Structures of the SARS-CoV-2 nucleocapsid and their perspectives for drug design

COVID-19, caused bySARS-CoV-2, has resulted in severe and unprecedented economic and social disruptions in the world. Nucleocapsid (N) protein, which is the major structural component of the virion and is involved in viral replication, assembly and immune regulation, plays key roles in the viral life cycle. Here, we solved the crystal structures of the N- and C-terminal domains (N-NTDand N-CTD) ofSARS-CoV-2 N protein, at 1.8 and 1.5 angstrom resolution, respectively. Both structures show conserved features from other CoV N proteins. The binding sites targeted by small molecules againstHCoV-OC43 andMERS-CoV, which inhibit viral infection by blocking theRNA-binding activity or normal oligomerization of N protein, are relatively conserved in our structure, indicating N protein is a promising drug target. In addition, certain areas of N-NTDand N-CTDdisplay distinct charge distribution patterns inSARS-CoV-2, which may alter theRNA-binding modes. The specific antigenic characteristics are critical for developing specific immune-based rapid diagnostic tests. Our structural information can aid in the discovery and development of antiviral inhibitors againstSARS-CoV-2 in the future.