Structure tridimensionnelle de la butyrylcholinestérase humaine :: Hypothèses mécanistiques et ingéniérie de mutéines dégradant les composés organophosphorés

Abstract

Cholinesterases are the main targets of organophosphorus compounds. Although progresses in prophylaxis and treatment of nerve agent poisoning have been achieved in the past twenty years, pharmacological protection and emergency treatment remain imperfect. All classical pharmacological ways have been explored and, the current medical counter-measure arsenal is generally not expected to change much. However, the emergence of the catalytic bioscavenger concept has aroused new hope. In addition, resolution of the three-dimensional structure of human butyrylcholinesterase (BChE) answered some fundamental issues in medical defense research: 1) a better description of cholinesterase catalytic mechanisms (substrate hydrolysis, inhibition by organophosphorus); 2) aging mechanism of phosphylated cholinesterases caused by the dealkylation of branched organophosphorous moiety; 3) reasoned site-directed mutagenesis of human BChE with the aim of making operational mutants capable of detoxifying organophosphorus substrates.