engleski

Effects of new oximes on cholinesterases inhibited by organophosporus pesticides

Through the last few decades, organophosphorus (OP) threats have strewn extensively across the world due to terrorism but also as a result of heightened agricultural use of pesticides. Organophosphorus pesticides, as methamidophos and fenamiphos, are recognized as potent inhibitors of acetylcholinesterase (AChE) that can affect the nervous system by interfering with normal nerve impulse transmission. These pesticides are described as phosphoramidates which makes them analogues of the well-known nerve agent tabun that has a similar effect on the nervous system. Current therapy for OP- poisoning relying on standard oximes is particularly ineffective for phosphoramide conjugates which show resistance to classical reactivators. There exists a strong need to find better reactivators than the current medically approved standard oxime-antidotes mainly because standard oximes do not cross the blood- brain barrier (BBB) at therapeutically relevant levels. Previous studies have shown new oximes with click chemistry that possess sufficient potency to reactivate tabun- inhibited AChE (Kovarik et al., 2019)1. Click chemistry enables a rapid synthesis of molecular libraries from readily available building blocks making oximes cogent to counteract effects of exposure to phosphoramide pesticides as post-treatment. There is also rising interest in pre-treatment that can be based on bioscavengers like the enzyme butyrylcholinesterase (BChE) that is considered to act as a co-regulator in neurotransmission and is a natural OP scavenger of AChE. Through our studies, we have identified several efficient reactivators of inhibited cholinesterases by OP pesticides which could due to their capacity be a fitting choice for further antidote development.

organophosphorus pesticides, butyrylcholinesterase, tabun, clik-chemistry

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