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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：
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
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/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

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.

总结