Departments of Chemistry and Immunology, Worm Institute of Research & Medicine, La Jolla, California 92037, United States.
ACS Chem Biol. 2010 Dec 17;5(12):1183-91. doi: 10.1021/cb1002366. Epub 2010 Oct 22.
Botulinum neurotoxins (BoNT) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. BoNT/A is the most toxic protein known to man and has been classified by the Centers of Disease Control (CDC) as one of the six highest-risk threat agents for bioterrorism. Of particular concern is the apparent lack of clinical interventions that can reverse cellular intoxication. Efforts to uncover molecules that can act within an intoxicated cell so as to provide symptomatic relief to BoNT/A are paramount. Aminopyridines have shown clinical efficacy for multiple sclerosis treatment as well as BoNT/A intoxication; yet, aminopyridines for BoNT/A treatment has been abandoned because of blood brain barrier (BBB) penetration producing undesired neurotoxic side effects. Two aminopyridines (5 and 11) exhibited inhibitory activity toward Shaker-IR voltage-gated potassium (K(V)1.x) channels with potencies similar to that of the previous "gold-standard", 3,4-diaminopyridine (3,4-DAP), including reversal of symptoms from BoNT-induced paralysis in phrenic nerve-hemidiaphragm preparations. Importantly, pharmacokinetic experiments revealed a lack of BBB penetration of 5, which is a significant advancement toward resolving the neurotoxicity issues associated with prolonged 3,4-DAP treatments. Finally, 5 was found to be as effective as 3,4-DAP in rescuing BoNT-poisoned mice in the mouse lethality assay, signifying an optimized balance between the undesired permeability across the BBB and the required permeability across lipid cellular membranes. The results demonstrate that 5 is the most promising small molecule K(+) channel inhibitor discovered to date for the treatment of BoNT/A intoxication.
肉毒杆菌神经毒素（BoNT）是引起肉毒中毒的病原体，该病的特征是周围神经肌肉阻滞和人类出现特征性弛缓性瘫痪。BoNT/A 是已知对人类最具毒性的蛋白质，已被疾病控制与预防中心（CDC）列为生物恐怖主义六大最高风险威胁因子之一。特别值得关注的是，目前似乎缺乏能够逆转细胞中毒的临床干预措施。寻找能够在中毒细胞内发挥作用的分子，为 BoNT/A 提供症状缓解，这一点至关重要。氨基吡啶类药物在多发性硬化症治疗以及 BoNT/A 中毒方面显示出了临床疗效；然而，由于血脑屏障（BBB）穿透会产生不良的神经毒性副作用，氨基吡啶类药物治疗 BoNT/A 的方法已被放弃。两种氨基吡啶类药物（5 和 11）对 Shaker-IR 电压门控钾（K(V)1.x）通道表现出抑制活性，其效力与先前的“金标准”3,4-二氨基吡啶（3,4-DAP）相似，包括逆转膈神经-半膈肌标本中由 BoNT 引起的麻痹症状。重要的是，药代动力学实验显示 5 缺乏 BBB 穿透，这是解决与延长 3,4-DAP 治疗相关的神经毒性问题的重要进展。最后，在小鼠致死性测定中，发现 5 与 3,4-DAP 一样有效，能挽救 BoNT 中毒的小鼠，这表明在 BBB 通透性和脂质细胞膜所需通透性之间达到了最佳平衡。结果表明，5 是迄今为止发现的治疗 BoNT/A 中毒最有前途的小分子 K(+) 通道抑制剂。
