Department of Pharmaceutical and Biomedical Sciences , University of Georgia , Athens , Georgia 30602 , United States.
Edgewood Chemical Biological Center, United States Army , Aberdeen Proving Ground, Aberdeen , Maryland 21010 , United States.
Chem Res Toxicol. 2018 Dec 17;31(12):1405-1417. doi: 10.1021/acs.chemrestox.8b00294. Epub 2018 Dec 4.
Over 50 years ago, the toxicity of irreversible organophosphate inhibitors targeting human acetylcholinesterase (hAChE) was observed to be stereospecific. The therapeutic reversal of hAChE inhibition by reactivators has also been shown to depend on the stereochemistry of the inhibitor. To gain clarity on the mechanism of stereospecific inhibition, the X-ray crystallographic structures of hAChE inhibited by a racemic mixture of VX (P ) and its enantiomers were obtained. Beyond identifying hAChE structural features that lend themselves to stereospecific inhibition, structures of the reactivator HI-6 bound to hAChE inhibited by VX enantiomers of varying toxicity, or in its uninhibited state, were obtained. Comparison of hAChE in these pre-reactivation and post-reactivation states along with enzymatic data reveals the potential influence of unproductive reactivator poses on the efficacy of these types of therapeutics. The recognition of structural features related to hAChE's stereospecificity toward VX shed light on the molecular influences of toxicity and their effect on reactivators. In addition to providing a better understanding of the innate issues with current reactivators, an avenue for improvement of reactivators is envisioned.
50 多年前，人们观察到针对人乙酰胆碱酯酶（hAChE）的不可逆有机磷抑制剂的毒性具有立体选择性。通过重活化剂逆转 hAChE 抑制的治疗作用也依赖于抑制剂的立体化学。为了阐明立体选择性抑制的机制，获得了 hAChE 被 VX（P）的外消旋混合物及其对映异构体抑制的 X 射线晶体结构。除了确定 hAChE 的结构特征，这些特征有助于立体选择性抑制，还获得了与 VX 对映异构体抑制的 hAChE 结合的再活化剂 HI-6 的结构，以及在其未被抑制的状态下。比较这些预再活化和后再活化状态下的 hAChE 以及酶数据揭示了非生产性再活化剂构象对这些类型治疗剂功效的潜在影响。对与 hAChE 对 VX 的立体选择性相关的结构特征的认识，揭示了毒性的分子影响及其对再活化剂的影响。除了更好地了解当前再活化剂的固有问题外，还设想了改进再活化剂的途径。
