LeSaint_2025_Chem.Biol.Interact__111675

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 countermeasure for aldicarb poisoning.