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:
- 金额:$ 29.74万
- 依托单位:
- 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:
- 关键词:Affinity ChromatographyAnimalsBiological AssayChemicalsClassificationCollaborationsCollectionComplex MixturesConeConotoxinConus genusCountryDataData SetDiabetes MellitusDiseaseDrug DesignEndocrine systemEnzymesEpidemicEpilepsyEvolutionFamilyFishesGlandGoalsGrantHandHealthHumanInflammationInsulinInsulin ComaInternationalIon ChannelKineticsKnowledgeLaboratory ResearchLibrariesLigandsMetalloproteasesMolecular TargetNatural ResourcesNervous system structureNeuromuscular JunctionNeurosciencesNeurotensinNeurotensin ReceptorsOutcomePainParalysedPathway interactionsPeptidesPeptidylprolyl IsomerasePharmaceutical PreparationsPharmacologyPharmacy (field)Phylogenetic AnalysisPhysiologicalPost-Translational Protein ProcessingPredatory BehaviorProcessProductionRecombinantsResearchRibosomesSamplingSedation procedureSnail VenomsSnailsSourceSpecificityStructureTargeted ToxinsTestingTherapeuticTimeToxinUniversitiesUtahVenomsWorkbasebioinformatics toolcomputational pipelinescomputational platformcostdesigndisulfide bonddrug candidatedrug developmentdrug discoveryexperienceimprovedinnovationlarge datasetslife historynext generation sequencingnovelnovel therapeuticsopioid epidemicpainful neuropathypreferencereceptorreconstitutionsensory systemtooltraittranscriptome 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:
- 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
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BALDOMERO M OLIVERA其他文献
BALDOMERO M OLIVERA的其他文献
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{{ truncateString('BALDOMERO M OLIVERA', 18)}}的其他基金
“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:
10592438 - 财政年份:2022
- 资助金额:
$ 29.74万 - 项目类别:
“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:
10346236 - 财政年份:2022
- 资助金额:
$ 29.74万 - 项目类别:
“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:
10798547 - 财政年份:2022
- 资助金额:
$ 29.74万 - 项目类别:
“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 - 财政年份:2022
- 资助金额:
$ 29.74万 - 项目类别:
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:
9896842 - 财政年份:2018
- 资助金额:
$ 29.74万 - 项目类别:
CONOTOXINS AND HOMERIC NICOTINIC ACETYLCHOLINE RECEPTORS
芋螺毒素和荷马烟碱乙酰胆碱受体
- 批准号:
6610794 - 财政年份:2003
- 资助金额:
$ 29.74万 - 项目类别:
CONANTOKINS: NMDA RECEPTOR SUBTYPES AND EPILEPSY
锥豆素:NMDA 受体亚型与癫痫
- 批准号:
6610790 - 财政年份:2003
- 资助金额:
$ 29.74万 - 项目类别:
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