| Popis: |
In 1940s cholinesterases became interest of study because of their role in nerve transmission, but it was soon shown that butyrylcholinesterase (BChE) is not so important because even with complete absence of BChE subjects were still alive and healthy. Lacking essential physiological function BChE hasn’t been topic of further investigation in the same length as acetylcholinesterase (AChE). Then through years evidence had arisen indicating that BChE has certain role in the development of the symptomatology of Alzheimer’s disease (AD). The hypothesis becomes more convincing when cholinesterase inhibitor therapies were shown to be effective in the improvement of main cognitive functions in patient with AD [1]. Except in AD therapy BChE is today associated with many different functions, like its involvement in metabolism of numerous drugs and poison esters even hunger hormone ghrelin, but highest interest was given to acknowledgment of BChE’s input against nerve agents’ toxicity. BChE placement in plasma gives it ability to act as stoichiometric bioscavanger for organophosphate (OP) before they pass blood brain barrier inhibiting native AChE, causing cholinergic crisis [2]. Due to its ability to act as a stoichiometric bioscavanger, BChE can be administered exogenously in the form of fresh-frozen plasma and thus may aid in recovery from OP poisoning as shown in the case of novichok poisoning [3]. Our hypothesis was that BChE in combination with its efficient reactivator could act as a pseudocatalytic scavenger as medical protection or therapy for detoxification, in this case from excess of OP. Through thorough research we identified efficient oximes based on “click chemistry” synthesis for BChE inhibited with OPs as sarin, cyclosarin, VX, and tabun. Interactions between inhibited BChE and oximes containing alkyne and azide building blocks with triazole linker were kinetically characterized in detail through in vitro, ex vivo and in silico experiments. For several oximes BChE reactivation potency was showed to be promising when compared to the standard oximes used in medical practice. Combination of BChE and oxime with high reactivation potency is appealing pseudocatalytic bioscavanger candidate for OP poisoning because once reactivated BChE is again able to bind OP from blood by which enabling further normal function of AChE. |
