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
• 负责人: Jiyong Hong
• 金额: $ 3.56万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384262
• 关键词: Address; Adenosine; Agonist; Antihypertensive Agents; Binding; Biochemical; Biological Assay; Biological Models; Biology; Blood; Cardiac; Cell membrane; Cells; Cellular Membrane; Chemicals; Clinic; Clinical; Clinical effectiveness; Complex; Cytosol; Data; Development; Dipyridamole; Engineering; Equilibrative Nucleoside Transporter 1; Equilibrium; Exhibits; FDA approved; Future; G-Protein-Coupled Receptors; Goals; Half-Life; Heart; Heart Diseases; Heart Transplantation; Human; Hybrids; Hypoxia; Infarction; Intervention; Intravenous; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Lead; Lung; Lung Transplantation; Lung diseases; Mediating; Membrane; Membrane Transport Proteins; Modeling; Molecular; Molecular Conformation; Mutagenesis; Myocardial Ischemia; Nucleoside Transporter; Nucleosides; Organ; Organ Transplantation; Organ failure; Outcome; Patients; Pharmacology; Property; Protein Isoforms; Purine Nucleosides; Purinergic P1 Receptors; Refractory; Renal Tissue; Reperfusion Injury; Reperfusion Therapy; Research; Series; Signal Transduction; Specificity; Structure; Substrate Specificity; Therapeutic; Therapeutic Intervention; Thioinosine; Tissues; Toxic effect; Variant; Work; adenosine receptor activation; adenosine transporter; analog; base; cardioprotection; clinically relevant; combat; design; experience; experimental study; extracellular; improved; inhibitor/antagonist; interest; novel; nucleoside analog; pharmacophore; prevent; protective effect; response; restoration; reuptake; side effect; survival outcome; therapeutic target; transplantation therapy; vasoactive agent

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）损伤是其中缺氧组织在缺氧后经历长时间损伤的现象。 氧合血的恢复，证明了器官移植中面临的普遍临床挑战， 心脏、肺和肾脏疾病。最终，IR损伤可导致增加的梗死面积、器官排斥和器官移植。 失败嘌呤核苷腺苷在细胞外对IR损伤产生应答， 通过激动腺苷G蛋白的心脏保护、肺保护和肾保护作用 偶联受体然而，细胞外腺苷的半衰期是非常短暂的，作为专门的 整合膜转运蛋白介导腺苷的快速膜渗透， 核苷最终在胞质溶胶内代谢。人平衡型核苷转运蛋白（hENTs）是 主要的细胞腺苷转运体。此外，腺苷再摄取抑制剂（ADRIs），一种化学上 不同种类的hENT抑制剂通过阻止其快速再摄取来增强细胞外腺苷信号传导 通过hENTs。因此，临床上将选择性地使用抗心律失常药物作为治疗心脏病的血管活性药物 和肾脏疾病。然而，由于其不良的生物相容性，目前的ARTIs在其临床有效性方面是有限的。 药理学性质和毒性。改进当前的CARIs或开发新的CARIs的努力已经完成。 由于缺乏关于hENTs的原子级信息和COGNRI的机制，这一拟议 研究试图通过采用分子、细胞和化学方法来解决这一知识缺口， 腺苷再摄取抑制、腺苷识别和转运机制的研究 由hENTs展示。值得注意的是，新的腺苷再摄取抑制剂的合理设计显示出改善的 将使用心脏和肾脏模型系统来追求亚型特异性。这项工作将揭示 hENTs所表现出的转运机制的沿着的腺苷识别、腺苷受体抑制剂活性的特征。在 总的来说，这项工作的成功完成将为改善药物干预提供框架， 腺苷生物学，这将对缺血性心脏，肺和肾脏的治疗产生深远的影响 疾病