Coronavirus RNA synthesis by multicomponent protein machines
- Funded by National Institutes of Health (NIH)
- Total publications:0 publications
Grant number: unknown
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Key facts
Disease
COVID-19Start & end year
20202025Known Financial Commitments (USD)
$437,931Funder
National Institutes of Health (NIH)Principal Investigator
PendingResearch Location
United States of AmericaLead Research Institution
UNIVERSITY OF WISCONSIN-MADISONResearch Priority Alignment
N/A
Research Category
Pathogen: natural history, transmission and diagnostics
Research Subcategory
Pathogen morphology, shedding & natural history
Special Interest Tags
N/A
Study Type
Non-Clinical
Clinical Trial Details
N/A
Broad Policy Alignment
Pending
Age Group
Not Applicable
Vulnerable Population
Not applicable
Occupations of Interest
Not applicable
Abstract
SUMMARYSARS-CoV-2, the causative agent of COVID-19, has emerged as a global human pathogen sweeping through ourcommunities. The development of strategies to prevent or treat COVID-19 is essential for mitigating disease and limitingfurther 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 anemphasis on characterizing the effects of existing antiviral therapeutics as well as the discovery of novel targets andcompounds. We are interested in how the virus nsp14 exonuclease contributes to viral RNA proofreading, reducingnucleotide misincorporations and providing natural resistance to nucleoside analogue drugs. We will also explore thefunction of the enigmatic nsp12 nucleotidyltransferase (NiRAN) and will piece together the network of viral proteininteractions responsible for the assembly of the RNA synthesis complex. To this we will use diverse methods includingbiochemistry, biophysics, cell biology, chemical biology and cryo-electron microscopy. These studies will provide newinsight 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 machineryacross the coronavirus family allows these studies of SARS-CoV-2 to be applicable to future emerging coronaviruses tohead off future viral pandemics before they become global crises.