Organophosphorus (OP) chemical warfare agents, such as sarin and soman, are acutely toxic compounds that act by inhibiting the activity of the enzyme acetylcholinesterase (AChE) at nerve-nerve and neuromuscular junctions in the central and peripheral nervous systems, respectively. Inhibition of the enzyme occurs by phosphylation of the active site serine nucleophile that is normally involved in catalysis. Prompt administration of oximes can lead to dephosphylation of the phosphyl-AChE adduct and hence is an antidote strategy. However, and particularly with the chemical warfare agent soman, the initial phosphyl-AChE adduct undergoes a dealkylation reaction that leads to what is called the aged adduct, for which there is no known antidote. This application proposes to address this perplexing problem by synthesis and evaluation of AChE ligands that can bind in the active site of the aged enzyme adduct, and subsequently serve as methyl transfer agents to realkylate the aged enzyme. This in turn will resurrect the susceptibility of the adduct to nucleophilic dephosphylation by oximes and hence lead to recovery of enzyme activity. Success in this endeavor should therefore open the door to the development of efficacious drugs for antidote therapy against currently intractable OP chemical warfare agents.

Public Health Relevance

This application endeavors to synthesize and evaluate ligands of the enzyme acetylcholinesterase that can serve as antidotes against organophosphorus (OP) chemical warfare agents. This work is motivated by the concern that terrorist organizations may aspire to inflict mass casualties by use of these agents. It is anticipated that as OP agent antidote therapy improves, the health and security risks that these agents pose to our society will be ameliorated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS076430-02
Application #
8338451
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (55))
Program Officer
Yeung, David
Project Start
2011-09-30
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$302,000
Indirect Cost
$102,000
Name
University of Iowa
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Topczewski, Joseph J; Quinn, Daniel M (2013) Kinetic assessment of N-methyl-2-methoxypyridinium species as phosphonate anion methylating agents. Org Lett 15:1084-7
Topczewski, Joseph J; Lodge, Alexander M; Yasapala, Sumana N et al. (2013) Reversible inhibition of human acetylcholinesterase by methoxypyridinium species. Bioorg Med Chem Lett 23:5786-9