Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Immunology and Microbial Sciences, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bioorg Med Chem Lett. 2013 Dec 15;23(24):6743-6. doi: 10.1016/j.bmcl.2013.10.029. Epub 2013 Oct 25.
The botulinum neurotoxins, characterized by their neuromuscular paralytic effects, are the most toxic proteins known to man. Due to their extreme potency, ease of production, and duration of activity, the BoNT proteins have been classified by the Centers for Disease Control as high threat agents for bioterrorism. In an attempt to discover effective BoNT therapeutics, we have pursued a strategy in which we leverage the blockade of K(+) channels that ultimately results in the reversal of neuromuscular paralysis. Towards this end, we utilized peptides derived from scorpion venom that are highly potent K(+) channel blockers. Herein, we report the synthesis of charybdotoxin, a 37 amino acid peptide, and detail its activity, along with iberiotoxin and margatoxin, in a mouse phrenic nerve hemidiaphragm assay in the absence and the presence of BoNT/A.
肉毒神经毒素以其神经肌肉麻痹作用为特征，是已知对人类最具毒性的蛋白质。由于其极高的效力、易于生产和活性持续时间，BoNT 蛋白已被疾病控制中心列为生物恐怖主义的高威胁制剂。为了寻找有效的 BoNT 治疗方法，我们采用了一种策略，利用阻断 K(+)通道的方法，最终逆转神经肌肉麻痹。为此，我们利用源自蝎子毒液的肽，这些肽是高效的 K(+)通道阻断剂。在此，我们报告了 charybdotoxin 的合成，这是一种 37 个氨基酸的肽，并详细描述了它在缺乏和存在 BoNT/A 的情况下在小鼠膈神经半膈肌测定中的活性，以及 iberiotoxin 和 margatoxin 的活性。
