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The Effect of Sulfur Atom Substitution on Organophosphorus Inhibitors of Butyrylcholinesterase
Author(s) -
Ly Phillippe,
Tran Trina,
Nieto Nicolas,
Artiga Karlo,
Nakayama Kensaku,
Schwans Jason
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.470.7
Subject(s) - chemistry , butyrylcholinesterase , sulfur , hydrolysis , acetylcholinesterase , medicinal chemistry , stereochemistry , enzyme , organic chemistry , aché
Butyrylcholinesterase (BuChE) is an enzyme that is highly upregulated in the pathogenesis of Alzheimer's Disease (AD) and contributes to the symptomatic cognitive decline through the hydrolysis of the neurotransmitter, acetylcholine. We have recently developed BuChE‐specific, reversible organophosphorus inhibitors in which two phosphates are linked by an alkyl chain. Subsequent changes in drug design led to a better and smaller inhibition constant (K i ) by replacing the two oxygen atoms in the linker with sulfur atoms. Therefore, it is hypothesized that the position as well as an increase in the number of sulfur substitutions around the phosphorus atom will lead to a more potent inhibitor design. To evaluate the effects of these sulfur atoms on inhibition, dibutyl hexyl phosphate will be used as a scaffold for making a library of potential compounds, each with different number and location of substitutions. The reversibility of inhibition and the specificity is determined through an in vitro competition assay by incubating BuChE with inhibitor for various time intervals and then doping in butyrylthiocholine, a molecule that can be hydrolyzed by BuChE; the hydrolyzed product will react with Ellman's reagent to give an absorbance reading at 412 nanometers. Preliminary data for a single sulfur atom substitution on the hexyl chain shows about a 50‐fold decrease in K i compared to the control that has all oxygen atoms (1.3 versus 50 μM, respectively). When assayed against acetylcholinesterase, no inhibition was observed. Analogs bearing a thiophosphoryl group (P=S) show decreased inhibition compared to the phosphoryl (P=O) compounds (1.3 versus 3.4 μM). Despite the difference in location, a single substitution has led to an irreversible, yet selective inhibition of BuChE. The insight from this study will give guidance towards the rational design of better inhibitors of BuChE that can potentially decelerate the symptomatic progression of AD. Support or Funding Information This project is supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R25GM071638. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.Library of phosphate and phosphorothioate compounds that will be evaluated for selective inhibition of butyrylcholinesteraseThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .