engleski

Analysis of Butyrylcholinesterase Interactions with Old Inhibitors and New Reactivators

Inhibition of the enzyme butyrylcholinesterase (BChE) in human tissues by binding of compounds to its active site serine is important for the detoxification and scavenging of xenobiotics such as organophosphates (OP). Although BChE is generally considered as having no physiological function, a growing body of evidence indicates that BChE plays a central role in the development of the symptomatology of Alzheimer’s disease (AD) and related dementias. The most likely function for BChE is as a backup for acetylcholinesterase (AChE) and protection of synaptic AChE from man-made and naturally occurring poisons. Newly considered strategies in medical protection against nerve agents focus on the use of exogenously administered BChE. The overall idea is to administer such an enzyme in combination with a specific oxime, to scavenge an organophosphate (OP) before it can reach and inhibit native AChE, thus helping organism detoxification from the excess OP. Starting with a directed library of pyridinium aldoximes, we identified efficient reactivators of sarin, cyclosarin, VX, and tabun-BChE conjugates and kinetically characterized their interactions in detail. Moreover, for several oximes BChE reactivation potency was showed to be promising when compared to the standard oximes used in medical practice. However, an absence of universality of reactivators underlies the comprehensiveness of the reactivation mechanism and the importance of the stabilization of the oxime group in the vicinity of the phosphorus conjugated at the catalytic serine. Its convenient position for the nucleophilic attack is the major criteria for efficient reactivation of OP-BChE conjugates. Notwithstanding, we identified several efficient reactivators of phosphylated BChE that, due to a cumulative capacity to reactivate both AChE and BChE, possess the potential for bioscavenging of OP. Acknowledgments: This work was supported by the Croatian Science Foundation (IP-2018-01-7683).

Butyrylcholinesterase ; Reactivation ; Oximes ; Organophosphates

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