Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase
Abstract
Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime–based therapies whose success rates are currently limited. The pyridinium cation hampers uptake of OPs into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are nonproductive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)–inhibited human AChE, here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved in vitro reactivation of diverse OP-human AChE conjugates. Oxime groupmore »
- Authors:
-
[4];
[5];
[5];
[6];
[5]
- Univ. of California, San Diego, CA (United States); Univ. of Defense, Trebesska (United States)
- Univ. of Tennessee, Knoxville, TN (United States); Tennessee Wesleyan Univ., Athens, TN (United States)
- The Ohio State Univ., Columbus, OH (United States)
- Univ. of Utah, Salt Lake City, UT (United States)
- Univ. of California, San Diego, CA (United States)
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Publication Date:
- Research Org.:
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH); National Inst. of Neurological Disorders and Stroke; UCSD
- OSTI Identifier:
- 1616801
- Grant/Contract Number:
- AC05-00OR22725; AC02-06CH11357; U01 NS083451; R21 NS098998; BG084144
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 295; Journal Issue: 13; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; acetylcholinesterase (AChE); crystal structure; molecular modeling; enzyme structure; drug design; structure-function; aliphatic bis-oxime; organophosphate intoxication; oxime reactivation; uncharged oxime antidote
Citation Formats
Gorecki, Lukas, Gerlits, Oksana, Kong, Xiaotian, Cheng, Xiaolin, Blumenthal, Donald K., Taylor, Palmer, Ballatore, Carlo, Kovalevsky, Andrii Y., and Radić, Zoran. Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase. United States: N. p., 2020.
Web. doi:10.1074/jbc.RA119.012400.
Gorecki, Lukas, Gerlits, Oksana, Kong, Xiaotian, Cheng, Xiaolin, Blumenthal, Donald K., Taylor, Palmer, Ballatore, Carlo, Kovalevsky, Andrii Y., & Radić, Zoran. Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase. United States. https://doi.org/10.1074/jbc.RA119.012400
Gorecki, Lukas, Gerlits, Oksana, Kong, Xiaotian, Cheng, Xiaolin, Blumenthal, Donald K., Taylor, Palmer, Ballatore, Carlo, Kovalevsky, Andrii Y., and Radić, Zoran. Tue .
"Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase". United States. https://doi.org/10.1074/jbc.RA119.012400. https://www.osti.gov/servlets/purl/1616801.
@article{osti_1616801,
title = {Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase},
author = {Gorecki, Lukas and Gerlits, Oksana and Kong, Xiaotian and Cheng, Xiaolin and Blumenthal, Donald K. and Taylor, Palmer and Ballatore, Carlo and Kovalevsky, Andrii Y. and Radić, Zoran},
abstractNote = {Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime–based therapies whose success rates are currently limited. The pyridinium cation hampers uptake of OPs into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are nonproductive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)–inhibited human AChE, here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved in vitro reactivation of diverse OP-human AChE conjugates. Oxime group reorientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Finally, our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, “smart” accelerated antidotes against OP toxicity.},
doi = {10.1074/jbc.RA119.012400},
journal = {Journal of Biological Chemistry},
number = 13,
volume = 295,
place = {United States},
year = {Tue Feb 04 00:00:00 EST 2020},
month = {Tue Feb 04 00:00:00 EST 2020}
}
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