Allosteric FBPase inhibitors gain 105 times in potency when simultaneously binding two neighboring AMP sites
Allosteric FBPase inhibitors gain 105 times in potency when simultaneously binding two neighboring AMP sites
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DOI：
10.1016/j.bmcl.2008.06.103
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发表时间：
2008-08-15
影响因子：
2.7
通讯作者：
Ruf, Armin
中科院分区：
文献类型：
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作者：
Hebeisen, Paul;Kuhn, Bernd;Ruf, Armin
人果糖-1,6-二磷酸酶（FBPase, EC 3.1.3.11）是一种关键的糖异生酶，负责将果糖-1,6-二磷酸水解为果糖-6-磷酸，因此为开发降低2型糖尿病患者肝脏葡萄糖生成的新疗法提供了机会。在其活性形式中，FBPase以同四聚体形式存在，并受AMP的变构调节。在HTS活动中，芳香磺酰脲被鉴定为模拟AMP的FBPase抑制剂。通过使用两个芳香磺酰脲作为锚定单元桥接两个相邻的变构结合位点，并将它们共价连接，有可能获得具有强抑制作用的双结合AMP位点抑制剂。(C) 2008 Elsevier Ltd版权所有。
Human fructose-1,6-bisphosphatase (FBPase, EC 3.1.3.11) is a key gluconeogenic enzyme, responsible for the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate, and thus presents an opportunity for the development of novel therapeutics focused on lowering the hepatic glucose production in type 2 diabetics. In its active form FBPase exists as a homotetramer and is allosterically regulated by AMP. In an HTS campaign aromatic sulfonylureas have been identified as FBPase inhibitors mimicking AMP. By bridging two adjacent allosteric binding sites using two aromatic sulfonylureas as anchor units and covalently linking them, it was possible to obtain dual binding AMP site inhibitors that exhibit a strong inhibitory effect. (C) 2008 Elsevier Ltd. All rights reserved.