Acetylcholinesterase reactivators



Acetylcholinesterase reactivators


C. Bartolucci, A. Cassetta, D.Lamba, A. Pesaresi*
[*] Research Associate


Acetylcholinesterase, Blood-brain barrier, Organophosphates, Reactivation, Sugar-oximes

Division of Biochemistry, Walter Reed Army Institute of Research, USA

Organophosphorous compounds have been used as chemical weapons and as insecticides. Exposure to even small amounts of an organophosphorus compound can be fatal. The mechanism of organophosphate poisoning involves phosphorylation of a serine hydroxyl group in the active site of acetylcholinesterase (AChE), leading to inactivation of this essential enzyme. The therapeutic approach to organophosphate poisoning is to reactivate AChE with a site-directed nucleophile. After reversibly binding to the active site, the nucleophile reacts with the phosphorylated hydroxyl group to release free, active enzyme while becoming phosphorylated itself in turn.
Drug design based on this chemical approach yielded 2-pralidoxime (2-PAM) and its analogs, which are effective antidotes for some organophosphates but not for others. Indeed, the variable performance is due to different rates of the irreversible dealkylation of various AChE-organophosphate conjugates.
The effect of 2-PAM depends for a given organophosphate on the equilibrium constants of Scheme I.

Acetylcholinesterase reactivators - Img

Prior to aging, oximes are effective only when enzyme dephosphorylation is faster than oxime dephosphorylation.
While 2-PAM effectively reactivates AChE in the body, it does not cross the blood-brain barrier (BBB) at therapeutically relevant levels.
To address this problem of central nervous system AChE reactivation, novel sugar-oxime conjugates have been synthesized. X-ray crystallography and enzyme kinetics studies have been undertaken exploring the structural and molecular determinants underlying their binding specificity-selectivity and the mechanism of AChE reactivation.
These 'sugar-oximes' would potentially be transported across the BBB because they contain a sugar moiety which would be recognized by the facilitative glucose transporters.

Garcia GE, Campbell AJ, Olson J, Moorad-Doctor D, Morthole VI. Novel oxime as blood-brain barrier penetrating cholinesterase reactivators. Chem Biol Interact (2010) doi:101016/j.cbi.2010.02.033.



Doriano Lamba
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Last Updated (Tuesday, 21 December 2010 17:03)