# Coronavirus Genome Replication

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $676,030

## Abstract

ABSTRACT
The world is currently in the midst of a global pandemic caused by the second severe acute respiratory
syndrome coronavirus (SARS2). In spite of the foreshadowing of such a pandemic by the emergence of
SARS1 in 2002 and Middle East respiratory syndrome coronavirus (MERS) in 2012, we were ill equipped to
address this scourge. Each of these early outbreaks yielded a substantial body of knowledge on the structures
of coronavirus proteins. As with previous outbreaks, we are witnessing a redoubled coronavirus research
effort. Structural biology continues to lead the way; however, our laboratory is now pledging a sustained
commitment to elucidation of the fundamental enzymology and corresponding mechanisms of coronavirus
genome replication. The SARS2 replisome has emerged as a clinically tractable target for development
antiviral therapeutics. Remdesivir is a nucleotide analog prodrug, metabolized to the triphosphate in cells, and
incorporated by the SARS2 replisome without excision by its proofreading exonuclease, ExoN. The
mechanism of action of remdesivir is unclear, and the mechanism of escape from ExoN is unknown. This
circumstance reflects the absence of a quantitative, mechanistic perspective of the SARS2 replisome. Such a
perspective will be essential to elucidation of the mechanism of drug action and the mechanism of drug
resistance. We have demonstrated the feasibility of elucidating the principles governing the dynamics and
function of the SARS2 core replicase using state-of-the-art ensemble and single-molecule approaches. We will
exploit these advances to pursue the following specific aims: study assembly and function of the SARS2 core
replicase and its sub-assemblies (Aim 1); study utilization of incorrect nucleotides and nucleotide analogues by
the SARS2 core replicase (Aim 2); and study the mechanism of error correction by the SARS2
exoribonuclease (Aim 3). Completion of these studies will represent the first, deep dive into the mechanistic
enzymology of the coronavirus replisome.

## Key facts

- **NIH application ID:** 10372189
- **Project number:** 5R01AI161841-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jamie Jon Arnold
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $676,030
- **Award type:** 5
- **Project period:** 2021-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372189

## Citation

> US National Institutes of Health, RePORTER application 10372189, Coronavirus Genome Replication (5R01AI161841-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10372189. Licensed CC0.

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