Neuropharmacology of Conophans and Hydroxyconophans

描述(申请人提供)：柯诺芬和羟柯芬的神经药理学这个领域的项目提案旨在研究柯芬和？-羟基柯芬的分离和功能表征，这是我们实验室发现的两类新的相关柯多肽，其商标是靠近C-末端的D-xaa-Trp基序(柯诺芬)和这个基序的D-氨基酸的？-羟基化(？-羟基柯芬)。这些化合物是从几种锥螺的毒液中分离出来的(目前为止，角螺、毛螺和毛螺)。锥螺毒液成分可引起广泛的神经生理反应，显示出巨大的治疗潜力。这种毒液的生物化学多样性是这些动物在海洋环境中有利地争夺猎物的神经化学策略的一部分。康诺芬和β-羟基康诺芬增加了分子，以进一步多样化这一策略，特别令人感兴趣的是，因为它们是线状多肽，也是迄今为止分离出的最小的柯柯多肽之一。该项目的贡献将是研究一类新的潜在治疗药物的神经药理学。这项工作将在这样一个环境中进行，该环境将培训学生和工作人员进行从海洋科学到合理药物发现的多学科项目，并作为PI研究计划发展的一部分。康诺芬和羟基康诺芬可以提供一套新颖的神经元探针或药理试剂，具有独特的良好药用性能，可以方便地合成。具体地说，我们建议完成以下目标：1)通过化学筛选斯氏柯萨尼、Arangoi、Delesertii和Lindae毒液，扩大现有的螺杆菌和？-羟基螺杆菌的文库。2)化学合成以Fmoc为基础的固相法发现的椰油酚；3)用固相法合成β-羟基椰油酚GLD-V*/GLD-V*‘和MUS-V*/MUS-V*’。4)体外功能筛选，以评价它们的神经调节作用，并在有利的情况下，确定它们的特异性神经元受体。5)建立可作为新型药物先导和神经生物学应用的探针的椰油酚/羟基椰油酚文库。刀豆肽是一种功能强大的神经药理制剂，具有广泛的应用前景。我们实验室发现了一类新的螺螺肽，我们将其命名为螺螺肽/？-羟基螺螺肽。这一发现代表了多肽和蛋白质生物化学的一个里程碑，因为这些化合物提供了氨基酸Valine的羟基化修饰的第一个例子。我们独一无二地准备探索这一巨大的“药物发现”潜力，因为我们拥有现存唯一的库？-羟基康诺菲的纳摩尔量。我们的目标是增加我们目前的椰子/？-羟基椰子的供应，以便进行广泛的生物测试，以评估这些新化合物作为治疗剂的潜力。

DESCRIPTION (provided by applicant): Neuropharmacology of Conophans and Hydroxyconophans This AREA project proposal is aimed at the isolations and functional characterization of conophans and ?-hydroxyconphans, two new classes of related conopeptides discovered in our laboratory, whose trademark is a D-Xaa-Trp motif near the C-terminal (Conophans) and the unexpected ?-hydroxylation of the D-amino acid of this motif (?- hydroxyconophans). These compounds were isolated from the venom of several cone snail species (C. gladiator, C. mus and C. villepinii, so far). Components of the venom of cone snails elicit a wide range of neurophysiological responses and show great potential as therapeutic agents. The biochemical diversity of the venom is part of a neurochemical strategy used by these animals to compete favorably for prey in the marine environment. Conophans and ?-hydroxyconophans add molecular to further diversity this strategy and are of particular interest as they are linear peptides and among the smallest conopeptides isolated to date. The contribution of this project will be to investigate the neuropharmacology of a new class of potential therapeutic agents. This is to be done in an environment that will train students and staff in a multidisciplinary project that ranges from marine science to rational drug discovery and as part of the development of the PI's research program. Conophans and hydroxyconophans can provide a novel set of neuronal probes or pharmacological agents with unique favorable medicinal properties that can be conveniently synthesized. Specifically, we propose to accomplish the following goals: 1) expansion of the current library of existing conophans and ?-hydroxyconophans by chemically screening the venom C. stimpsoni, C. arangoi, C. delesertii and C. lindae. 2) Chemically synthesis the conophans discovered using Fmoc-based solid phase methods 3) To synthesize ?- hydroxyconophans gld-V*/ gld-V*' and mus-V*/ mus-V*' using solid-phase methods. 4) In vitro functional screening of the ?-hydroxyconophans and the conophans to evaluate their neuromodulatory effects and in favorable cases, define their specific neuronal receptor 5) Compilation of a conophans/?-hydroxyconophan library that can serve as novel drugs leads and as probes for neurobiology applications. Conopeptides are powerful neuropharmacological agents that can be used for wide variety of applications. Our laboratory has found a new class of conopeptides that we have named conophans/?-hydroxyconophans. This discovery represents a landmark in peptide and protein biochemistry as these compounds provide the very first examples ?- hydroxylated modifications of the amino acid Valine. We are uniquely poised to explore this great potential for "Drug discovery" as we posses nanomolar quantities of the only existing library ?-hydroxyconophans. Our goal is to augment our current supply of conophans/?-hydroxyconophans in order to carry out extensive biological assays geared towards the evaluation of these new compounds as potential as therapeutic agents.