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Development of Enterovirus anti-viral agents that target the viral 2C protein

View ORCID ProfileRishabh Kejriwal, Tristan Evans, Joshua Calabrese, Lea Swistak, Lauren Alexandrescu, Michelle Cohen, Nahian Rahman, View ORCID ProfileNiel Henriksen, View ORCID ProfileRadha Charan Dash, M. Kyle Hadden, View ORCID ProfileNicola J. Stonehouse, View ORCID ProfileDavid J. Rowlands, View ORCID ProfileNatalie J. Kingston, Madeline Hartnoll, View ORCID ProfileSamuel J. Dobson, View ORCID ProfileSimon J. White
doi: https://doi.org/10.1101/2022.10.06.511132
Rishabh Kejriwal
1Biology/Physics Building, Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Unit-3125. Storrs, CT 06269-3125, USA
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  • ORCID record for Rishabh Kejriwal
Tristan Evans
1Biology/Physics Building, Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Unit-3125. Storrs, CT 06269-3125, USA
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Joshua Calabrese
1Biology/Physics Building, Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Unit-3125. Storrs, CT 06269-3125, USA
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Lea Swistak
2Institut Pasteur, Université Paris Cité, Dynamics of Host-Pathogen Interactions unit, F-75015 Paris, France
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Lauren Alexandrescu
1Biology/Physics Building, Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Unit-3125. Storrs, CT 06269-3125, USA
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Michelle Cohen
1Biology/Physics Building, Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Unit-3125. Storrs, CT 06269-3125, USA
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Nahian Rahman
1Biology/Physics Building, Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Unit-3125. Storrs, CT 06269-3125, USA
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Niel Henriksen
3Atomwise Inc. 717 Market St #800, San Francisco, CA 94103
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Radha Charan Dash
4Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT, 06029-3092, United States
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M. Kyle Hadden
4Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT, 06029-3092, United States
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Nicola J. Stonehouse
5School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
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David J. Rowlands
5School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
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Natalie J. Kingston
5School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
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Madeline Hartnoll
5School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
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Samuel J. Dobson
5School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
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Simon J. White
1Biology/Physics Building, Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Unit-3125. Storrs, CT 06269-3125, USA
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  • For correspondence: simon.white@uconn.edu
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Abstract

The enterovirus (EV) genus includes a number of important human and animal pathogens. EV-A71, EV-D68, poliovirus (PV), and coxsackievirus (CV) outbreaks have affected millions worldwide causing a range of upper respiratory, skin, neuromuscular diseases, including acute flaccid myelitis, and hand-foot-and-mouth disease. There are no FDA-approved anti-viral therapeutics for these enteroviruses. In this study, we describe novel broad spectrum anti-viral compounds targeting the conserved non-structural viral protein 2C that have low micro-molar to nanomolar IC50 values. The selection of resistant mutants resulted in amino acid substitutions in the viral capsid protein, implying a role for 2C in capsid assembly, as has been seen in PV. The assembly and encapsidation stages of the viral life cycle are not fully understood and the inhibitors reported here could be useful probes in understanding these processes.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 07, 2022.
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Development of Enterovirus anti-viral agents that target the viral 2C protein
Rishabh Kejriwal, Tristan Evans, Joshua Calabrese, Lea Swistak, Lauren Alexandrescu, Michelle Cohen, Nahian Rahman, Niel Henriksen, Radha Charan Dash, M. Kyle Hadden, Nicola J. Stonehouse, David J. Rowlands, Natalie J. Kingston, Madeline Hartnoll, Samuel J. Dobson, Simon J. White
bioRxiv 2022.10.06.511132; doi: https://doi.org/10.1101/2022.10.06.511132
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Development of Enterovirus anti-viral agents that target the viral 2C protein
Rishabh Kejriwal, Tristan Evans, Joshua Calabrese, Lea Swistak, Lauren Alexandrescu, Michelle Cohen, Nahian Rahman, Niel Henriksen, Radha Charan Dash, M. Kyle Hadden, Nicola J. Stonehouse, David J. Rowlands, Natalie J. Kingston, Madeline Hartnoll, Samuel J. Dobson, Simon J. White
bioRxiv 2022.10.06.511132; doi: https://doi.org/10.1101/2022.10.06.511132

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