# Improved Therapeutics for the Resurrection of the Aged Form of  Acetylcholinesterase

> **NIH NIH U01** · OHIO STATE UNIVERSITY · 2020 · $405,802

## Abstract

One of the major deficiencies of current medical countermeasures is that current oximes cannot
reactivate nerve agent-inhibited acetylcholinesterase (AChE) that has aged after exposure to
organophosphorus G- and V-type chemical nerve agents. Our team has demonstrated the first, and
only, compounds that have the capability to “resurrect” in vitro the methylphosphonate-aged
form of AChE to an active, native state. We posit that this resurrection accomplishes two distinct steps
– first, to realkylate the anionic aged form back to a neutral, phosphylated (inhibited) serine residue and
then to reactivate the inhibited form back to the native AChE. This proposal focuses on expanding on
these successful chemical frameworks in order to identify even more efficacious drug-like molecules that
will enable the aged form of AChE to be resurrected in vivo. Using various quinone methide precursor
(QMP) frameworks, we will use computational and experimental approaches to prepare a chemical
library and then to screen these compounds for efficacy in resurrecting the aged form of AChE back to
native activity.
There are no approved countermeasures that can resurrect the aged form of AChE to its active form;
however, resurrection of aged AChE is the holy grail against OP exposure. If realkylation of aged AChE
can occur, then AChE can be fully rejuvenated as oximes (and other reactivators) exist that are potent
nucleophiles for cleaving the O–P bond of the phosphylated serine, thereby reforming active AChE.
Thus, the objective of this proposal is to expand on our successful chemical frameworks to react
selectively with aged AChE to form stable alkylphosphonate-AChE adducts that can then be
reactivated to the native state, thereby reversing the effects of aging by chemical nerve agents.
The design of alkylating compounds will be guided by state-of-the-art computational methods (molecular
dynamics, molecular docking, and quantum mechanical methods) that predict the ligand-receptor
interactions of alkylating compounds with aged AChE. Using in silico guidance, libraries of alkylating
quinone methide precursor (QMP) compounds will be synthesized, and then tested in a kinetic screening
process, and complemented by mass spectrometric and proteomic studies. The best lead compounds
will be evaluated for their in vitro drug-like properties and tested in vivo in a humanized mouse model for
AChE.

## Key facts

- **NIH application ID:** 9977281
- **Project number:** 5U01NS112101-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Christopher M. Hadad
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,802
- **Award type:** 5
- **Project period:** 2019-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977281

## Citation

> US National Institutes of Health, RePORTER application 9977281, Improved Therapeutics for the Resurrection of the Aged Form of  Acetylcholinesterase (5U01NS112101-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977281. Licensed CC0.

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