Life history-guided drug discovery from venomous marine snails

以生活史为指导的有毒海洋蜗牛药物发现

• 批准号: 10361532
• 负责人: BALDOMERO M OLIVERA
• 金额: $ 29.74万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361532
• 关键词: Affinity Chromatography; Animals; Biological Assay; Chemicals; Classification; Collaborations; Collection; Complex Mixtures; Cone; Conotoxin; Conus genus; Country; Data; Data Set; Diabetes Mellitus; Disease; Drug Design; Endocrine system; Enzymes; Epidemic; Epilepsy; Evolution; Family; Fishes; Gland; Goals; Grant; Hand; Health; Human; Inflammation; Insulin; Insulin Coma; International; Ion Channel; Kinetics; Knowledge; Laboratory Research; Libraries; Ligands; Metalloproteases; Molecular Target; Natural Resources; Nervous system structure; Neuromuscular Junction; Neurosciences; Neurotensin; Neurotensin Receptors; Outcome; Pain; Paralysed; Pathway interactions; Peptides; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Pharmacology; Pharmacy (field); Phylogenetic Analysis; Physiological; Post-Translational Protein Processing; Predatory Behavior; Process; Production; Recombinants; Research; Ribosomes; Sampling; Sedation procedure; Snail Venoms; Snails; Source; Specificity; Structure; Targeted Toxins; Testing; Therapeutic; Time; Toxin; Universities; Utah; Venoms; Work; base; bioinformatics tool; computational pipelines; computational platform; cost; design; disulfide bond; drug candidate; drug development; drug discovery; experience; improved; innovation; large datasets; life history; next generation sequencing; novel; novel therapeutics; opioid epidemic; painful neuropathy; preference; receptor; reconstitution; sensory system; tool; trait; transcriptome sequencing

SUMMARY Venomous marine snails in the superfamily Conoidea capture their prey by injecting a complex mixture of ribosomally-synthesized peptides that undergo extensive post-translational modification. These conopeptides target receptors and ion channels in the prey's nervous, endocrine and sensory system with remarkable potency and specificity. Owing to their diversity and target selectivity, conopeptides have become invaluable tools for ion channel research and as therapeutics. The rationale of using cone snail venoms as a source for drug discovery is that homologs of many molecular targets expressed in the prey of cone snails are also found in humans where they are implicated in diverse physiological disorders, including inflammation, epilepsy, neuropathic pain and diabetes. Several recent discoveries made in my group now demonstrate that each of the ~700 cone snail species produces a distinct set of conopeptides that are finely tuned for a specific set of receptors in its prey. Thus, the central hypothesis of this grant is that drug discovery can be maximized by sequencing and characterizing the venom composition of many species from diverse lineages of cone snails, including those that induce diverse physiological endpoints in their prey. This is a highly innovative approach because it takes full advantage of the unique strategies that evolved in these animals for prey capture: species that induce rapid paralysis in their prey are likely to express toxins that target the neuromuscular junction and pain circuits whereas those that induce hypoactivity and sedation are more likely to have evolved toxins that target the sensory and endocrine system. Our preliminary research has already identified several unique drug leads for the treatment of diabetes, a disease that has been recognized as a global epidemic, and pain, a leading cause for the current opioid epidemic. This proposal will enable us to efficiently scale these promising initial efforts. The specific aims of this project are (Aim 1) to undertake a large-scale, evolution-guided collection and next-generation sequencing effort of venoms from all ~50 major lineages of cone snails, (Aim 2) to develop an innovative computational pipeline, the Taxonomer Venoms Module, to analyze these large sequencing datasets, and (Aim 3) to use a tiered, data-driven selection process to pharmacologically characterize the most promising novel toxins from these large datasets. We will also seek to identify and characterize conopeptide biosynthetic pathways. Doing so will improve synthetic and recombinant means for production of conopeptides for functional studies. The expected outcomes are significant. We will provide a computational pipeline for drug discovery that will lead to the identification of many novel classes of conopeptides and their biosynthetic enzymes that will fuel scientific discovery and drug development activities for decades to come.

概括 Conoidea 总科中的有毒海洋蜗牛通过注射一种复合物来捕获猎物 经过广泛翻译后修饰的核糖体合成肽的混合物。 这些锥肽以猎物神经、内分泌和神经系统中的受体和离子通道为目标。 具有显着效力和特异性的感觉系统。由于其多样性和目标 选择性，锥肽已成为离子通道研究的宝贵工具 疗法。使用锥螺毒液作为药物发现来源的基本原理是： 在锥蜗牛猎物中表达的许多分子靶标的同源物也在人类中发现 它们与多种生理疾病有关，包括炎症、癫痫、 神经性疼痛和糖尿病。我的小组最近的几项发现表明 大约 700 种锥形蜗牛中的每一种都会产生一组经过精细调整的独特锥形肽 寻找猎物体内的一组特定受体。因此，这项资助的中心假设是药物 通过对许多毒液成分进行测序和表征，可以最大限度地发现毒液 来自锥形蜗牛不同谱系的物种，包括那些诱导不同生理功能的物种 终点是他们的猎物。这是一种高度创新的方法，因为它充分利用了 这些动物为捕获猎物而进化出的独特策略：导致快速麻痹的物种 猎物体内可能会表达针对神经肌肉接头和疼痛回路的毒素 而那些引起活动减退和镇静的物质更有可能进化出毒素， 针对感觉和内分泌系统。我们的初步研究已经确定了一些 治疗糖尿病这一被公认为全球性疾病的独特药物先导化合物 流行病和疼痛是当前阿片类药物流行的主要原因。该提案将使我们能够 有效地扩展这些有希望的初步努力。该项目的具体目标是（目标 1） 进行大规模、进化引导的收集和下一代测序工作 来自大约 50 个主要锥蜗牛谱系的毒液，（目标 2）开发一种创新的计算方法 管道、分类器毒液模块，用于分析这些大型测序数据集，以及（目标 3） 使用分层的、数据驱动的选择过程来从药理学上表征最有前途的药物 从这些大型数据集中发现新的毒素。我们还将寻求识别和表征共肽 生物合成途径。这样做将改进生产的合成和重组方法 用于功能研究的锥肽。预期成果是显着的。我们将提供一个 药物发现的计算管道将导致许多新类别的识别 锥肽及其生物合成酶将推动科学发现和药物开发 未来几十年的发展活动。

项目成果

Ero1-Mediated Reoxidation of Protein Disulfide Isomerase Accelerates the Folding of Cone Snail Toxins.

• DOI: 10.3390/ijms19113418
• 发表时间: 2018-10-31
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: O'Brien H;Kanemura S;Okumura M;Baskin RP;Bandyopadhyay PK;Olivera BM;Ellgaard L;Inaba K;Safavi-Hemami H
• 通讯作者: Safavi-Hemami H