SAR STUDIES OF A TOXIC PEPTIDE

有毒肽的 SAR 研究

• 批准号: 3418025
• 负责人: JOSEPH J MCARDLE
• 金额: $ 10.25万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3418025
• 关键词: acetylcholine; brain cell; calcium channel; cholinergic receptors; electrophysiology; embryo /fetus tissue /cell culture; excitatory aminoacid; hippocampus; laboratory mouse; neuromuscular junction; neuromuscular transmission; neuropeptide receptor; neurotoxins; nicotinic receptors; peptides; potassium channel; protein purification; protein sequence; protein structure function; reptile poison; single cell analysis; sodium channel; spinal ganglion; voltage /patch clamp; voltage gated channel

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.

最近，一组来自Trimeresurus Wagleri毒液的肽，或 瓦格勒的毒蛇，已被纯化和表征 他们对老鼠的致命性。 关于分子的知之甚少 这类肽作用的机制称为 瓦格林。 但是，初步数据表示以下操作 最有效的瓦格林之一，肽I：1。 大鼠骨骼肌的烟碱乙酰胆碱受体； 2。 抑制自发的，但没有刺激诱发的，数量释放 大鼠神经肌肉连接处的发射器； 3。增强的“破败” 重复性神经刺激期间的端板电流； 4。抑制 来自小鼠的神经元中的电压激活的钠和钾电流 脑。 本研究建议旨在确认这些 初步发现并验证了以下假设 T. wagleri的毒液是神经毒性的。 此外，这项工作将使 测试单个多肽的结构可以是 对几个功能过程的毒性。 最后，实验是 提议探索涉及的结构活动关系（SAR） 纯化的Waglerins，合成类似物或片段的作用 它。 为了满足这些目标，传统的电生理学 记录将用于探索浓度依赖性效应 7纯waglerin肽在前后功能上的功能 小鼠三角形肌肉的神经肌肉连接。 在 此外，将采用补丁电压钳技术来探索 这些肽与电压门控的相互作用的分子基础 鼠脑细胞中的离子通道。 预计这样的研究 将导致新的毒素来探索可兴奋的功能 细胞以及用于控制神经元功能的新治疗剂。