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用高通量查识别糖原合成酶激酶3alpha/beta作为HBV转录所需的宿主因子

Hironori Nishitsuji^1,2, Yui Naito¹, Yuuna Murakami¹

¹Department of Virology, Fujita Health University School of Medicine, Toyoake, Japan.

Hepatology (Baltimore, Md.)

|January 23, 2025

概括

研究人员确定了糖原合成酶激酶3 (GSK3) 抑制剂作为B型肝炎病毒 (HBV) 感染的潜在治疗方法. 这些GSK3抑制剂通过向FOXK2蛋白来抑制HBV复制,为肝病提供了新的治疗途径.

科学领域:

肝病学和病毒学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

乙型肝炎病毒 (HBV) 感染会导致严重的肝脏疾病,如肝硬化和肝细胞癌 (HCC).
确定调节HBV复制的宿主因素对于开发新的治疗点至关重要.
作为HBV入口受体的甲酸共运输聚 (NTCP) 的发现促进了研究HBV感染的基于细胞的试验的开发.

研究的目的:

建立基于HBV的强大的记者基因表达系统,用于宿主因子查.
识别调节HBV复制和传播的宿主因素和化合物.
调查糖原合成酶激酶3 (GSK3) 和其下游点在HBV感染中的作用.

主要方法:

开发一种基于HBV的记者基因表达系统,模仿完整的HBV复制周期.
对1827个食品和药物管理局批准的化合物的查,以识别抗HBV药物.
蛋白质组分析以确定由GSK3alpha/beta酸化的宿主蛋白质,并通过基因淘汰和救援实验调查它们在HBV复制中的作用.

主要成果:

鉴定出GSK3α/β抑制剂 (例如,AZD1080,BIO) 是一种强大的抗HBV化合物,抑制HBeAg和HBsAg的产生.
发现GSK3alpha/beta可以酸化叉盒K1/2 (FOXK1/2).
淘汰FOXK1/2减少了HBV复制,FOXK2在Ser 424上的酸化对GSK3介导的HBV传播至关重要. 观察到FOXK2可以结合HBV DNA.

结论:

开发的基于HBV的查系统有效地发现了新的治疗点.
GSK3抑制剂代表了有前途的抗HBV药物,向FOXK2-介导的复制途径.
针对GSK3/FOXK2轴提供了管理HBV感染的潜在策略.

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