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

基本信息

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
项目类别：
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

项目摘要

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.

概括 Covid-19（冠状病毒疾病2019）是由SARS-COV-2引起的一种传染性上呼吸道疾病（严重的急性呼吸道综合征冠状病毒2）感染，其发病率高，迅速在全球范围内传播。针对COVID-19的疗法是紧迫的，需要缩短的一条途径有效药物的时间是重新利用现有的抗病毒药或利用抗病毒药物。三在临床前或临床环境中表现出最初有望的治疗剂是核苷 - 阿诺格抗病毒药Remdesivir，NHC（β-D-N4-羟基胞丁胺）和Galidesivir。目前，NHC和Galidesivir在临床试验和Remdesivir被批准在美国紧急使用，这些药物之间的共同点为它们是针对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，专门的膜转运蛋白的细胞摄取所必需的。在人类，两个蛋白质家族介导核苷的选择性膜渗透：浓度核苷转运蛋白（CNT）和平衡性核苷转运蛋白（ENT）。这些已经建立了这些核苷转运蛋白控制许多核苷 - 抗病毒和抗癌疗法的药物疗效以临床相关的方式。因此，我们认为上述候选者的细胞摄取人核苷转运蛋白的COVID-19疗法对其抗病毒疗效至关重要。我们旨在通过执行这些转运蛋白在这些核苷抗病人的细胞摄取中的作用抗病毒疗效测定，药物转换蛋白相互作用的结构研究以及体外转运测定。潜在的共证抗病毒药物与人类之间相互作用的结构和机械研究细胞转运蛋白将发现人类抗病毒药细胞转运的分子基础。这样的信息将为通过增强的效力提高疗效的理性设计铺平道路药物处置特性，以及用于通过药物转运蛋白的个性化抗COVID-19 药物基因组学。