Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening.
Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening.
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DOI：
10.1371/journal.pone.0005274
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Leissring MA
中科院分区：
文献类型：
--
作者：
Cabrol C;Huzarska MA;Dinolfo C;Rodriguez MC;Reinstatler L;Ni J;Yeh LA;Cuny GD;Stein RL;Selkoe DJ;Leissring MA
胰岛素降解酶（IDE）对淀粉样蛋白β (Aβ)的低分解代谢与阿尔茨海默病（AD）的发病机制有关，使IDE的药理激活成为一种有吸引力的治疗策略。然而，目前尚未确定IDE的蛋白水解活性是否可以通过药物样化合物增强。基于ATP和其他核苷酸多磷酸盐在生理浓度下调节IDE活性的发现，我们在ATP缺失或存在的情况下进行了平行的高通量筛选活动，并确定了两种化合物-指定为Ia1和ia2 -显著刺激IDE蛋白水解活性。这两种化合物都干扰了光亲和ATP类似物与IDE的交联，表明它们与IDE内真正的ATP结合结构域相互作用。出乎意料的是，当在ATP存在的情况下测试Ia1或Ia2的活性时，我们观察到高度协同的激活效应，这一发现对ATP介导的IDE激活机制有影响。值得注意的是，Ia1和Ia2分别激活了~ 700%和~ 400%的a β降解，尽管只有当a β存在于含有较短底物的混合物中时。本研究描述了第一个合成IDE小分子激活剂的例子，表明用药物样化合物对这种重要蛋白酶的药理激活是可以实现的。这些新的激活剂有助于建立假定的ATP结合域作为IDE蛋白水解活性的关键调节剂，并为ATP的调节作用提供了新的见解。从该筛选中提取的几个更大的经验教训将有助于为未来筛选活动的设计提供信息，并促进具有治疗效用的IDE激活剂的最终开发。
Hypocatabolism of the amyloid β-protein (Aβ) by insulin-degrading enzyme (IDE) is implicated in the pathogenesis of Alzheimer disease (AD), making pharmacological activation of IDE an attractive therapeutic strategy. However, it has not been established whether the proteolytic activity of IDE can be enhanced by drug-like compounds. Based on the finding that ATP and other nucleotide polyphosphates modulate IDE activity at physiological concentrations, we conducted parallel high-throughput screening campaigns in the absence or presence of ATP and identified two compounds—designated Ia1 and Ia2—that significantly stimulate IDE proteolytic activity. Both compounds were found to interfere with the crosslinking of a photoaffinity ATP analogue to IDE, suggesting that they interact with a bona fide ATP-binding domain within IDE. Unexpectedly, we observed highly synergistic activation effects when the activity of Ia1 or Ia2 was tested in the presence of ATP, a finding that has implications for the mechanisms underlying ATP-mediated activation of IDE. Notably, Ia1 and Ia2 activated the degradation of Aβ by ∼700% and ∼400%, respectively, albeit only when Aβ was presented in a mixture also containing shorter substrates. This study describes the first examples of synthetic small-molecule activators of IDE, showing that pharmacological activation of this important protease with drug-like compounds is achievable. These novel activators help to establish the putative ATP-binding domain as a key modulator of IDE proteolytic activity and offer new insights into the modulatory action of ATP. Several larger lessons abstracted from this screen will help inform the design of future screening campaigns and facilitate the eventual development of IDE activators with therapeutic utility.
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影响因子：
4.8
作者：
Song, ES;Mukherjee, A;Hersh, LB
通讯作者：
Hersh, LB
影响因子：
4.8
作者：
Leissring, MA;Lu, A;Selkoe, DJ
通讯作者：
Selkoe, DJ
DOI：
10.1073/pnas.0801261105
发表时间：
2008-07-15
影响因子：
11.1
作者：
Neant-Fery, Marie;Garcia-Ordonez, Ruben D.;Leissring, Malcolm A.
通讯作者：
Leissring, Malcolm A.
影响因子：
6
作者：
El-Amouri, Salim S.;Zhu, Hong;Kindy, Mark S.
通讯作者：
Kindy, Mark S.
影响因子：
2.9
作者：
Malito, Enrico;Ralat, Luis A.;Manolopoulou, Marika;Tsay, Julie L.;Wadlington, Natasha L.;Tang, Wei-Jen
通讯作者：
Tang, Wei-Jen