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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：
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
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/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

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.

总结

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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