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In Vitro and In Vivo Characterization of the Anti-Zika Virus Activity of ProTides of 2'-C-β-Methylguanosine.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-06-11 , DOI: 10.1021/acsinfecdis.0c00091
Marcos Romário Matos de Souza , Marcela Sabino Cunha , Aniekan Okon 1 , Fábio Luís Lima Monteiro , Loraine Campanati , Carston R Wagner 1 , Luciana Jesus da Costa
Affiliation  

The ProTide approach has emerged as a powerful tool to improve the intracellular delivery of nucleotide analogs with antiviral and anticancer activity. Here, we characterized the anti-ZIKV (ZIKV, Zika virus) activity of two ProTides of 2′-C-β-methylguanosine. ProTide UMN-1001 is a 2′-C-β-methylguanosine tryptamine phosphoramidate monoester, and ProTide UMN-1002 is a 2-(methylthio)-ethyl-2′-C-β-methylguanosine tryptamine phosphoramidate diester. UMN-1002 undergoes stepwise intracellular activation to the corresponding nucleotide monophosphate followed by P–N bond cleavage by intracellular histidine triad nucleotide binding protein 1 (Hint1). UMN-1001 is activated by Hint1 but is less cell-permeable than UMN-1002. UMN-1001 and UMN-1002 were found to be more potent than 2′-C-β-methylguanosine against ZIKV in human-derived microvascular endothelial and neuroblastoma cells and in reducing ZIKV RNA replication. Studies with a newborn mouse model of ZIKV infection demonstrated that, while treatment with 2′-C-β-methylguanosine and UMN-1001 was lethal, treatment with UMN-1002 was nontoxic and significantly reduced ZIKV infection. Our data suggests that anchimeric activated ProTides of 2′-C-β-methyl nucleosides should be further investigated for their potential as anti-ZIKV therapeutics.

中文翻译:

2'-C-β-甲基鸟苷脯氨酸的抗寨卡病毒活性的体外和体内表征。

ProTide方法已经成为一种强大的工具,可以改善具有抗病毒和抗癌活性的核苷酸类似物的细胞内递送。在这里,我们表征了两个2'-C-β-甲基鸟苷ProTide的抗ZIKV(ZIKV,Zika病毒)活性。ProTide UMN-1001是2'-C-β-甲基鸟苷色胺磷酰胺酸酯单酯,ProTide UMN-1002是2-(甲硫基)-乙基-2'-C-β-甲基鸟苷色胺磷酰胺酸酯二酯。UMN-1002逐步经历细胞内活化,形成相应的单磷酸核苷酸,然后通过细胞内组氨酸三联体核苷酸结合蛋白1(Hint1)进行P–N键裂解。UMN-1001被Hint1激活,但比UMN-1002的细胞渗透性低。在人源性微血管内皮细胞和神经母细胞瘤细胞中,发现UMN-1001UMN-1002比2'-C-β-甲基鸟苷对ZIKV更有效,并且在减少ZIKV RNA复制方面也更有效。对ZIKV感染的新生小鼠模型的研究表明,虽然2'-C-β-甲基鸟苷和UMN-1001的治疗具有致命性,但UMN-1002的治疗无毒,可显着减少ZIKV感染。我们的数据表明,应进一步研究2'-C-β-甲基核苷的嵌合体活化ProTides作为抗ZIKV治疗剂的潜力。
更新日期:2020-07-10
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