Abstract

Aldicarb is known to be the most toxic carbamate pesticide and could be used easily by terrorists to cause a mass casualty incident. It is highly desired to discover a medical countermeasure for aldicarb poisoning. Based on structural insights from molecular modeling and in vitro experimental validation, CocH3-Fc(M3), a potent cocaine hydrolase engineered from human butyrylcholinesterase (BChE), has a ~4-fold improved binding affinity with aldicarb compared to wild-type human acetylcholinesterase (AChE) and BChE and a 9-28-fold improved bimolecular rate constant for the carbamylation with aldicarb compared to AChE. CocH3-Fc(M3) also has significant catalytic activity for aldicarb hydrolysis and, hence, is identified as an aldicarb hydrolase. To the best of our knowledge, this is the first aldicarb hydrolase identified so far. Due to significant catalytic activity against aldicarb, CocH3-Fc(M3) effectively and dose-dependently rescued all mice that had been injected with a lethal dose of aldicarb, demonstrating the promise of CocH3-Fc(M3) as a potential medical counter-measure for aldicarb poisoning.

Document Type

Article

Publication Date

2025

Notes/Citation Information

0009-2797/© 2025 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.cbi.2025.111675

Funding Information

This work was supported in part by the National Institutes of Health (NIH grants UG3/UH3 NS134920, U01 DA051079, UH2/UH3 DA041115, R01 DA056646, U18 DA052319, R01 DA035552, R01 DA032910, and R01 DA013930) and the Molecular Modeling and Biopharmaceutical Center (MMBC).

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