Engineering subtype selective inhibitors of voltage-sensitive sodium channels

在寻找电压敏感性钠通道抑制剂的过程中，我们从澳洲郁金香芋螺和C.抑制神经元和肌肉形式的河豚毒素敏感性（TTX-S）钠通道。从这些和相关的类似物中，我们已经鉴定了许多选择性和高效的VSSC抑制剂，从而打开了产生可用于癫痫和中风等疾病的第一种亚型选择性TTX-S抑制剂的可能性。这些类似物还显示出对TTX-S钠通道的高选择性，而不是TTX-R亚型hPN 3，hPN 3是我们最近从人类背根神经节克隆的参与神经性疼痛传递的关键通道。鉴于TTX-S和TTX-R钠通道具有相同的整体结构，但在可能影响μ-芋螺毒素结合的相对少量的关键位置处不同，我们相信有可能反向工程化μ-芋螺毒素药理学以有利于TTX-R形式。本项目将通过了解μ-芋螺毒素如何以及在何处与钠通道结合来设计神经中钠通道的亚型特异性抑制剂。我们的长期目标是使用m-芋螺毒素作为模板生产钠通道候选药物，用于开发TTX-S和TTX-R钠通道的亚型选择性抑制剂。这项研究的结果旨在最大限度地发挥这类肽的潜力，从而开发出一种新的疼痛、癫痫和中风治疗药物。

During efforts to find new inhibitors of voltage sensitive sodium channels (VSSCs), we have discovered two new families of mu-conotoxins from Australian Conus tulipa and C. striatus that inhibit neuronal and muscle forms of the tetrodotoxin-sensitive (TTX-S) sodium channel. From these and related analogues we have identified a number of selective and highly potent inhibitors of VSSCs, opening the possibility of producing the first subtype selective TTX-S inhibitors useful in diseases such as epilepsy and stroke. These analogues also showed high selectivity for TTX-S sodium channels over a TTX-resistant (TTX-R) subtype hPN3, a key channel involved in the transmission of neuropathic pain that we recently cloned from human dorsal root ganglia. Given that TTX-S and TTX-R sodium channels have the same overall structure but differ at a relatively small number of key positions likely to affect mu-conotoxin binding, we believe it is possible to reverse engineer mu-conotoxin pharmacology in favour of the TTX-R form. This project will engineer subtype specific inhibitors of sodium channels in nerves through an understanding of how and wheremu-conotoxin bind to the sodium channel. Our long-term goal is to produce sodium channel drug candidates using m-conotoxins as templates for the development of subtype selective inhibitors of TTX-S and TTX-R sodium channels. The results of this study are designed to maximise the potential of this class of peptides as leads to the development of a new classes of therapeutics for pain, epilepsy and stroke.