Aging of Phosphylated Cholinesterases: Mechanistic and Structural Aspects, and New Possibility for Resurrection of Aged Cholinesterases

Cholinesterases (ChEs) are irreversibly inhibited by organophosphorous compounds (OP). Then, OP-inhibited ChEs undergo a reaction that progressively decreases reactivatability. This process called “aging” results from dealkylation of the adduct. Aged ChEs are resistant to antidotal oximes. Structural and conformational changes in the aged phosphylated ChE active site pocket impair enzyme reactivatability. Thus, reactivation of aged ChEs was a challenge for more than 70 years. However, it was postulated that realkylation of aged adducts could lead to reactivation of enzymes. This hypothesis was confirmed in 2018 when a new generation of reactivators, electrophilic quinone methide precursors (QMPs), capable of resuscitating or resurrecting aged ChEs were synthesized. The QMP-mediated resurrection process of ChEs by these first “resurrectors” is still very slow. Thus, substantial optimization in the chemical design of new drugs and drug-targeted delivery are needed before the resurrection approach can be translated into clinically viable therapies. However, despite limitations, the first achievements resolving the non-reactivatability issue of OP-aged cholinesterases and successful administration of these new reactivators can be regarded as a major step forward in improving the therapy of OP poisoning.