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一种高度选择性和强大的PTP-MEG2抑制剂,对2型糖尿病具有治疗潜力

Sheng Zhang¹, Sijiu Liu, Rongya Tao

¹Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.

Journal of the American Chemical Society

|October 19, 2012

概括

研究人员开发了一种新的化学策略,用于制造蛋白质氨酸酸酶 (PTPs) 的强效和选择性抑制剂,这些酶对细胞信号传递至关重要. 这些新的PTP抑制剂显示出改善胰岛素敏感性和葡萄糖平衡的前景.

科学领域:

生物化学和分子生物学
药理学药理学是指药理学的学科.
代谢疾病代谢疾病

背景情况:

蛋白氨酸酸酶 (PTPs) 是细胞信号通路的关键调节者.
由于缺乏特定的细胞透性抑制剂,PTPs在生理学和疾病中的研究受到限制.
PTP-MEG2与肝脏胰岛素信号传递和代谢失调有关.

研究的目的:

开发一种强大且有选择性的PTP-MEG2抑制剂,针对肝脏胰岛素信号传递.
展示一种可推广的策略,用于创建PTP超级家族的特定抑制剂.
在肥胖的小鼠模型中评估开发的PTP抑制剂的体内疗效.

主要方法:

使用逐步聚焦的库方法来优化一种非水解的pTyr模拟物 (F(2) Pmp).
确定了PTP-MEG2抑制剂复合物的晶体结构,以指导抑制剂的设计.
试验室试验评估了抑制剂的强度和选择性;细胞活性和体内疗效在饮食诱导的肥胖小鼠中进行了测试.

主要成果:

已经成功地将F(2) Pmp支架转化为一种高度强效和选择性的PTP-MEG2抑制剂.
结构分析揭示了关键的相互作用,通过激活活跃和外围结合点来实现特异性.
在肥胖小鼠中,PTP-MEG2抑制剂表现出显著的细胞活性,改善了胰岛素信号传递,胰岛素敏感性和葡萄糖平衡.

结论:

可以有效地修改F(2) Pmp支架,以产生强效的选择性PTP抑制剂,具有强大的体内疗效.
这种化学策略广泛适用于开发针对其他PTP家族成员的特定抑制剂.
向PTP-MEG2为胰岛素抵抗和2型糖尿病等代谢障碍提供了可行的治疗策略.

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