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Exploring the Implication of DDX3X in DENV Infection: Discovery of the First-in-Class DDX3X Fluorescent Inhibitor.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-04-09 , DOI: 10.1021/acsmedchemlett.9b00681
Annalaura Brai 1 , Adele Boccuto 2 , Martina Monti 3 , Serena Marchi 3 , Ilaria Vicenti 2 , Francesco Saladini 2 , Claudia Immacolata Trivisani 1 , Alessandro Pollutri 1 , Claudia Maria Trombetta 3 , Emanuele Montomoli 3, 4 , Valentina Riva 5 , Anna Garbelli 5 , Emanuele Maria Nola 5 , Maurizio Zazzi 2 , Giovanni Maga 5 , Elena Dreassi 1 , Maurizio Botta 1, 6
Affiliation  

In the absence of effective drugs or vaccines for the treatment of the five Dengue Virus serotypes, the search for novel antiviral drugs is of primary importance for the scientific community. In this context, drug repurposing represents the most used strategy; however, the study of host targets is now attracting attention since it allows identification of broad-spectrum drugs endowed with high genetic barrier. In the last ten years our research group identified several small molecules DDX3X inhibitors and proved their efficacy against different viruses including novel emerging ones. Herein, starting from a screening of our compounds, we designed and synthesized novel derivatives with potent activity and high selectivity. Finally, we synthesized a fluorescent inhibitor that allowed us to study DDX3X cellular localization during DENV infection in vitro. Immunofluorescence analysis showed that our inhibitor colocalized with DDX3X, promoting the reduction of infected cells and recovering the number of viable cells.

中文翻译:

探索DDX3X在DENV感染中的意义:发现一流的DDX3X荧光抑制剂。

在缺乏有效的药物或疫苗来治疗五种登革热病毒血清型的情况下,寻找新的抗病毒药物对科学界至关重要。在这种情况下,重新利用毒品是最常用的策略。但是,由于可以鉴定具有高遗传屏障的广谱药物,因此对宿主靶标的研究现在引起了人们的注意。在过去的十年中,我们的研究小组鉴定了几种小分子DDX3X抑制剂,并证明了它们对包括新出现的新病毒在内的不同病毒的功效。在此,从筛选化合物开始,我们设计并合成了具有强活性和高选择性的新型衍生物。最后,我们合成了一种荧光抑制剂,使我们能够在体外DENV感染期间研究DDX3X细胞的定位。免疫荧光分析表明,我们的抑制剂与DDX3X共定位,促进了感染细胞的减少并恢复了活细胞的数量。
更新日期:2020-04-09
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