Neuropharmacology of Conophans and Hydroxyconophans

描述（由申请人提供）：芋螺烷和羟基芋螺烷的神经药理学本区域项目提案旨在对芋螺烷和羟基芋螺烷进行分离和功能表征。羟基conphans，在我们的实验室发现的两个新的相关conopeptides类，其商标是一个D-Xaa-色氨酸基序附近的C-末端（Conophans）和意想不到的？该基序的D-氨基酸的羟基化（？-羟基conophans）。这些化合物是从几种锥螺（C. Gladiator角mus和C. villepinii，到目前为止）。锥螺毒液的组分引起广泛的神经生理反应，并显示出作为治疗剂的巨大潜力。毒液的生化多样性是这些动物在海洋环境中有利地竞争猎物的神经化学策略的一部分。康诺芬和？-羟基芋螺烷增加了分子以进一步使该策略多样化，并且特别令人感兴趣，因为它们是线性肽并且是迄今为止分离的最小芋螺肽之一。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。这将在一个环境中完成，该环境将在一个多学科项目中培训学生和工作人员，该项目从海洋科学到合理的药物发现，并作为PI研究计划发展的一部分。芋螺烷和羟基芋螺烷可以提供一组新的神经元探针或药理学试剂，其具有独特的有利的药用性质，可以方便地合成。具体来说，我们建议实现以下目标：1）扩大现有的conophans和？通过化学方法筛选出C. stimpsoni，C. arangoi，C. delesertii和C. Lindae。2)利用Fmoc固相法发现的conophans的化学合成3）合成？-羟基芋头烷gld-V*/ gld-V*'和mus-V*/ mus-V*'。4)体外功能筛选的？-羟基芋螺素和芋螺素，以评估其神经调节作用，并在有利的情况下，确定其特异性神经元受体5）芋螺素/？羟基芋螺多糖文库，可作为新药先导和神经生物学应用的探针。芋螺肽是一种功能强大的神经药理学药物，具有广泛的应用前景。我们的实验室发现了一类新的芋螺肽，我们将其命名为conophans/？-羟基芋螺。这一发现代表了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第一个例子？氨基酸缬氨酸的羟基化修饰。我们是独一无二的准备探索这一巨大潜力的“药物发现”，因为我们nanomolar量的唯一现有的图书馆？-羟基芋螺。我们的目标是增加我们现有的conophans/？-本发明的目的是为了进行广泛的生物测定，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.