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

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• 作者：Shing-Yen Lin ; Chia-Ling Liu ; Yu-Ming Chang ; Jincun Zhao ; Stanley Perlman ; Ming-Hon Hou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2247-2257
• 全文大小：479K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

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鈥檚 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鈥?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鈥檚 RNA-binding affinity and hindered viral replication. We also determined the crystal structure of the N-NTD鈥揚J34 complex. On the basis of these findings, we propose guidelines for developing new N protein-based antiviral agents that target CoVs.