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Anchimerically Activatable Antiviral ProTides
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2017-08-24 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00277
Aniekan Okon , Marcos Romário Matos de Souza 1 , Rachit Shah , Raquel Amorim 1 , Luciana Jesus da Costa 1 , Carston R. Wagner
Affiliation  

This work describes the synthesis and biological evaluation of an anchimerically activated proTide of 2′-C-β-methylguanosine as an inhibitor of dengue virus 2 (DENV-2). The proTide incorporates a chemically cleavable 2-(methylthio)ethyl moiety and a HINT1 hydrolyzable tryptamine phosphoramidate. Inhibition of DENV-2 replication by proTide 6 was 5-fold greater than the parent nucleoside while displaying no apparent cytotoxicity. Furthermore, we demonstrate with a HINT1 inhibitor that the anti DENV-2 activity of the proTide correlates with the activity of HINT1. Taken together, these results demonstrate that a phosphoramidate based pronucleotide that undergoes an initial nonenzymatic activation step based on anchimeric assistance followed by P–N bond cleavage by HINT1 can be prepared.

中文翻译:

可以嵌合的抗病毒蛋白

这项工作描述了作为登革热病毒2(DENV-2)抑制剂的2' - C -β-甲基鸟苷的经嵌合活化的蛋白质的合成和生物学评估。该proTide结合了化学可裂解的2-(甲硫基)乙基部分和HINT1可水解的色胺磷酰胺盐。proTide 6对DENV-2复制的抑制作用是亲本核苷的5倍以上,而没有明显的细胞毒性。此外,我们用HINT1抑制剂证明了proTide的抗DENV-2活性与HINT1的活性相关。综上所述,这些结果表明,可以制备基于氨基磷酸酯的原核苷酸,该原核苷酸基于基于嵌合体的辅助作用,然后通过HINT1进行P–N键裂解,进行初始的非酶活化步骤。
更新日期:2017-08-24
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