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

– 芋螺毒液肽及其分子靶标：使用药理学和神经行为学作为发现框架 –

• 批准号: 10810172
• 负责人: BALDOMERO M OLIVERA
• 金额: $ 1.08万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810172
• 关键词: Achievement; Affect; Alzheimer' s Disease; Animals; Basic Science; Behavior; Biochemical; Biological; Biological Assay; Biological Models; Calcium; Chemicals; Clinical Trials; Collection; Complex; Cone; Conotoxin; Consumption; Conus Venom; Conus genus; Development; Diagnostic; Electrophysiology (science); Epilepsy; FDA approved; Fishes; Functional disorder; Gland; Goals; Grant; Hour; Human; Individual; Investigation; Ion Channel; Ion Channel Gating; Laboratories; Libraries; Ligands; Link; Macrophage; Methods; Molecular; Molecular Target; Mus; National Institute of General Medical Sciences; Natural Products; Nervous System; Nicotinic Receptors; Pain; Pathology; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Potassium Channel; Proteomics; Purinoceptor; Rationalization; Resources; Respiratory distress; Role; Route; Science; Snail Venoms; Snails; Spinal Ganglia; Structure; System; Therapeutic; Time; Venoms; Vertebrates; Voltage-Gated Potassium Channel; basal forebrain; bioactive natural products; biophysical properties; cell type; chronic pain; ganglion cell; imaging platform; improved; inhibitor; insight; macromolecule; marine; marine natural product; neuroethology; novel; novel strategies; pathogen; pharmacologic; programs; receptor; screening; spinal cord injury pain; tool; transcriptomics; voltage

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.

项目摘要/摘要 锥形蜗牛的毒液中的数百种不同的生物活性成分已经证明 过去，非凡的生物医学潜力，包括作为FDA批准的药物发育。然而， 它们的发现和表征通常受到可访问的少量毒液的限制。 我们的实验室已经开发了一个与选择性药理学相结合的钙成像平台 （“星座药理学”），当结合转录组和最新技术进步时 蛋白质组学分析和电生理学（我们称为药物学的集成平台）完全 改变了新型毒液成分的发现和表征的景观。使用 药学，一个目标是紧密搭配个体的发现和生化特征 毒液成分阐明了分子和细胞机制，这些机制是其生物学的基础 活动。药学方法还揭示了单个成分如何影响生理 系统和整个动物水平。我们将使用从生物活性毒液的特征中获得的见解 锥形蜗牛的特定规范行为和神经地体学及其是鱼类猎物的组成部分。 这些新工具应允许新型生物活性锥毒的前所未有的发现率 组件与阐明其分子靶标紧密相关。 尽管该项目的重点是毒液宠物及其分子靶标的 药学方法可用于阐明任何与任何物理相关的分子靶标 天然产品。将天然产品的巨大化学多样性与它们的同源大分子联系起来 接收者也应大大扩展天然产品作为基础研究中的药物工具 作为他们的治疗和其他生物医学应用。

项目成果

A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3.

• DOI: 10.1371/journal.pbio.3002217
• 发表时间: 2023-08
• 期刊: PLOS BIOLOGY
• 影响因子: 9.8
• 作者: Hackney, Celeste D.;Salcedo, Paula Florez;Mueller, Emilie;Koch, Thomas Lund;Kjelgaard, Lau R.;Watkins, Maren J.;Zachariassen, Linda S.;Tuelund, Pernille Sonderby;McArthur, Jeffrey K.;Adams, David;Kristensen, Anders;Olivera, Baldomero;Finol-Urdaneta, Rocio;Safavi-Hemami, Helena;Morth, Jens Preben;Ellgaard, Lars
• 通讯作者: Ellgaard, Lars