# Broad-spectrum antiviral GS-5734 to treat MERS-CoV and related emerging CoV

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $1,166,670

## Abstract

Project Summary
Zoonotic viruses, like filoviruses and coronaviruses (CoV), represent a continuous and growing threat to global
public health because they unpredictably emerge causing devastating outbreaks of pandemic disease. In the
21st century, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory
syndrome coronavirus (MERS-CoV) emerged from zoonotic pools of viruses, causing severe disease in
humans. MERS-CoV is endemic in camels in the Middle East with continuous new infections in humans.
Although SARS-CoV is not currently a threat, several “prepandemic” SARS-like CoVs have been isolated from
bats that replicate efficiently in human cells and are resistant to existing therapies. With the unpredictable
overlap of human and wild animal ecologies, the potential for novel CoV emergence into humans is highly
probable. Currently, there are no approved antiviral therapies for any human CoV infection. Broad-spectrum
CoV therapies that control known human and zoonotic CoV infections would address an immediate unmet
medical need and could counter future pandemic episodes. In partnership with Gilead Sciences, we have
demonstrated that the nucleoside prodrug, GS-5734, is highly efficacious in inhibiting multiple human and
zoonotic CoV in vitro and SARS-CoV in vivo. The primary goal of our program is to accelerate the preclinical
development of GS-5734 and promote IND licensure for the MERS-CoV indication. To thoroughly evaluate the
breadth of antiviral activity and predict efficacy against future emerging CoV, we will also assess efficacy
against a panel of CoV representative of family-wide genetic diversity, including prepandemic zoonotic strains
poised for emergence. Focusing on the highly pathogenic MERS-CoV, our unique partnership integrates: i)
metagenomics and recombinant virus synthetic genome recovery, ii) primary human lung cell models, iii)
cutting edge virology and biochemistry, iv) robust murine and primate models of human disease and v) state of
the art metabolic and pharmacokinetic analysis. In Aim 1, we refine the pharmacokinetics, pharmacodynamics
and breadth of GS-5734 through efficacy and metabolism studies in various primary human cells with a diverse
array of human and zoonotic CoV and through the evaluation of in vivo efficacy in murine and non-human
primate models of MERS- and SARS-CoV. In Aim 2, we select for resistance against SARS-CoV and MERS-
CoV, and determine the effect of resistance on virus replication, fitness and susceptibility to treatment. In Aim
3, we determine if the mechanism of action of GS-5734 is a result of direct effects on viral RNA replication
and/or alteration of antiviral immunity via deep sequencing and single molecule RNA fluorescence in situ
hybridization of vehicle or drug treated infected cells and mice. We articulate a development strategy for broad-
spectrum therapeutics that could be extended to a multitude of emerging viral pathogens threatening global
public health.

## Key facts

- **NIH application ID:** 10229552
- **Project number:** 5R01AI132178-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ralph S Baric
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,166,670
- **Award type:** 5
- **Project period:** 2017-08-09 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229552

## Citation

> US National Institutes of Health, RePORTER application 10229552, Broad-spectrum antiviral GS-5734 to treat MERS-CoV and related emerging CoV (5R01AI132178-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10229552. Licensed CC0.

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