Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress

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• 作者：H. Marie Loughran^a ; Ziying Han^b ; Jay E. Wrobel^a ; ; Sarah E. Decker^a ; Gordon Ruthel^b ; Bruce D. Freedman^b ; Ronald N. Harty^b ; Allen B. Reitz^a
• 关键词：Ebola virus ; Marburg virus ; RNA viruses ; Virus egress ; PPxY ; Nedd4 ; L-domain ; Budding ; Antiviral therapeutic
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 August 2016
• 年：2016
• 卷：26
• 期：15
• 页码：3429-3435
• 全文大小：1166 K

文摘

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.