# Coronavirus RNA synthesis by multicomponent protein machines

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $437,931

## Abstract

SUMMARY
SARS-CoV-2, the causative agent of COVID-19, has emerged as a global human pathogen sweeping through our
communities. The development of strategies to prevent or treat COVID-19 is essential for mitigating disease and limiting
further viral spread. A key target of antiviral therapeutics is the virus RNA replication complex. The SARS-CoV-2
replication complex is a large multi-subunit machine with multiple co-factors, enzymes and host modulating proteins.
How these protein subunits assemble and cooperate to carryout viral RNA replication and transcription remains unclear.
The overarching theme of this work is to examine understudied aspects of the coronavirus replication complex with an
emphasis on characterizing the effects of existing antiviral therapeutics as well as the discovery of novel targets and
compounds. We are interested in how the virus nsp14 exonuclease contributes to viral RNA proofreading, reducing
nucleotide misincorporations and providing natural resistance to nucleoside analogue drugs. We will also explore the
function of the enigmatic nsp12 nucleotidyltransferase (NiRAN) and will piece together the network of viral protein
interactions responsible for the assembly of the RNA synthesis complex. To this we will use diverse methods including
biochemistry, biophysics, cell biology, chemical biology and cryo-electron microscopy. These studies will provide new
insight into the workings of this complicated machine, provide new mechanisms of action for existing therapeutics and
discover novel antiviral compounds. In addition, the high conservation of components of the replication machinery
across the coronavirus family allows these studies of SARS-CoV-2 to be applicable to future emerging coronaviruses to
head off future viral pandemics before they become global crises.

## Key facts

- **NIH application ID:** 10187774
- **Project number:** 1R01AI158463-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Robert N Kirchdoerfer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,931
- **Award type:** 1
- **Project period:** 2020-08-05 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187774

## Citation

> US National Institutes of Health, RePORTER application 10187774, Coronavirus RNA synthesis by multicomponent protein machines (1R01AI158463-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10187774. Licensed CC0.

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