One of the major deficiencies of current medical countermeasures is that current oximes cannot reactivate nerve agent-inhibited acetylcholinesterase (AChE) that has aged. This proposal focuses on identifying organic molecules that will enable aged nerve agent-AChE to be reactivated. The objective of this proposal is to discover alkylating compounds that selectively react with aged agent-inhibited AChE to form stable methylalkylphosphonate-AChE adducts that can be reactivated with conventional oximes. This drug discovery effort will be conducted as an in vitro research project in which the alkylation process and the oxime reactivation process will be investigated as separate and sequential problems.
The specific aims of this proposal are: to design and synthesize novel alkylating compounds and test their in vitro ability to alkylate small methylphosphonates and methylphosphonate-peptides that mimic aged agent-AChE, to design and synthesize novel alkylating compounds specific for AChE and test their in vitro ability to alkylate aged agent-AChE and restore the ability of aged agent-AChE to be reactivated, and to down-select for the alkylating compound that will provide the most improved oxime reactivation of aged agent-AChE. The design of alkylating compounds will be guided by state-of-the-art computational methods that predict the ligand-receptor interactions of alkylating compound with aged agent-AChE, thereby providing rational guidance for the synthesis of novel therapeutics. Alkylation of model methylphosphonates, methylphosphonate-peptides and aged agent-AChE will be determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS), along with novel solid-phase methods. Oxime reactivation of alkylated aged agent-AChE will be determined by spectrophotometric methods.

Public Health Relevance

Many organophosphorus (OP) compounds are chemical warfare agents or pesticides and are potential threats to human society (as recently seen in Syria). These chemical agents inhibit the enzyme acetylcholinesterase (AChE) in the human body, and this efficient enzyme is responsible for the hydrolysis of the neurotransmitter, acetylcholine, at a neurosynaptic junction. Upon exposure to OP chemical nerve agents, AChE undergoes an aging process, and current oximes cannot reactivate nerve agent-inhibited acetylcholinesterase (AChE) that has aged. This application focuses on identifying drug-like molecules that will enable the aged form of AChE to be reactivated, thereby fully reversing the effects of OP exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS087983-01
Application #
8735550
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (50))
Program Officer
Yeung, David
Project Start
2014-08-15
Project End
2017-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$377,033
Indirect Cost
$127,033
Name
Ohio State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210