Department of Biochemistry, Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, UK.
Department of Biochemistry, Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, UK; Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge, UK.
Toxicol Lett. 2021 Apr 1;340:114-122. doi: 10.1016/j.toxlet.2021.01.013. Epub 2021 Jan 19.
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. Non-oxime 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, εY131, 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.
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。它们通过共价修饰乙酰胆碱酯酶，阻止乙酰胆碱（ACh）的分解，随后丧失突触传递，这可能导致死亡。尽管有几种针对 OPNA 暴露的解毒剂，但没有一种直接针对烟碱型乙酰胆碱受体（nAChR）介导的毒性成分。先前已经表明，非肟双吡啶鎓化合物（BPD）可部分抵消 NAs 对骨骼肌组织的影响，这归因于抑制肌肉 nAChR。功能数据表明，通过增加 BPD 吡啶部分之间的烷基连接链的长度，可以提高 nAChRs 的拮抗活性。存在 BPD 时的成人肌肉 nAChR 的分子动力学模拟确定了可能参与结合的关键残基。随后的双电极电压钳记录表明，一个残基，εY131，作为 BPD 结合的变构决定因素，较长的 BPD 对正位环 C 的稳定作用大于较短的 BPD。所报道的工作将为治疗 NA 暴露的新型解毒剂的未来设计工作提供信息。
