New therapeutic approaches and novel alternatives for organophosphate toxicity.
New therapeutic approaches and novel alternatives for organophosphate toxicity.
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DOI：
10.1016/j.toxlet.2018.03.028
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发表时间：
2018-07
影响因子：
3.5
通讯作者：
Stojanovic MN
中科院分区：
文献类型：
--
作者：
Katz FS;Pecic S;Schneider L;Zhu Z;Hastings-Robinson A;Luzac M;Macdonald J;Landry DW;Stojanovic MN
有机磷化合物(OPC)通常被用作杀虫剂，并被开发为化学战的神经毒剂。由于OPC的共价结合和对乙酰胆碱酯酶(AChE)的抑制，暴露于OPC会导致毒性。对OPC暴露所致毒性的治疗主要集中在通过对磷中心的直接亲核攻击，由基于肟类的化合物重新激活AChE。然而，由于现有的基于肟基的复活剂用于治疗OPC中毒的缺点，我们考虑了非肟基的复活机制。对化合物文库进行高通量筛选，以发现以前未鉴定的再活化化合物，然后对其类似物进行研究。在这个过程中，我们发现了多种非肟类化合物，我们已经报道了其中最强健的一类。在这里，我们报告了我们在屏幕上发现的其他类型的化合物，它们在重新激活方面是有效的。在生化表征过程中，我们还发现了一些具有其他活性的化合物，这些化合物可能会启发治疗OPC毒性的新方法。具体地说，我们发现了(1)增加底物AChE的水解率和(2)保护酶不受OPC抑制的化合物。此外，我们还发现，部分激活化合物可以从AChE和相关的丁酰胆碱酯酶(BUCHE)中恢复活性。我们现在报告这些化合物，它们的活性，并讨论每一种与治疗方法的关系，这些方法将提供传统的基于肟的再激活的替代方案。
Organophosphate compounds (OPCs) are commonly used as pesticides and were developed as nerve agents for chemical warfare. Exposure to OPCs results in toxicity due to their covalent binding and inhibition of acetylcholinesterase (AChE). Treatment for toxicity due to OPC exposure has been largely focused on the reactivation of AChE by oxime-based compounds via direct nucleophilic attack on the phosphorous center. However, due to the disadvantages to existing oxime-based reactivators for treatment of OPC poisoning, we considered non-oxime mechanisms of reactivation. A high throughput screen of compound libraries was performed to discover previously unidentified reactivation compounds, followed by studies on their analogs. In the process, we discovered multiple non-oxime classes of compounds, the most robust of which we have already reported. Herein, we report other classes of compounds we identified in our screen that are efficient at reactivation. During biochemical characterization, we also found some compounds with other activities that may inspire novel therapeutic approaches to OPC toxicity. Specifically, we found compounds that (1) increase the rate of substrate hydrolysis by AChE and, (2) protect the enzyme from inhibition by OPC. Further, we discovered that a subset of reactivator compounds recover activity from both AChE and the related enzyme butyrylcholinesterase (BuChE). We now report these compounds, their activities and discuss how each relates to therapeutic approaches that would provide alternatives to traditional oxime-based reactivation.
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影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
FEATHERSTONE, RM
影响因子：
7.3
作者：
Carletti, Eugenie;Colletier, Jacques-Philippe;Nachon, Florian
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Nachon, Florian
影响因子：
3.9
作者：
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影响因子：
3.1
作者：
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通讯作者：
Lockridge, Oksana
DOI：
10.1016/s0925-4439(02)00071-6
发表时间：
2002-05-21
影响因子：
6.2
作者：
Müller, TC;Rocha, JBT;Schetinger, MRC
通讯作者：
Schetinger, MRC