Structural biology of SARS-CoV-2 nucleocapsid

The main focus of drug development against COVID-19 is on the spike protein and proteases. However, such drugs can be problematic because of mutations (in the case of the spike protein) and harmful to cellular homologs (in case of the proteases). Here, we review a viral protein that due to its conserved and multifunctional nature may be an alternative drug target: SARS-CoV-2 nucleocapsid. This protein consists of two ordered and three disordered domains, all of which exhibit RNA binding activity and are important for ribonucleoprotein complex assembly. This complex protects the viral RNA and is important for viral replication. Nucleocapsid might also be connected to modulation of the host cell cycle, replication, translation, viral assembly, and other parts of the infection cycle. The two ordered domains, the RNA binding domain and the dimerization domain, mediate packaging of the RNA into the ribonucleoprotein complex and bind it to membrane proteins. The actual organization of this complex has not been conclusively verified yet, but the large SARS-CoV-2 RNA genome is efficiently packed yet is very flexible. A better understanding of this protein could lead to an efficient therapeutic measure against the virus and would improve our understanding of COVID-19.