“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.

项目概要/摘要 锥蜗牛毒液中数百种不同的生物活性成分已被证明 过去具有非凡的生物医学潜力，包括作为 FDA 批准的药物进行开发。 它们的发现和表征通常受到可获取的少量毒液的限制。 我们实验室开发了结合选择性药理学的钙成像平台 （“Constellation Pharmacology”），当与转录组学和 蛋白质组学分析和电生理学（我们称之为药物经济学的综合平台）完全 改变了新毒液成分的发现和表征方面的情况。 药物经济学，一个目标是将个体的发现和生化特征紧密结合起来 毒液成分及其生物学基础的分子和细胞机制的阐明 药理学方法还揭示了各个成分如何影响生理学。 我们将利用从生物活性毒液的表征中获得的见解。 使锥形蜗牛及其鱼类猎物的物种特异性行为和神经行为学合理化的组件。 这些新工具应该能够以前所未有的速度发现新型生物活性锥蜗牛毒液 与其分子靶点的阐明紧密相关的成分。 尽管该项目的重点是毒液肽及其分子靶标， 药理学方法可用于阐明任何药物的生理相关分子靶点 将天然产物的巨大化学多样性与其同源大分子联系起来。 受体应该大大扩展天然产物作为基础研究中药理学工具的使用，以及 作为它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