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：
10338157
负责人：
Jiyong Hong
金额：
$ 40.66万
依托单位：
DUKE UNIVERSITY
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338157
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 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 interest novel nucleoside analog organ transplant rejection pharmacophore prevent protective effect rational design response restoration reuptake side effect survival outcome therapeutic target transplantation therapy vasoactive 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）损伤是缺氧组织在缺血后遭受长期损伤的现象。含氧血液的返回，证明器官移植和缺血性面临的普遍临床挑战心脏、肺和肾脏疾病。最终，IR损伤可导致梗塞面积增加、器官排斥和器官损伤。失败。嘌呤核苷腺苷是响应 IR 损伤而在细胞外产生的，并引发通过激动腺苷 G 蛋白发挥心脏保护、肺保护和肾保护作用偶联受体。然而，细胞外腺苷的半衰期极其短暂，因为专门整合膜转运蛋白介导腺苷的快速膜渗透，其中核苷最终在细胞质内代谢。人类平衡核苷转运蛋白 (hENT) 是主要的细胞腺苷转运蛋白。此外，腺苷再摄取抑制剂（AdoRIs）是一种化学不同类别的 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 hENT。因此，临床上选择AdoRIs作为血管活性药物治疗心脏病和肾脏疾病。然而，目前的 AdoRIs 由于其效果较差，其临床效果有限。药理特性和毒性。改进现有 AdoRI 或开发新型 AdoRI 的努力一直在由于缺乏有关 hENT 和 AdoRI 机制的原子级信息而面临挑战。这个提议研究旨在通过采用分子、细胞和化学方法来解决这一知识差距探究腺苷再摄取抑制、腺苷识别和转运机制的特征 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。这项工作将揭示分子 AdoRI 活性特征、腺苷识别以及 hENTs 表现出的转运机制。在总体而言，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、肺和肾的治疗产生深远的影响疾病。