Molecular determinants of binding of non-oxime bispyridinium nerve agent antidote compounds to the adult muscle nAChR
Molecular determinants of binding of non-oxime bispyridinium nerve agent antidote compounds to the adult muscle nAChR
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DOI：
10.1016/j.toxlet.2021.01.013
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发表时间：
2021-01-25
影响因子：
3.5
通讯作者：
Biggin, Philip C.
中科院分区：
文献类型：
--
作者：
Epstein, Max;Bali, Karan;Biggin, Philip C.
有机磷神经毒剂（NAs）是最致命的化学战剂，自20世纪30年代发现以来一直被国家和非国家行为者使用。它们共价修饰乙酰胆碱酯酶，防止乙酰胆碱（ACh）分解，随后失去突触传递，这可能导致死亡。尽管有几种OPNA暴露的解毒剂，但没有一种直接靶向烟碱乙酰胆碱受体（nAChR）介导的毒性成分。非肟双吡啶化合物（BPD）以前已被证明部分抵消的影响，NA在骨骼肌组织，这已被归因于抑制肌肉nAChR。功能数据表明，通过增加BPD的吡啶鎓部分之间的烷基接头的长度，可以改善对nAChR的拮抗活性。成人肌肉乙酰胆碱受体的分子动力学模拟中存在的BPD确定的关键残基可能参与结合。随后的双电极电压钳记录表明，其中一个残基，BPDY131，作为BPD结合的变构决定因素，和较长的BPDs有更大的稳定作用的正构环C比较短的。报告的工作将通知未来的设计工作，新的解毒剂治疗NA暴露。(C)2021爱思唯尔有限公司版权所有。
Organophosphorus nerve agents (NAs) are the most lethal chemical warfare agents and have been used by state and non-state actors since their discovery in the 1930s. They covalently modify acetylcholinesterase, preventing the breakdown of acetylcholine (ACh) with subsequent loss of synaptic transmission, which can result in death. Despite the availability of several antidotes for OPNA exposure, none directly targets the nicotinic acetylcholine receptor (nAChR) mediated component of toxicity. Nonoxime bispyridinium compounds (BPDs) have been shown previously to partially counteract the effects of NAs at skeletal muscle tissue, and this has been attributed to inhibition of the muscle nAChR. Functional data indicate that, by increasing the length of the alkyl linker between the pyridinium moieties of BPDs, the antagonistic activity at nAChRs can be improved. Molecular dynamics simulations of the adult muscle nAChR in the presence of BPDs identified key residues likely to be involved in binding. Subsequent two-electrode voltage clamp recordings showed that one of the residues, epsilon Y131, acts as an allosteric determinant of BPD binding, and that longer BPDs have a greater stabilizing effect on the orthosteric loop C than shorter ones. The work reported will inform future design work on novel antidotes for treating NA exposure. (C) 2021 Elsevier B.V. All rights reserved.