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重新组装的肉毒神经毒素抑制中枢神经系统功能而无全身毒性。

Re-assembled botulinum neurotoxin inhibits CNS functions without systemic toxicity.

机构信息

Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.

出版信息

Toxins (Basel). 2011 Apr;3(4):345-55. doi: 10.3390/toxins3040345. Epub 2011 Mar 24.

DOI:10.3390/toxins3040345
PMID:22069712
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3202830/
Abstract

The therapeutic potential of botulinum neurotoxin type A (BoNT/A) has recently been widely recognized. BoNT/A acts to silence synaptic transmission via specific proteolytic cleavage of an essential neuronal protein, SNAP25. The advantages of BoNT/A-mediated synaptic silencing include very long duration, high potency and localized action. However, there is a fear of possible side-effects of BoNT/A due to its diffusible nature which may lead to neuromuscular blockade away from the injection site. We recently developed a "protein-stapling" technology which allows re-assembly of BoNT/A from two separate fragments. This technology allowed, for the first time, safe production of this popular neuronal silencing agent. Here we evaluated the re-assembled toxin in several CNS assays and assessed its systemic effects in an animal model. Our results show that the re-assembled toxin is potent in inhibiting CNS function at 1 nM concentration but surprisingly does not exhibit systemic toxicity after intraperitoneal injection even at 200 ng/kg dose. This shows that the re-assembled toxin represents a uniquely safe tool for neuroscience research and future medical applications.

摘要

肉毒毒素 A 型（BoNT/A）的治疗潜力最近得到了广泛认可。BoNT/A 通过特异性蛋白水解切割神经元中必需的蛋白 SNAP25 来抑制突触传递。BoNT/A 介导的突触沉默具有持续时间长、效力高和作用部位局限等优点。但是，由于其可扩散的性质，人们担心 BoNT/A 可能会产生副作用，从而导致注射部位以外的神经肌肉阻滞。我们最近开发了一种“蛋白质订书钉”技术，该技术可以将 BoNT/A 重新组装成两个单独的片段。这项技术首次实现了这种广受欢迎的神经元沉默剂的安全生产。在这里，我们在几种中枢神经系统（CNS）测定中评估了重新组装的毒素，并在动物模型中评估了其全身效应。我们的结果表明，重新组装的毒素在 1 nM 浓度下即可有效抑制 CNS 功能，但令人惊讶的是，即使在 200 ng/kg 的剂量下经腹腔注射也没有表现出全身毒性。这表明重新组装的毒素代表了一种用于神经科学研究和未来医学应用的独特安全工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/76d099106a34/toxins-03-00345-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/3e90f9aaa601/toxins-03-00345-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/c45c8c68ff15/toxins-03-00345-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/b2394c1c826e/toxins-03-00345-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/16621133da7d/toxins-03-00345-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/76d099106a34/toxins-03-00345-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/3e90f9aaa601/toxins-03-00345-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/c45c8c68ff15/toxins-03-00345-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/b2394c1c826e/toxins-03-00345-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/16621133da7d/toxins-03-00345-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/359f/3202830/76d099106a34/toxins-03-00345-g005.jpg

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