Cureus | Structural Basis for the Identification of the N-Terminal Domain of Coronavirus Nucleocapsid Protein as an Antiviral Target
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Research Article

Structural Basis for the Identification of the N-Terminal Domain of Coronavirus Nucleocapsid Protein as an Antiviral Target

Shing-Yen Lin, Chia-Ling Liu, Yu-Ming Chang, Jincun Zhao, Stanley Perlman, Ming-Hon Hou

Published: February 24, 2015

DOI: 10.1021/jm500089r

License: Copyright © 2014 American Chemical Society2014American Chemical Society

Abstract

Coronaviruses (CoVs) cause numerous diseases, including Middle East respiratory syndrome and severe acute respiratory syndrome, generating significant health-related and economic consequences. CoVs encode the nucleocapsid (N) protein, a major structural protein that plays multiple roles in the virus replication cycle and forms a ribonucleoprotein complex with the viral RNA through the N protein’s N-terminal domain (N-NTD). Using human CoV-OC43 (HCoV-OC43) as a model for CoV, we present the 3D structure of HCoV-OC43 N-NTD complexed with ribonucleoside 5′-monophosphates to identify a distinct ribonucleotide-binding pocket. By targeting this pocket, we identified and developed a new coronavirus N protein inhibitor, N-(6-oxo-5,6-dihydrophenanthridin-2-yl)(N,N-dimethylamino)acetamide hydrochloride (PJ34), using virtual screening; this inhibitor reduced the N protein’s RNA-binding affinity and hindered viral replication. We also determined the crystal structure of the N-NTD–PJ34 complex. On the basis of these findings, we propose guidelines for developing new N protein-based antiviral agents that target CoVs.


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Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. SIQ™ assesses article importance and quality by embracing the collective intelligence of the Cureus community-at-large. All registered users are invited to contribute to the SIQ™ of any published article. (Authors cannot rate their own articles.)

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