“Conus venom peptides and their molecular targets: Using pharmaconomics and neuroethology as a framework for discovery”

项目摘要/摘要 锥螺毒液中数百种不同的生物活性成分已经证明 过去具有非凡的生物医学潜力，包括开发成为FDA批准的药物。然而， 它们的发现和特征通常受到可接触到的少量毒液的限制。 我们实验室开发了一种结合选择性药理的钙成像平台 (“星座药理学”)，当结合最近的技术进步，转录和 蛋白质组分析和电生理学(我们称之为药物经济学的综合平台)完全 在发现和表征新的毒液成分方面，改变了格局。vbl.使用 药理学，一个目标是将个体的发现和生物化学特征紧密结合起来 毒液成分，阐明其生物学基础的分子和细胞机制 活动。药理学方法还揭示了个体成分如何影响人体的生理功能。 系统和整个动物的水平。我们将利用从生物活性毒液的表征中获得的见解 组件，以合理化物种特有的行为和神经行为学的锥螺和它的鱼的猎物。 这些新工具应该会以前所未有的速度发现新的生物活性锥形蜗牛毒液 与其分子靶标的阐明紧密相连的成分。 虽然这个项目的重点是毒肽及其分子靶标，但 药物经济学方法可以用来阐明任何与生理相关的分子靶点。 天然产物。将天然产物的巨大化学多样性与其同源大分子联系起来 受体也应该大大扩大天然产物在基础研究中作为药理工具的使用。 作为它们的治疗和其他生物医学应用。

Project Summary/Abstract The hundreds of different bioactive components in the venoms of cone snails have demonstrated extraordinary biomedical potential in the past, including development as an FDA-approved drug. However, their discovery and characterization is generally limited by the small amounts of venom that are accessible. Our laboratory has developed a calcium-imaging platform combined with selective pharmacology (“Constellation Pharmacology”), that when combined with recent technical advances in transcriptomic and proteomic analysis and electrophysiology (an integrated platform that we call Pharmaconomics) completely changes the landscape with respect to discovery and characterization of novel venom components. Using pharmaconomics, one goal is to tightly couple the discovery and biochemical characterization of individual venom components with the elucidation of the molecular and cellular mechanisms that underlie their biological activity. The pharmaconomics approach also uncovers how individual components affect physiology at the system’s and whole animal level. We will use the insights gained from the characterization of bioactive venom components to rationalize the species-specific behavior and neuroethology of the cone snail and it’s fish prey. These new tools should allow an unprecedented rate of discovery of novel bioactive cone snail venom components tightly linked to the elucidation of their molecular targets. Although the focus of this project is on venom peptides and their molecular targets, the pharmaconomics approach can be used for elucidating the physiologically-relevant molecular target of any natural product. Linking the vast chemical diversity of natural products to their cognate macromolecular receptors should greatly expand the use of natural products as pharmacological tools in basic research, as well as their therapeutic and other biomedical applications.