# Long-acting aldicarb hydrolase as a medical countermeasure for aldicarb poisoning

> **NIH NIH UG3** · UNIVERSITY OF KENTUCKY · 2024 · $532,962

## Abstract

As one of the Chemicals of Concern (CoC) identified by the US Department of Homeland Security, aldicarb
belongs to the Cholinergic Warfare and Pesticides category. As the most toxic carbamate pesticide – a potent,
fast-acting inhibitor of acetylcholinesterase (AChE), aldicarb is readily absorbed from all routes of exposure,
including oral and dermal exposure. In all species tested, the acute oral toxicities of aldicarb are similar. Due to
its physical properties documented in literature, aldicarb could be used by terrorists to cause mass casualty.
Organophosphorus (OP) warfare/pesticides and carbamate pesticides have a common mode of action for their
neurotoxicity as AChE inhibitors. Currently available options for treating this type of poisoning, such as
administration of atropine or co-administration of atropine and pralidoxime (2-PAM), have limited efficacy. There
have been extensive efforts in development of improved options for treatment of OP poisoning. Relatively less
studies have been carried out in development of aldicarb poisoning treatment. Reported studies indicated that
2-PAM had neither positive nor negative effects on survival in animal studies on aldicarb intoxication. This
outcome is understandable, as 2-PAM was developed to reactivate phosphorylated AChE (an intermediate
formed from the inhibition reaction of AChE with an OP), but not carbamylated AChE (an intermediate formed
from the reaction of AChE with a carbamate like aldicarb). It is highly desired to develop a new, effective post-
exposure treatment option for aldicarb poisoning. This investigation will focus on rational design and discovery
of an engineered enzyme capable of rapidly and efficiently detoxifying aldicarb as a catalytic aldicarb
bioscavenger for aldicarb poisoning. As an effective bioscavenger, it must be able to react with aldicarb more
rapidly than AChE so as to protect AChE from reaction (carbamylation) with aldicarb. In preliminary studies, we
have demonstrated that an Fc-fused cocaine hydrolase (Fc-CocH), developed previously in our lab for treatment
of cocaine use disorders (CUDs), can more potently bind with aldicarb than with AChE and wild-type
butyrylcholinesterase (BChE) and can also catalyze aldicarb hydrolysis. In further in vivo rescue experiment, this
Fc-CocH protein powerfully rescued all mice that had been injected intraperitoneally (IP) with a lethal dose (~2
× LD50) of aldicarb. With the encouraging preliminary data, taking advantage of our positive experience in
preclinical and clinical development of Fc-CocHs, we propose to first evaluate an in-house library of Fc-CocHs
for their activities with aldicarb in order to select the one with the highest catalytic activity for aldicarb hydrolysis
and the best overall in vivo profiles, followed by lead optimization to optimize its catalytic activity against aldicarb,
substrate selectivity, post-exposure in vivo efficacy, and toxicity/immunogenicity profiles. Accomplishment of this
investigation ...

## Key facts

- **NIH application ID:** 10917295
- **Project number:** 5UG3NS134920-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** CHANG-GUO ZHAN
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $532,962
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917295

## Citation

> US National Institutes of Health, RePORTER application 10917295, Long-acting aldicarb hydrolase as a medical countermeasure for aldicarb poisoning (5UG3NS134920-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10917295. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*