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: 10348225
• 负责人: Seok-Yong Lee
• 金额: $ 24万
• 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/10348225
• 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; Crystallization; 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 of activation protein; 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; Virus; Work; anti-cancer therapeutic; anti-viral efficacy; antiviral nucleoside analog; base; 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; 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.

总结 COVID-19（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 （严重急性呼吸系统综合症冠状病毒2型）感染，发病率高， 传播到世界各地迫切需要开发针对COVID-19的治疗方法， 有效药物的时间是重新利用现有的抗病毒药物或利用那些在管道中。三 在临床前或临床环境中显示出初步前景的治疗剂是核苷类似物 抗病毒药物remdesivir、NHC（β-D-N4-羟基胞苷）和galidesivir。目前，NHC和Galidesivir在 这些药物之间的共同点是， 它们是靶向SARS-CoV-2 RNA依赖性RNA聚合酶的核苷类似物。因为 核苷是亲水性的，细胞摄取需要专门的膜转运蛋白。在 在人类中，两个蛋白质家族介导核苷的选择性膜渗透： 核苷转运蛋白（CNT）和平衡型核苷转运蛋白（ENT）。这是公认的， 核苷转运蛋白控制许多核苷类似物抗病毒和抗癌治疗药物的药效 以临床相关的方式。因此，我们推断，上述候选物的细胞摄取 通过人类核苷转运蛋白的COVID-19治疗将证明对其抗病毒功效至关重要。我们 目的是研究这些转运蛋白在细胞摄取这些核苷类抗病毒药物中的作用， 抗病毒功效测定、药物-转运蛋白相互作用的结构研究和体外转运测定。 潜在的COVID-19抗病毒药物与人之间相互作用的结构和机制研究 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。等 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，以及通过药物转运蛋白进行个性化抗COVID-19治疗 药物基因组学