Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress.
Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress.
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DOI：
10.1016/j.bmcl.2016.06.053
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发表时间：
2016-08-01
影响因子：
2.7
通讯作者：
Reitz AB
中科院分区：
文献类型：
--
作者：
Loughran HM;Han Z;Wrobel JE;Decker SE;Ruthel G;Freedman BD;Harty RN;Reitz AB
我们制备了一系列喹喔啉-2-巯基-乙酰基-脲类似物，并在HEK 293 T细胞中的马尔堡和埃博拉病毒VP 40 VLP出芽测定中评价了它们抑制病毒流出的能力。我们还在双分子互补试验（BiMC）中评价了选定的化合物，以检测和可视化活哺乳动物细胞中的马尔堡mVP 40-Nedd 4相互作用。使用表达EBOV VP 40 PPxY L-结构域的活重组水泡性口炎病毒（VSV）（M40病毒）评估所选化合物的抗病毒活性。最后，在几种ADME测定中评价所选化合物，以对其药物性质进行早期评估。我们的化合物在这些测定中具有低nM效力（例如，化合物21、24、26、39），并且具有良好的人肝微粒体稳定性，以及对P450 3A 4的抑制很少或没有抑制。
We prepared a series of quinoxalin-2-mercapto-acetyl-urea analogs and evaluated them for their ability to inhibit viral egress in our Marburg and Ebola VP40 VLP budding assays in HEK293T cells. We also evaluated selected compounds in our bimolecular complementation assay (BiMC) to detect and visualize a Marburg mVP40-Nedd4 interaction in live mammalian cells. Antiviral activity was assessed for selected compounds using a live recombinant vesicular stomatitis virus (VSV) (M40 virus) that expresses the EBOV VP40 PPxY L-domain. Finally selected compounds were evaluated in several ADME assays to have an early assessment of their drug properties. Our compounds had low nM potency in these assays (e.g., compounds 21, 24, 26, 39), and had good human liver microsome stability, as well as little or no inhibition of P450 3A4.