Title : Tuning Butyrylcholinesterase Inactivation and Reactivation by Polymer-Based Protein Engineering - Zhang_2020_Adv.Sci.(Weinh)_7_1901904 |
Author(s) : Zhang L , Baker SL , Murata H , Harris N , Ji W , Amitai G , Matyjaszewski K , Russell AJ |
Ref : Adv Sci (Weinh) , 7 :1901904 , 2020 |
Abstract :
Organophosphate nerve agents rapidly inhibit cholinesterases thereby destroying the ability to sustain life. Strong nucleophiles, such as oximes, have been used as therapeutic reactivators of cholinesterase-organophosphate complexes, but suffer from short half-lives and limited efficacy across the broad spectrum of organophosphate nerve agents. Cholinesterases have been used as long-lived therapeutic bioscavengers for unreacted organophosphates with limited success because they react with organophosphate nerve agents with one-to-one stoichiometries. The chemical power of nucleophilic reactivators is coupled to long-lived bioscavengers by designing and synthesizing cholinesterase-polymer-oxime conjugates using atom transfer radical polymerization and azide-alkyne "click" chemistry. Detailed kinetic studies show that butyrylcholinesterase-polymer-oxime activity is dependent on the electrostatic properties of the polymers and the amount of oxime within the conjugate. The covalent coupling of oxime-containing polymers to the surface of butyrylcholinesterase slows the rate of inactivation of paraoxon, a model nerve agent. Furthermore, when the enzyme is covalently inhibited by paraoxon, the covalently attached oxime induced inter- and intramolecular reactivation. Intramolecular reactivation will open the door to the generation of a new class of nerve agent scavengers that couple the speed and selectivity of biology to the ruggedness and simplicity of synthetic chemicals. |
PubMedSearch : Zhang_2020_Adv.Sci.(Weinh)_7_1901904 |
PubMedID: 31921563 |
Zhang L, Baker SL, Murata H, Harris N, Ji W, Amitai G, Matyjaszewski K, Russell AJ (2020)
Tuning Butyrylcholinesterase Inactivation and Reactivation by Polymer-Based Protein Engineering
Adv Sci (Weinh)
7 :1901904
Zhang L, Baker SL, Murata H, Harris N, Ji W, Amitai G, Matyjaszewski K, Russell AJ (2020)
Adv Sci (Weinh)
7 :1901904