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

基本信息

批准号：
9896842
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
项目类别：
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/9896842
关键词：
Affinity Chromatography Animals Bioavailable Biological Assay Chemicals Classification Cleaved cell 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

项目摘要

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.

概括超家族Conoidea中有毒的海洋蜗牛通过注入复合物来捕获猎物核糖体合成的肽的混合物，经过广泛的翻译后修饰。这些综合肽靶向受体和离子通道在猎物的神经，内分泌和具有显着效力和特异性的感觉系统。由于它们的多样性和目标选择性，综合肽已成为离子渠道研究的宝贵工具，疗法。使用锥蜗牛毒液作为药物发现来源的理由是在人类中也发现了在锥蜗牛猎物中表达的许多分子靶标的同源物它们与各种生理疾病有关，包括炎症，癫痫，神经性疼痛和糖尿病。我小组中最近发现的几个发现证明了〜700个锥形蜗牛物种中的每一个都会产生一组明显的构肽用于猎物中的一组特定受体。因此，这笔赠款的核心假设是药物可以通过测序和表征许多许多人的毒液组成来最大化发现的发现锥蜗牛的多种谱系中的物种，包括诱导多种生理的物种猎物的终点。这是一种高度创新的方法，因为它充分利用了这些动物在捕食捕获中进化的独特策略：诱导快速麻痹的物种在他们的猎物中，可能表达靶向神经肌肉连接和疼痛电路的毒素而那些诱导性低和镇静的人更有可能进化出毒素针对感官和内分泌系统。我们的初步研究已经确定了几个独特的药物导致治疗糖尿病，这种疾病已被认为是全球性的流行病和疼痛，这是当前阿片类药物流行的主要原因。该建议将使我们能够有效地扩展这些有希望的初始努力。该项目的具体目的是（目标1）进行大规模的，进化引导的收集和下一代测序工作来自所有〜50个主要锥蜗牛的毒液，（目标2）开发创新的计算管道，分类器毒液模块，分析这些大型测序数据集，并（AIM 3）使用分层，数据驱动的选择过程以药理表征最有前途的这些大数据集中的新型毒素。我们还将寻求识别和表征综合肽生物合成途径。这样做将改善生产的合成和重组手段综合肽用于功能研究。预期的结果很重要。我们将提供一个药物发现的计算管道将导致识别许多新型类别链肽及其生物合成酶会促进科学发现和药物几十年来的开发活动。