Molecular principles of anti-COVID-19 drug uptake by human nucleoside transporters

人类核苷转运蛋白摄取抗COVID-19药物的分子原理

• 批准号: 10703355
• 负责人: Seok-Yong Lee
• 金额: $ 19.97万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10703355
• 关键词: 2019-nCoV; Adenosine; Affect; Affinity; Antibodies; Antiviral Agents; Binding; Biological Assay; Biological Availability; COVID-19; COVID-19 therapeutics; COVID-19 treatment; Carrier Proteins; Cell Line; Cells; Cellular Assay; Clinical; Clinical Trials; Complex; Cryoelectron Microscopy; Data; Disease; Drug Controls; Drug Design; Drug Interactions; Drug Transport; Emergency Situation; Epithelial Cells; Equilibrium; Exhibits; FDA approved; GS-441524; Genes; Goals; Health; Hepatitis C; Hospitalization; Human; In Vitro; Infection; Knock-out; Lung; Measures; Mediating; Mediator; Medicine; Membrane; Membrane Transport Proteins; Molecular; Morbidity - disease rate; Nucleoside Transporter; Nucleosides; Oocytes; Permeability; Personal Satisfaction; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Play; Polymerase; Population; Prognostic Marker; Property; Protein Family; Public Health; Publishing; RNA; RNA-Directed RNA Polymerase; Respiratory Disease; Ribavirin; Role; Route; SARS-CoV-2 antiviral; SARS-CoV-2 infection; Single Nucleotide Polymorphism; Sodium; Structure; Symptoms; System; Therapeutic; Time; Viral; Viral Cancer; Virus; Work; anti-cancer; anti-cancer therapeutic; anti-viral efficacy; antiviral nucleoside analog; clinically relevant; drug disposition; drug efficacy; drug structure; experimental study; gemcitabine; hydrophilicity; improved; inhibitor; insight; molnupiravir; novel; novel coronavirus; nucleoside analog; pancreatic cancer patients; personalized medicine; pharmacologic; pre-clinical; radiotracer; rational design; remdesivir; respiratory; response; reuptake; three dimensional structure; uptake

Summary COVID-19 (coronavirus disease 2019) is a contagious upper respiratory disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, which features high morbidity and is rapidly spreading worldwide. The need to develop therapeutics against COVID-19 is urgent, and one route to shorten the time to an effective medicine is repurposing existing antiviral drugs or utilizing those in the pipeline. Three therapeutics that have shown initial promise in either pre-clinical or clinical settings are nucleoside-analog antivirals remdesivir, NHC (beta-D-N4-hydroxycytidine), and galidesivir. Currently, NHC and galidesivir are in clinical trials and remdesivir is approved for emergency use in U.S. The commonality between these drugs is that they are nucleoside analogs that target the SARS-CoV-2 RNA-dependent RNA polymerase. Because nucleosides are hydrophilic, specialized membrane transport proteins are required for their cellular uptake. In humans, two protein families mediate the selective membrane permeation of nucleosides: concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs). It is well established these nucleoside transporters control drug efficacies of many nucleoside-analog antiviral and anticancer therapeutics in a clinically relevant manner. Therefore, we reason that the cellular uptake of the aforementioned candidate COVID-19 therapeutics by human nucleoside transporters would prove critical to their antiviral efficacies. We aim to study the role of these transporters in the cellular uptake of these nucleoside antivirals by performing antiviral efficacy assays, structural studies of drug-transporter interactions, and in vitro transport assays. Structural and mechanistic studies of the interactions between potential COVID-19 antiviral drugs and human cellular transport proteins would uncover the molecular basis of antiviral drug cellular transport in humans. Such information would pave the way for the rational design of therapeutics with improved efficacies via enhanced drug disposition properties, and for personalized anti-COVID-19 treatments via drug-transporter pharmacogenomics.

摘要 新冠肺炎(冠状病毒病2019)是由SARS-CoV-2引起的一种传染性上呼吸道疾病 (严重急性呼吸综合征冠状病毒2)感染，发病率高，速度快 在世界范围内蔓延。迫切需要开发针对新冠肺炎的疗法，其中一条途径是缩短 获得有效药物的时机是重新调整现有抗病毒药物的用途，或者利用那些正在研发中的药物。三 在临床前或临床环境中显示出初步希望的治疗药物是核苷类似物 抗病毒药物雷米昔韦、NHC(β-D-N4-羟基胞苷)和伽利西韦。目前，NHC和伽利西韦正在 临床试验和雷米地韦在美国被批准用于紧急用途。这些药物之间的共同点是 它们是针对SARS-CoV-2RNA依赖的RNA聚合酶的核苷类似物。因为 核苷是亲水性的，特殊的膜转运蛋白是细胞摄取所必需的。在……里面 人类，两个蛋白质家族调节核苷选择性膜渗透：浓缩性 核苷转运体(CNTs)和平衡核苷转运体(Ents)。这些都是公认的 核苷转运体控制许多核苷类似物抗病毒和抗癌治疗的药效 以临床相关的方式。因此，我们推断，前述候选者的细胞吸收 事实证明，人类核苷转运蛋白开发的新冠肺炎疗法对其抗病毒效果至关重要。我们 目的研究这些转运体在这些核苷类抗病毒药物细胞摄取中的作用。 抗病毒疗效分析，药物转运体相互作用的结构研究，以及体外转运试验。 新冠肺炎潜在抗病毒药物与人体相互作用的结构和机理研究 细胞转运蛋白将揭示抗病毒药物在人体内细胞转运的分子基础。是这样的 信息将为合理设计治疗方法铺平道路，通过增强 药物处置特性，以及通过药物转运体进行个性化抗新冠肺炎治疗 药物基因组学。