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

> **NIH NIH R21** · DUKE UNIVERSITY · 2022 · $240,020

## Abstract

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.

## Key facts

- **NIH application ID:** 10348225
- **Project number:** 1R21AI166134-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Seok-Yong Lee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $240,020
- **Award type:** 1
- **Project period:** 2022-09-12 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348225

## Citation

> US National Institutes of Health, RePORTER application 10348225, Molecular principles of anti-COVID-19 drug uptake by human nucleoside transporters (1R21AI166134-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10348225. Licensed CC0.

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