Development of Small Molecules that Enhance the Delivery and the Pharmacological Effects of Oligonucleotides
开发增强寡核苷酸递送和药理作用的小分子
基本信息
- 批准号:8980120
- 负责人:
- 金额:$ 31.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-15 至 2017-08-14
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAttentionBehaviorBiochemicalBiodistributionBiologyBloodCategoriesCell Culture TechniquesCell NucleusCellsChemicalsClinicalComplexCytosolDevelopmentDiseaseDoseDrug KineticsEffectivenessEndocytosis PathwayEndosomesGene ExpressionGenesGoalsInvestigationInvestmentsKineticsMalignant NeoplasmsMalignant neoplasm of ovaryModelingModificationMolecularMovementMusNanotechnologyNorth CarolinaOligonucleotidesOrganPathogenesisPathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologic SubstancePhasePropertyProteinsRNA SplicingResourcesSeriesSiteSmall Business Technology Transfer ResearchSmall Interfering RNAStructure-Activity RelationshipTechnologyTherapeuticTherapeutic UsesTimeTissuesToxic effectTransgenic MiceTransgenic ModelUniversitiesXenograft Modelanalogbasecommercializationdrug discoveryhigh throughput screeningimprovedin vivoinnovationlate endosomemouse modelnanocarriernew technologynovel strategiespublic health relevanceresponsesmall moleculesmall molecule librariestherapeutic effectivenesstraffickingtumortumor growthtumor xenograft
项目摘要
DESCRIPTION (provided by applicant): Antisense and siRNA oligonucleotides offer the promise of highly precise manipulation of genes involved in disease pathogenesis. However, despite the investment of enormous resources, that promise has been fulfilled to only a limited degree. A key impediment to oligonucleotide-based therapeutics is the difficulty in delivering these large, highly polar molecules to their sites of action in the cytosol or nucleus of tissue cells. While chemical modification of oligonucleotides and the utilization of various nanotechnology-based delivery approaches have been helpful, the delivery problem remains challenging. Much of the oligonucleotide accumulated by cells remains non-productively entrapped in endosomes. The complex pathways of endocytosis and intracellular trafficking are being increasingly understood at the molecular level; however, there is a paucity of small molecule probes for these pathways. Here we describe a novel technology based on the use of small organic molecules to enhance the functional delivery and pharmacological effectiveness of oligonucleotides by manipulating their intracellular trafficking. We have established a proof of
principle for this strategy by identifying compounds using a high throughout screen of >100,000 small molecules. Three distinct compound series were discovered from this screen that significantly enhance oligonucleotide effects in cell culture, and in one case in a transgenic mouse model. We now propose medicinal chemistry efforts to build structure activity relationships and improve both potency and pharmacological properties with the end goal of creating molecules that can effectively and safely be used in vivo. Promising leads will be examined for their pharmacokinetic and biodistribution behavior. Finally, these leads will be evaluated in a xenograft tumor model. The identification of potent and non-toxic enhancing molecules will likely have a major impact on the entire field of oligonucleotide therapeutics.
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
Oligonucleotide-based therapies for cystic fibrosis.
- DOI:10.1016/j.coph.2022.102271
- 发表时间:2022-08
- 期刊:
- 影响因子:4
- 作者:S. Kreda
- 通讯作者:S. Kreda
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Stephen Vernon Frye其他文献
Stephen Vernon Frye的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Stephen Vernon Frye', 18)}}的其他基金
PROBING ALLOSTERY IN METHYL-LYSINE READER DOMAINS
探索甲基赖氨酸阅读器结构域中的变构
- 批准号:
10369586 - 财政年份:2021
- 资助金额:
$ 31.2万 - 项目类别:
PROBING ALLOSTERY IN METHYL-LYSINE READER DOMAINS
探索甲基赖氨酸阅读器结构域中的变构
- 批准号:
10558469 - 财政年份:2021
- 资助金额:
$ 31.2万 - 项目类别:
DISCOVERY OF IN VIVO CHEMICAL PROBES FOR POLYCOMB CBX DOMAINS
Polycomb CBX 域体内化学探针的发现
- 批准号:
9907857 - 财政年份:2018
- 资助金额:
$ 31.2万 - 项目类别:
DISCOVERY OF CHEMICAL PROBES FOR METHYL-LYSINE READERS
甲基赖氨酸读数器化学探针的发现
- 批准号:
8460807 - 财政年份:2012
- 资助金额:
$ 31.2万 - 项目类别:
DISCOVERY OF CHEMICAL PROBES FOR METHYL-LYSINE READERS
甲基赖氨酸读数器化学探针的发现
- 批准号:
8270684 - 财政年份:2012
- 资助金额:
$ 31.2万 - 项目类别:
Discovery of Small Molecule MBT Domain Antagonists
小分子 MBT 结构域拮抗剂的发现
- 批准号:
7943037 - 财政年份:2009
- 资助金额:
$ 31.2万 - 项目类别:
Discovery of Small Molecule MBT Domain Antagonists
小分子 MBT 结构域拮抗剂的发现
- 批准号:
7812717 - 财政年份:2009
- 资助金额:
$ 31.2万 - 项目类别:
相似国自然基金
多模态超声VisTran-Attention网络评估早期子宫颈癌保留生育功能手术可行性
- 批准号:
- 批准年份:2022
- 资助金额:30 万元
- 项目类别:青年科学基金项目
Ultrasomics-Attention孪生网络早期精准评估肝内胆管癌免疫治疗的研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
相似海外基金
Identifying risk earlier: Prenatal exposures, neurodevelopment, and infant sleep as pathways to toddler attention and behavior dysregulation
及早识别风险:产前暴露、神经发育和婴儿睡眠是导致幼儿注意力和行为失调的途径
- 批准号:
10752879 - 财政年份:2023
- 资助金额:
$ 31.2万 - 项目类别:
Brain-behavior vulnerability to sleep loss in children: a dimensional study of attention and impulsivity
儿童睡眠不足的大脑行为脆弱性:注意力和冲动的维度研究
- 批准号:
10629272 - 财政年份:2021
- 资助金额:
$ 31.2万 - 项目类别:
Brain-behavior vulnerability to sleep loss in children: a dimensional study of attention and impulsivity
儿童睡眠不足的大脑行为脆弱性:注意力和冲动的维度研究
- 批准号:
10297377 - 财政年份:2021
- 资助金额:
$ 31.2万 - 项目类别:
Combining attention and metacognitive training to improve goal directed behavior in Veterans with TBI
结合注意力和元认知训练来改善患有 TBI 的退伍军人的目标导向行为
- 批准号:
9892500 - 财政年份:2020
- 资助金额:
$ 31.2万 - 项目类别:
Examining naturalistic social engagement: Using mobile eye-tracking to investigate individual differences and within-person variation in adolescent behavior, attention, and neural processing
检查自然主义的社会参与:使用移动眼动追踪来研究青少年行为、注意力和神经处理的个体差异和人内差异
- 批准号:
10115522 - 财政年份:2020
- 资助金额:
$ 31.2万 - 项目类别:
Nobel test batteries and therapies development for the time perception skill of the Attention-Deficit Hyperactivity Disorder children based on brain activities and behavior
诺贝尔奖测试电池和疗法开发基于大脑活动和行为的注意力缺陷多动障碍儿童的时间感知能力
- 批准号:
20K14058 - 财政年份:2020
- 资助金额:
$ 31.2万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Examining naturalistic social engagement: Using mobile eye-tracking to investigate individual differences and within-person variation in adolescent behavior, attention, and neural processing
检查自然主义的社会参与:使用移动眼动追踪来研究青少年行为、注意力和神经处理的个体差异和人内差异
- 批准号:
10321277 - 财政年份:2020
- 资助金额:
$ 31.2万 - 项目类别:
Combining attention and metacognitive training to improve goal directed behavior in Veterans with TBI
结合注意力和元认知训练来改善患有 TBI 的退伍军人的目标导向行为
- 批准号:
10390281 - 财政年份:2020
- 资助金额:
$ 31.2万 - 项目类别:
Examining naturalistic social engagement: Using mobile eye-tracking to investigate individual differences and within-person variation in adolescent behavior, attention, and neural processing
检查自然主义的社会参与:使用移动眼动追踪来研究青少年行为、注意力和神经处理的个体差异和人内差异
- 批准号:
9911085 - 财政年份:2020
- 资助金额:
$ 31.2万 - 项目类别:
Shyness, Attention and Anxiety: Bridging Physiology and Behavior in the Prediction of Social Outcomes
害羞、注意力和焦虑:在预测社会结果中连接生理学和行为
- 批准号:
518802-2018 - 财政年份:2020
- 资助金额:
$ 31.2万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral