Conus Peptides and Their Receptor Targets

简介（由申请人提供）：本港约有1万余种属螺科的有毒海螺；超科中的一类是圆锥蜗牛（Conus）。这个项目的总体目标是从conoidea毒液中开发出高度选择性的肽配体，这些配体对各种离子通道和受体亚型具有新的药理特异性。我们的实验室以前已经从圆锥虫毒液中分离出这种肽，这些肽已经被许多实验室广泛用于基础研究，并且已经出现了重要的转化应用。特别是，圆锥肽已经发现了减轻疼痛的新机制。该计划的总体目标是为新靶标开发高选择性肽配体。在下一个资助期，我们计划扩大一般生物资源的范围，从700只锥螺的毒液扩展到整个锥螺科的有毒蜗牛。本项目的发现活动遵循在上一个资助期得到令人信服的验证的进化策略。我们相信，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。与通常的“生物勘探”程序相比，枝层发现策略更系统、更科学、更有效。该计划分为四个核心和四个项目。核心人员共同支持本计划的所有发现活动，包括任何项目不支持的大量发现活动。此外，这些岩心还将加强将支链发现策略扩展到Conoidea超科所有群所需的科学基础。该项目的目标是为烟碱受体家族、钠通道家族、g蛋白偶联肽受体家族和K通道开发高度亚型特异性肽配体。每个项目也有特定的转化应用，包括开发用于疼痛的镇痛化合物和用于缺血引起的心肌梗死的心脏保护化合物。一个实验计划，以澄清基础的每一个转化应用程序的基本机制将继续进行。这一发现项目导致一种化合物已经被批准为商业药物，还有许多化合物已经进入人体临床试验或处于高级临床前开发阶段。所采用的进化策略，以及可获得的更大的生物资源，应该会大大加快发现的步伐，最终导致新的转化应用。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界以及开发新的治疗和诊断应用的临床研究界广泛互动。

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.