A Chemical Strategy for Intracellular Arming of an Endogenous Broad-Spectrum Antiviral Nucleotide,Journal of Medicinal Chemistry

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A Chemical Strategy for Intracellular Arming of an Endogenous Broad-Spectrum Antiviral Nucleotide
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-18 , DOI: 10.1021/acs.jmedchem.1c01481
Kellan T Passow ₁ , Haley S Caldwell _{2,

3} , Kiet A Ngo ₃ , Jamie J Arnold ₄ , Nicole M Antczak ₅ , Anoop Narayanan ₄ , Joyce Jose _{4,

6} , Shana J Sturla ₅ , Craig E Cameron ₄ , Alexander T Ciota _{2,

3} , Daniel A Harki ₁

Affiliation

The naturally occurring nucleotide 3′-deoxy-3′,4′-didehydro-cytidine-5′-triphosphate (ddhCTP) was recently found to exert potent and broad-spectrum antiviral activity. However, nucleoside 5′-triphosphates in general are not cell-permeable, which precludes the direct use of ddhCTP as a therapeutic. To harness the therapeutic potential of this endogenous antiviral nucleotide, we synthesized phosphoramidate prodrug HLB-0532247 (1) and found it to result in dramatically elevated levels of ddhCTP in cells. We compared 1 and 3′-deoxy-3′,4′-didehydro-cytidine (ddhC) and found that 1 more effectively reduces titers of Zika and West Nile viruses in cell culture with minimal nonspecific toxicity to host cells. We conclude that 1 is a promising antiviral agent based on a novel strategy of facilitating elevated levels of the endogenous ddhCTP antiviral nucleotide.

中文翻译：

内源性广谱抗病毒核苷酸的细胞内武装化学策略

最近发现天然存在的核苷酸 3'-deoxy-3',4'-didehydro-cytidine-5'-triphosphate ( ddhCTP ) 具有强效和广谱的抗病毒活性。然而，核苷 5'-三磷酸通常不具有细胞渗透性，这排除了直接使用ddhCTP作为治疗剂。为了利用这种内源性抗病毒核苷酸的治疗潜力，我们合成了氨基磷酸酯前药 HLB-0532247 ( 1 ) 并发现它导致细胞中ddhCTP水平显着升高。我们比较了1和 3'-deoxy-3',4'-didehydro-cytidine ( ddhC )，发现1更有效地降低细胞培养中寨卡病毒和西尼罗河病毒的滴度，对宿主细胞的非特异性毒性最小。我们得出结论，基于促进内源性ddhCTP抗病毒核苷酸水平升高的新策略， 1是一种有前途的抗病毒剂。

更新日期：2021-10-28

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