Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale Des Armées, F-91220 Brétigny-Sur-Orge, France.
Normandie Université, COBRA, UMR 6014 & FR 3038, Université de Rouen, INSA Rouen, CNRS, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France.
J Med Chem. 2022 Mar 24;65(6):4649-4666. doi: 10.1021/acs.jmedchem.1c01748. Epub 2022 Mar 7.
Recent events demonstrated that organophosphorus nerve agents are a serious threat for civilian and military populations. The current therapy includes a pyridinium aldoxime reactivator to restore the enzymatic activity of acetylcholinesterase located in the central nervous system and neuro-muscular junctions. One major drawback of these charged acetylcholinesterase reactivators is their poor ability to cross the blood-brain barrier. In this study, we propose to evaluate glucoconjugated oximes devoid of permanent charge as potential central nervous system reactivators. We determined their reactivation efficacy on inhibited human acetylcholinesterase, the crystal structure of two compounds in complex with the enzyme, their protective index on intoxicated mice, and their pharmacokinetics. We then evaluated their endothelial permeability coefficients with a human model. This study shed light on the structural restrains of new sugar oximes designed to reach the central nervous system through the glucose transporter located at the blood-brain barrier.
最近发生的事件表明，有机磷神经毒剂对平民和军人都是严重的威胁。目前的治疗方法包括吡啶醛肟作为重活化剂，以恢复位于中枢神经系统和神经肌肉接头的乙酰胆碱酯酶的酶活性。这些带电荷的乙酰胆碱酯酶重活化剂的一个主要缺点是它们穿过血脑屏障的能力很差。在这项研究中，我们提出评估无永久电荷的葡萄糖醛酸肟作为潜在的中枢神经系统重活化剂。我们测定了它们对抑制的人乙酰胆碱酯酶的重活化效果、两种化合物与酶复合物的晶体结构、对中毒小鼠的保护指数以及它们的药代动力学。然后，我们用人模型评估了它们的内皮通透性系数。这项研究揭示了新的糖肟的结构限制，这些肟旨在通过位于血脑屏障的葡萄糖转运体到达中枢神经系统。
