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

doi:10.1021/jm500089r

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Structural basis for the identification of the N-terminal domain of coronavirus nucleocapsid protein as an antiviral target

Journal article

Open access

Peer reviewed

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 and Ming-Hon Hou

Journal of medicinal chemistry, Vol.57(6), pp.2247-2257

03/27/2014

DOI: 10.1021/jm500089r

PMCID: PMC3983370

PMID: 24564608

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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.

Virus Replication - drug effects

Antiviral Agents - pharmacology

Mutagenesis, Site-Directed

Humans

Molecular Conformation

Models, Molecular

Nucleocapsid Proteins - chemistry

Structure-Activity Relationship

Nucleocapsid Proteins - drug effects

Poly(ADP-ribose) Polymerase Inhibitors

Phenanthrenes - pharmacology

Phenanthrenes - chemical synthesis

Antiviral Agents - chemistry

Coronavirus - drug effects

X-Ray Diffraction

Drug Design

RNA, Viral - metabolism

Kinetics

RNA, Viral - drug effects

Real-Time Polymerase Chain Reaction

Details

Title: Subtitle: Structural basis for the identification of the N-terminal domain of coronavirus nucleocapsid protein as an antiviral target
Creators: Shing-Yen Lin - College of Life Science, ‡Institute of Genomics and Bioinformatics, and §Agriculture Biotechnology Center, National Chung Hsing University , Taichung 40254, Taiwan
Chia-Ling Liu
Yu-Ming Chang
Jincun Zhao
Stanley Perlman
Ming-Hon Hou
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.57(6), pp.2247-2257
DOI: 10.1021/jm500089r
PMID: 24564608
PMCID: PMC3983370
NLM abbreviation: J Med Chem
ISSN: 1520-4804
eISSN: 1520-4804
Publisher: United States
Grant note: NS36592 / NINDS NIH HHS R01 NS036592 / NINDS NIH HHS
Language: English
Date published: 03/27/2014
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9983777348602771

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