Structural biology of the SARS-CoV-2 replisome: evolutionary and therapeutic implications

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is a betacoronavirus endowed with one of the largest known RNA viral genomes. Two-thirds of its approximately 30,000 nts encode components of the replication–transcription complex, also known as replisome. This complex includes eight nonstructural proteins (nsps 7–10, 12–14, and 16). Nsp12 is a monomeric RNA-dependent RNA polymerase (RdRp) homologous to the RdRps found in all known RNA viruses, making it one of the most attractive therapeutic targets. Although SARS-CoV-2 and the hepatitis C virus (HCV) are not phylogenetically close, the structural similarities of the HCV NS3/4A with the coronaviral Mpro proteases support the possibility that the HCV protease inhibitors may also be used against SARS-CoV-2. The design of treatment guidelines against SARS-CoV-2, consisting of a combination of repurposed drugs against different viral targets, must be developed. Together with the RdRp and Mpro, another important therapeutic target would be the nsp14. This 527-amino acid exonuclease has a proofreading activity that attenuates the virus mutation rates by increasing replication fidelity. As mentioned here, the ExoN domain has played a key role in coronaviral evolution and appears to have been hijacked from a host cell.