SAR STUDIES OF A TOXIC PEPTIDE

最近，从竹叶青蛇（Trimeresurus wagleri）毒液中提取了一组肽， 瓦格勒的蝮蛇，已经被纯化，并根据 它们对老鼠的杀伤力 关于分子水平知之甚少。 这类肽的作用机制称为 Waglerins 然而，初步数据表明， 一种更有效的waglerins肽I：1。一种“箭毒样”的作用， 大鼠骨骼肌烟碱型乙酰胆碱受体; 2. 抑制自发的，但不是刺激诱发的，量子释放 大鼠神经肌肉接头处的递质; 3.加强“纲要”的 重复神经刺激期间的终板电流; 4.制止 小鼠神经元电压激活钠钾电流 个脑袋 目前的研究计划旨在确认这些 初步调查结果，并验证了长期的假设， T.毒液wagleri有神经毒性。 此外，这项工作将使 检验单个多肽的结构可以被 对几种功能过程具有同等毒性。 最后，实验 建议探索结构活性关系（SAR）， 纯化的Waglerins、合成的类似物或片段的作用 它们的 为了满足这些目标，常规电生理学 记录将用于探索以下物质的浓度依赖性效应： 7纯waglerin肽对突触前和突触后功能的影响 小鼠胸骨三角肌的神经肌肉接头。 在 此外，还将采用膜片钳技术来探讨 这些肽与电压门控的相互作用的分子基础 离子通道。 预计这些研究 将导致新的毒素与探索功能的兴奋 细胞以及控制神经元功能的新治疗剂。

Recently, a group of peptides from the venom of Trimeresurus wagleri, or Wagler's pit viper, have been purified and characterized in terms of their lethality to mice. Little is known concerning the molecular mechanism underlying the action of this class of peptides known as the waglerins. However, preliminary data indicate the following actions of one of the more potent waglerins, peptide I: 1. a "curare-like" action on the nicotinic acetylcholine receptor of rat skeletal muscle; 2. suppression of spontaneous, but not stimulus-evoked, quantal release of transmitter at the rat neuromuscular junction; 3. enhanced "rundown" of end-plate currents during repetitive nerve stimulation; 4. suppression of voltage-activated sodium and potassium currents in neurons from mouse brain. The present research proposal is designed to confirm these preliminary findings and validate the longstanding hypothesis that the venom of T. wagleri is neurotoxic. In addition, this work will enable a test of the hypothesis that the structure of a single polypeptide can be equi-toxic to several functional processes. Finally, experiments are proposed to explore the structure-activity relations (SAR) involved in the action of the purified waglerins, synthetic analogues, or fragments thereof. To meet these objectives, conventional electrophysiological recording will be used to explore the concentration-dependent effects of 7 pure waglerin peptides on pre- and postsynaptic functions of the neuromuscular junction of the mouse Triangularis sterni muscle. In addition, patch voltage-clamp techniques will be employed to explore the molecular basis of the interaction of these peptides with voltage-gated ion channels in murine brain cells. It is anticipated that such studies will lead to new toxins with which to explore the function of excitable cells as well as to new therapeutic agents to control neuronal function.