A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC₅₀ = 0.101 ± 0.003 µM and HssBChE IC₅₀ = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.

A系列毒剂A-234属于新一代神经毒剂。2018 年 3 月，前俄罗斯间谍谢尔盖·斯克里帕尔 (Sergei Skripal) 及其女儿在英国索尔兹伯里中毒，导致 A-234 和其他 A 系列特工被纳入《化学武器公约》。尽管已经过去了五年，但关于其化学性质、生物活性以及现有解毒剂的治疗方案的信息仍然很少。在本文中，我们首先评估了 A-234 在中性 pH 条件下的稳定性，以供后续实验使用。然后，我们确定了其对人重组乙酰胆碱酯酶（Hss AChE；EC 3.1.1.7）和丁酰胆碱酯酶（Hss BChE；EC 3.1.1.8）的抑制潜力，HI-6、奥比肟、解磷定、甲肟和曲甲肟重新激活抑制的能力胆碱酯酶（ChEs）、其对大鼠的毒性以及不同解毒方法的治疗效果。最后，我们利用分子动力学来解释我们的发现。A-234 自发水解的结果显示出一个缓慢的过程，反应速率在前 72 小时内呈现三相过程（残留浓度 86.2%）。A-234 被发现是两种人类 ChE 的有效抑制剂（Hss AChE IC ₅₀  = 0.101 ± 0.003 µM 和Hss BChE IC ₅₀  = 0.036 ± 0.002 µM），而五种市售肟对 A-234-的再激活能力可以忽略不计。抑制Hss AChE 和Hss BChE。A-234 的急性毒性与 VX 相当，在治疗中，阿托品和地西泮可有效减轻 A-234 的致死率。尽管给予肟可能会引起轻微的改善，但选定的肟（HI-6 和甲肟）不会在体内重新激活 ChE。分子动力学表明所有市售肟都是弱亲核试剂，这可能解释了未能重新激活以低部分电荷为特征的A-234磷-丝氨酸氧键，特别是HI-6和曲甲肟肟氧可能无法有效接近A-234磷，而解磷定显示出低相互作用能。这项研究首次提供了 A-234 化合物的重要临床前实验数据。