Engineering subtype selective inhibitors of voltage-sensitive sodium channels

在寻找新的电压敏感钠通道(VSSCs)抑制剂的过程中，我们从澳大利亚郁金香圆锥和条纹圆锥中发现了两个新的芋螺毒素家族，它们抑制河豚毒素敏感(河豚毒素-S)钠通道的神经元和肌肉形式。从这些类似物和相关类似物中，我们已经确定了一些选择性和高效力的VSSCs抑制剂，从而为生产第一种亚型选择性TTX-S抑制剂提供了可能性，这些抑制剂可用于癫痫和中风等疾病。这些类似物对河豚毒素抗性(TTX-R)亚型hPN3也显示出对河豚毒素-S钠通道的高选择性，hPN3是我们最近从人背根神经节克隆的参与神经病理性疼痛传递的关键通道。鉴于河豚毒素-S和河豚毒素-R钠通道具有相同的整体结构，但在可能影响芋螺毒素结合的关键位置上存在相对较少的差异，我们相信有可能通过反向工程来支持河豚毒素-R形式。这个项目将通过了解芋螺毒素如何以及在哪里结合到钠通道来设计神经中钠通道的亚型特异性抑制剂。我们的长期目标是以芋螺毒素为模板生产钠通道候选药物，用于开发河豚毒素-S和河豚毒素-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多肽的潜力，从而开发出一种治疗疼痛、癫痫和中风的新疗法。

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.