PDF(Pubmed)
Abstract：
Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood-brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10-30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.
摘要：
奥利肟,带有肟基团的胆固醇衍生物，具有穿越血脑屏障的能力，并在临床研究中表现出优异的安全性和耐受性。这些特征表明它可以作为乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的中心活性配体，其与有机磷酸酯化合物（OP）的活性破坏导致不受控制的兴奋和潜在的威胁生命的症状。为了评估奥列肟作为人AChE和BChE的结合配体和再激活因子，我们对杀虫剂对硫磷的活性代谢产物进行了体外动力学研究，对氧磷,战争神经毒剂沙林，环沙林,tabun,VX。我们的结果表明，这两种酶都在中微摩尔范围内对奥列肟具有结合亲和力，高于使用中的解毒剂(即，2-PAM,HI-6等).虽然奥列肟显示出弱的重新激活AChE的能力，环沙林抑制的BChE以与标准肟HI-6相当的总体再激活速率常数再激活。此外，与肟2-PAM组合，环沙林和沙林抑制的BChE的再激活最大值增加了10-30％。分子建模揭示了奥列肟和BChE之间的生产性相互作用，强调奥列肟是一种潜在的BChE靶向治疗。此外，它可能被添加到OP中毒治疗中，以增加BChE再激活的功效，其胆固醇支架可为新型肟解毒剂的开发提供依据。
