Bester_2018_Chem.Res.Toxicol_31_1405

Reference

Title : Structural Insights of Stereospecific Inhibition of Human Acetylcholinesterase by VX and Subsequent Reactivation by HI-6 - Bester_2018_Chem.Res.Toxicol_31_1405
Author(s) : Bester SM , Guelta MA , Cheung J , Winemiller MD , Bae SY , Myslinski J , Pegan SD , Height JJ
Ref : Chemical Research in Toxicology , 31 :1405 , 2018
Abstract : 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 R/S) 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.
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PubMedID: 30462502
Gene_locus related to this paper: human-ACHE

Related information

Gene_locus related to this paper: human-ACHE

Citations formats

Bester SM, Guelta MA, Cheung J, Winemiller MD, Bae SY, Myslinski J, Pegan SD, Height JJ (2018)
Structural Insights of Stereospecific Inhibition of Human Acetylcholinesterase by VX and Subsequent Reactivation by HI-6
Chemical Research in Toxicology 31 :1405

Bester SM, Guelta MA, Cheung J, Winemiller MD, Bae SY, Myslinski J, Pegan SD, Height JJ (2018)
Chemical Research in Toxicology 31 :1405