Dataset Information

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

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

Zhao Chenglong C Weber Stefan S Schols Dominique D Balzarini Jan J Meier Chris C

Angewandte Chemie (International ed. in English) 20200930 49

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 γ-phosphate was modified covalently by lipophilic alkyl residues, and acyloxybenzyl prodrugs of these γ-alkyl-modified d4TTPs, with the aim of delivering of γ-alkyl-d4TTP into cells. Selective formation of γ-alkyl-d4TTP was proven with esterase and in CD4<sup>+</sup> -cell extracts. In contrast to d ...[more]

PMID: 32379948

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Project description:Background & aimsWhile certain nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are efficacious in treating HBV infection, their effects are yet to be optimized and the emergence of NRTI-resistant HBV variants is an issue because of the requirement for lifelong treatment. The development of agents that more profoundly suppress wild-type and drug-resistant HBVs, and that have a long-acting effect, are crucial to improve patient outcomes.MethodsHerein, we synthesized a novel long-acting 4'-modified NRTI termed E-CFCP. We tested its anti-HBV activity in vitro, before evaluating its anti-HBV activity in HBV-infected human-liver-chimeric mice (PXB-mice). E-CFCP's long-acting features and E-CFCP-triphosphate's interactions with the HBV reverse transcriptase (HBV-RT) were examined.ResultsE-CFCP potently blocked HBVWTD1 production (IC50qPCR_cell=1.8 nM) in HepG2.2.15 cells and HBVWTC2 (IC50SB_cell=0.7 nM), entecavir (ETV)-resistant HBVETV-RL180M/S202G/M204V (IC50SB_cell=77.5 nM), and adefovir-resistant HBVADV-RA181T/N236T production (IC50SB_cell=14.1 nM) in Huh7 cells. E-CFCP profoundly inhibited intracellular HBV DNA production to below the detection limit, but ETV and tenofovir alafenamide (TAF) failed to do so. E-CFCP also showed less toxicity than ETV and TAF. E-CFCP better penetrated hepatocytes and was better tri-phosphorylated; E-CFCP-triphosphate persisted intracellularly for longer than ETV-triphosphate. Once-daily peroral E-CFCP administration over 2 weeks (0.02~0.2 mg/kg/day) reduced HBVWTC2-viremia by 2-3 logs in PXB-mice without significant toxicities and the reduction persisted over 1-3 weeks following treatment cessation, suggesting once-weekly dosing capabilities. E-CFCP also reduced HBVETV-RL180M/S202G/M204V-viremia by 2 logs over 2 weeks, while ETV completely failed to reduce HBVETV-RL180M/S202G/M204V-viremia. E-CFCP's 4'-cyano and fluorine interact with both HBVWT-RT and HBVETV-RL180M/S202G-M204 -RT via Van der Waals and polar forces, being important for E-CFCP-triphosphate's interactions and anti-HBV potency.ConclusionE-CFCP represents the first reported potential long-acting NRTI with potent activity against wild-type and treatment-resistant HBV.Lay summaryAlthough there are currently effective treatment options for HBV, treatment-resistant variants and the need for lifelong therapy pose a significant challenge. Therefore, the development of new treatment options is crucial to improve outcomes and quality of life. Herein, we report preclinical evidence showing that the anti-HBV agent, E-CFCP, has potent activity against wild-type and treatment-resistant variants. In addition, once-weekly oral dosing may be possible, which is preferrable to the current daily dosing regimens.

Dataset Information

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

Publications

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

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