Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates.
Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates.
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DOI：
10.1002/cbic.201500348
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发表时间：
2015-10-12
期刊：
影响因子：
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通讯作者：
Stojanovic MN
中科院分区：
文献类型：
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作者：
Katz FS;Pecic S;Tran TH;Trakht I;Schneider L;Zhu Z;Ton-That L;Luzac M;Zlatanic V;Damera S;Macdonald J;Landry DW;Tong L;Stojanovic MN
乙酰胆碱酯酶（AChE）被有机磷化合物（OPCs），如神经毒剂和农药，共价抑制，传统上是用亲核肟重新激活。然而，人们清楚地认识到需要能够以改善的体内功效重新激活受抑制的AChE的新型化合物。在这里，我们描述了我们发现的新的功能组-曼尼希酚和一般的基地，能够重新激活OPC抑制乙酰胆碱酯酶比标准肟更有效地，我们描述了这些功能传递到活性位点的合作机制。这些发现，在体内的初步结果和晶体学数据的支持下，显着拓宽了可用的方法重新激活乙酰胆碱酯酶。
Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups—Mannich phenols and general bases—that are capable of reactivating OPC-inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.