and HIV-2 also in thymidine-kinase-deficient T-cell cultures (CEM/TK À). Thus,t he intracellular delivery of such g-alkyl-nucleoside triphosphates may potentially lead to nucleoside triphosphates with ah igher selectivity towards the viral polymerase that can act in virus-infected cells.
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