Molecular basis of adenosine transport and reuptake inhibition in human
人体腺苷转运和再摄取抑制的分子基础
基本信息
- 批准号:10549779
- 负责人:
- 金额:$ 40.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAddressAdenosineAgonistAntihypertensive AgentsBindingBiochemicalBiological AssayBiological ModelsBiologyBloodCardiacCell membraneCellsCellular MembraneChemicalsClinicClinicalClinical effectivenessComplexCrystallographyCytosolDataDevelopmentDipyridamoleEngineeringEquilibrative Nucleoside Transporter 1EquilibriumExhibitsFDA approvedFutureG-Protein-Coupled ReceptorsGoalsHalf-LifeHeartHeart DiseasesHeart TransplantationHumanHybridsHypoxiaInfarctionInterventionIntravenousKidneyKidney DiseasesKidney TransplantationKnowledgeLungLung TransplantationLung diseasesMediatingMembraneMembrane Transport ProteinsModelingMolecularMolecular ConformationMutagenesisMyocardial IschemiaNucleoside TransporterNucleosidesOrgan TransplantationOrgan failureOutcomePatientsPropertyProtein IsoformsPurine NucleosidesPurinergic P1 ReceptorsRefractoryRenal TissueReperfusion InjuryReperfusion TherapyResearchSeriesSignal TransductionSpecificityStructureSubstrate SpecificityTherapeuticTherapeutic InterventionThioinosineTissuesToxic effectVariantWorkadenosine receptor activationadenosine transporteranalogcardioprotectionclinically relevantcombatdesignexperienceexperimental studyextracellularimprovedinhibitorinterestnovelnucleoside analogorgan transplant rejectionpharmacologicpharmacophorepreventprotective effectrational designresponserestorationreuptakeside effectsurvival outcometherapeutic targetvasoactive agent
项目摘要
Ischemia-reperfusion (IR) injury is a phenomenon in which hypoxic tissue undergoes prolonged damage after
the return of oxygenated blood, proving a prevalent clinical challenge faced in organ transplant, and ischemic
heart, lung and kidney diseases. Ultimately, IR injury can lead to increased infarct size, organ rejection and organ
failure. The purine nucleoside adenosine is produced extracellularly in response to IR injury, and elicits
cardioprotective, pulmonary protective and renal protective effects through agonizing adenosine G-protein
coupled receptors. However, the half-life of extracellular adenosine is extremely short-lived, as specialized
integral membrane transport proteins mediate the rapid membrane permeation of adenosine, where the
nucleoside is ultimately metabolized within the cytosol. Human equilibrative nucleoside transporters (hENTs) are
the main cellular adenosine transporters. Furthermore, adenosine reuptake inhibitors (AdoRIs), a chemically
diverse class of hENT inhibitors, potentiate extracellular adenosine signaling by preventing its rapid reuptake
through hENTs. Therefore, select AdoRIs are clinically used as vasoactive agents in the treatment of cardiopathy
and renal disorders. However, current AdoRIs are limited in their clinical effectiveness due to their poor
pharmacological properties and toxicities. Efforts to improve current AdoRIs or develop novel AdoRIs has been
challenged by the lack of atomic-level information on hENTs and the mechanism of AdoRIs. This proposed
research seeks to address this gap in knowledge by employing molecular, cellular, and chemical approaches to
interrogate features of adenosine reuptake inhibition, adenosine recognition and the transport mechanism
exhibited by hENTs. Notably, the rational design of novel adenosine reuptake inhibitors displaying improved
subtype specificity will be pursued using cardiac and renal model systems. This work will uncover the molecular
features of AdoRI activity, adenosine recognition, along with the transport mechanism exhibited by hENTs. In
total, successful completion of this work will provide the framework for improved pharmacological intervention of
adenosine biology, which will have far-reaching implications in the treatment of ischemic heart, lung, and kidney
disease.
缺血再灌注(IR)损伤是指缺氧后组织遭受长期损伤的一种现象
氧合血液回流,证明是器官移植面临的普遍临床挑战,以及缺血
心、肺、肾疾病。最终,IR损伤可导致梗塞面积扩大、器官排斥反应和器官
失败了。嘌呤核苷腺苷是在细胞外产生的对IR损伤的反应,并引起
激动型腺苷G蛋白的心脏保护、肺保护和肾脏保护作用
偶联受体。然而,细胞外腺苷的半衰期是极其短暂的,因为
完整的膜转运蛋白介导腺苷的快速膜渗透,其中
核苷最终在胞质中代谢。人平衡核苷转运体(HENTs)是
细胞内主要的腺苷转运体。此外,腺苷再摄取抑制剂(ADORI),一种化学上的
不同种类的hent抑制剂通过阻止腺苷的快速再摄取来增强细胞外的腺苷信号
通过hENTs。因此,精选的ADORI在心脏病的治疗中被用作血管活性物质
和肾脏疾病。然而,目前的ADORI由于其较差的临床效果而受到限制。
药理特性和毒性。一直在努力改进现有的ADORI或开发新的ADORI
面临缺乏关于hENTs和ADORI机制的原子水平信息的挑战。这项建议
研究试图通过使用分子、细胞和化学方法来解决这一知识差距
腺苷再摄取抑制、腺苷识别及其转运机制的研究
由hENTs展出。值得注意的是,新型腺苷再摄取抑制剂的合理设计显示出改进
将使用心脏和肾脏模型系统进行亚型特异性研究。这项工作将揭开分子
ADORI活性、腺苷识别以及hENTs的转运机制。在……里面
总之,这项工作的成功完成将为改进药物干预提供框架
腺苷生物学在心、肺、肾缺血治疗中的深远意义
疾病。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Recent advances on the inhibition of human solute carriers: Therapeutic implications and mechanistic insights.
- DOI:10.1016/j.sbi.2022.102378
- 发表时间:2022-06
- 期刊:
- 影响因子:6.8
- 作者:Wright, Nicholas J.;Lee, Seok-Yong
- 通讯作者:Lee, Seok-Yong
Toward a Molecular Basis of Cellular Nucleoside Transport in Humans.
- DOI:10.1021/acs.chemrev.0c00644
- 发表时间:2021-05-12
- 期刊:
- 影响因子:62.1
- 作者:Wright, Nicholas J.;Lee, Seok-Yong
- 通讯作者:Lee, Seok-Yong
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Jiyong Hong其他文献
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{{ truncateString('Jiyong Hong', 18)}}的其他基金
Molecular basis of adenosine transport and reuptake inhibition in human
人体腺苷转运和再摄取抑制的分子基础
- 批准号:
10338157 - 财政年份:2020
- 资助金额:
$ 40.66万 - 项目类别:
Molecular basis of adenosine transport and reuptake inhibition in human
人体腺苷转运和再摄取抑制的分子基础
- 批准号:
10384262 - 财政年份:2020
- 资助金额:
$ 40.66万 - 项目类别:
Study of Subglutinol A as a Potential Immunomodulatory Agent
Subglutinol A 作为潜在免疫调节剂的研究
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9226543 - 财政年份:2016
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Targeting Rev1-mediated Translesion Synthesis for Cancer Therapy
靶向 Rev1 介导的跨损伤合成用于癌症治疗
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9099802 - 财政年份:2015
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PKC zeta-Specific Inhibitors for Treatment of Methamphetamine Addiction
用于治疗甲基苯丙胺成瘾的 PKC zeta 特异性抑制剂
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7826641 - 财政年份:2009
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$ 40.66万 - 项目类别:
PKC zeta-Specific Inhibitors for Treatment of Methamphetamine Addiction
用于治疗甲基苯丙胺成瘾的 PKC zeta 特异性抑制剂
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7641187 - 财政年份:2009
- 资助金额:
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