Conus Peptides and Their Receptor Targets

圆锥肽及其受体靶点

• 批准号: 7938325
• 负责人: BALDOMERO M OLIVERA
• 金额: $ 68.7万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938325
• 关键词: Conus; Peptides; Their; Receptor; Targets

DESCRIPTION (provided by applicant): There are >10,000 species of venomous marine snails belonging to the superfamily Conoidea; one group in the superfamily are the cone snails (Conus). The general goal of this program is to develop highly selective peptide ligands derived from Conoidean venoms that have novel pharmacological specificity for various ion channel and receptor subtypes. Our laboratories have previously isolated such peptides from Conus venoms, and these have been used extensively in basic research by many laboratories, and important translational applications have emerged. In particular, Conus peptides have uncovered novel mechanisms to alleviate pain. A general goal of this Program is to develop highly selective peptide ligands for novel targets. In the next grant period, we plan to expand the general biological resource to be accessed, from the venoms of the 700 cone snails to the venomous snails in the entire family of Conoidea. The discovery activities of this Program follow a cladistic strategy that was convincingly validated in the last grant period. We believe that this discovery strategy represents a potential paradigm shift in how discovery of lead compounds from animal biodiversity will be carried out in the future. The cladistic discovery strategy is more systematic, science based and efficient than the usual procedures for "bioprospecting". The Program is organized into four Cores and four Projects. Together, the Cores support all of the discovery activities of this Program, including a significant number of discovery initiatives that are not supported by any of the Projects. Furthermore, the Cores will also strengthen the scientific foundation required for extending the cladistic discovery strategy to all groups in the superfamily Conoidea. The goals of the Projects are to develop panels of highly subtype-specific peptide ligands for the nicotinic receptor family, for the sodium channel family, for the G-protein coupled-peptide receptor family, and for K channels. Each project also has specific translational applications, including the development of analgesic compounds for pain and cardioprotective compounds for myocardial infarction due to ischemia. An experimental plan to clarify basic mechanisms that underlie each translational application will be pursued. This discovery program has led to one compound already approved as a commercial drug, and many others that have either reached human clinical trials or are in advanced preclinical development. The cladistic strategy to be employed, and the larger biological resource to be accessed, should greatly accelerate the pace of discovery ultimately leading to novel translational applications. Thus, the research activities of this program interact broadly with the basic research community studying ion channels and receptors, as well as the more clinically oriented community developing novel therapeutic and diagnostic applications.

描述（由申请人提供）：有超过10 000种有毒的海洋蜗牛属于芋螺总科;总科中的一个类群是锥形蜗牛（芋螺属）。该计划的总体目标是开发高选择性的肽配体，这些肽配体来源于芋螺毒液，对各种离子通道和受体亚型具有新的药理学特异性。我们的实验室以前从芋螺毒液中分离出这样的肽，这些肽已被许多实验室广泛用于基础研究，并出现了重要的翻译应用。特别是，芋螺肽已经发现了减轻疼痛的新机制。该计划的总体目标是开发用于新靶点的高选择性肽配体。在下一个资助期内，我们计划扩大可获得的一般生物资源，从700种锥螺的毒液到整个芋螺科的有毒蜗牛。本计划的发现活动遵循在上一个资助期内令人信服地验证的分支策略。我们认为，这种发现策略代表了未来如何从动物生物多样性中发现先导化合物的潜在范式转变。分支发现策略比通常的“生物勘探”程序更系统，更科学，更有效。该计划分为四个核心和四个项目。这些核心共同支持本计划的所有发现活动，包括大量不受任何项目支持的发现计划。此外，核心还将加强将分支发现策略扩展到Conoidea超家族中所有群体所需的科学基础。该项目的目标是开发烟碱受体家族、钠通道家族、G蛋白偶联肽受体家族和K通道的高度亚型特异性肽配体。每个项目也有具体的翻译应用，包括开发用于疼痛的止痛化合物和用于缺血性心肌梗死的心脏保护化合物。一个实验性的计划，以澄清每一个翻译应用程序的基础的基本机制将被追求。这一发现计划已经导致一种化合物已经被批准为商业药物，以及许多其他已经达到人体临床试验或处于高级临床前开发阶段的化合物。分支策略的采用，和更大的生物资源的访问，应大大加快发现的步伐，最终导致新的翻译应用。因此，该计划的研究活动与研究离子通道和受体的基础研究社区以及开发新型治疗和诊断应用的临床社区广泛互动。