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Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase

Journal Article · · Journal of Biological Chemistry
 [1];  [2];  [3];  [3];  [4];  [5];  [5];  [6];  [5]
  1. Univ. of California, San Diego, CA (United States); Univ. of Defense, Trebesska (United States)
  2. Univ. of Tennessee, Knoxville, TN (United States); Tennessee Wesleyan Univ., Athens, TN (United States)
  3. The Ohio State Univ., Columbus, OH (United States)
  4. Univ. of Utah, Salt Lake City, UT (United States)
  5. Univ. of California, San Diego, CA (United States)
  6. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
+ Show Author Affiliations

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.

Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE; National Institutes of Health (NIH); National Inst. of Neurological Disorders and Stroke; UCSD
Grant/Contract Number:
AC05-00OR22725; AC02-06CH11357
OSTI ID:
1616801
Alternate ID(s):
OSTI ID: 1616601
Journal Information:
Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 13 Vol. 295; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
acetylcholinesterase (AChE)
aliphatic bis-oxime
crystal structure
drug design
enzyme structure
molecular modeling
organophosphate intoxication
oxime reactivation
structure-function
uncharged oxime antidote