Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
Virology. 2023 Jun;583:1-13. doi: 10.1016/j.virol.2023.03.016. Epub 2023 Apr 5.
Type I interferon (IFN-I) evasion by Dengue virus (DENV) is key in DENV pathogenesis. The non-structural protein 5 (NS5) antagonizes IFN-I response through the degradation of the signal transducer and activator of transcription 2 (STAT2). We developed a K562 cell-based platform, for high throughput screening of compounds potentially counteracting the NS5-mediated antagonism of IFN-I signaling. Upon a screening with a library of 1220 approved drugs, 3 compounds previously linked to DENV inhibition (Apigenin, Chrysin, and Luteolin) were identified. Luteolin and Apigenin determined a significant inhibition of DENV2 replication in Huh7 cells and the restoration of STAT2 phosphorylation in both cell systems. Apigenin and Luteolin were able to stimulate STAT2 even in the absence of infection. Despite the "promiscuous" and "pan-assay-interfering" nature of Luteolin, Apigenin promotes STAT2 Tyr 689 phosphorylation and activation, highlighting the importance of screening for compounds able to interact with host factors, to counteract viral proteins capable of dampening innate immune responses.
Ⅰ型干扰素（IFN-I）逃避登革热病毒（DENV）是 DENV 发病机制的关键。非结构蛋白 5（NS5）通过降解信号转导和转录激活因子 2（STAT2）来拮抗 IFN-I 反应。我们开发了一种基于 K562 细胞的高通量筛选化合物的平台，这些化合物可能对抗 NS5 介导的 IFN-I 信号转导拮抗作用。在对 1220 种已批准药物的文库进行筛选后，发现了 3 种先前与 DENV 抑制相关的化合物（芹菜素、白杨素和木樨草素）。木樨草素和芹菜素可显著抑制 Huh7 细胞中的 DENV2 复制，并在两种细胞系统中恢复 STAT2 磷酸化。芹菜素和木樨草素即使在没有感染的情况下也能刺激 STAT2。尽管木樨草素有“混杂”和“全分析干扰”的性质，但芹菜素能促进 STAT2 Tyr 689 的磷酸化和激活，这突出了筛选能够与宿主因子相互作用的化合物以对抗能够抑制先天免疫反应的病毒蛋白的重要性。
