Inhibition of SARS-CoV-2 replication in cells by G-quadruplex ligands

The coronavirus SARS-CoV-2 continues to spread worldwide. Dozens of compounds have been discovered based on the structure of viral proteins. However, the candidate drugs are still some distance away from clinical use. It is worth exploring new targets for drug discovery against the virus. RNA structures are expected to play a regulatory role in the life cycle of RNA viruses and to provide novel drug targets. Recently, G-quadruplex (G4) has been reported as a promising therapeutic target against SARS-CoV-2. This study identified nine putative G4 sequences (PQSs) that fold into parallel G4 structures in the SARS-CoV-2 genome, five of which are located in the ORF1ab, S, and N genes and are regulated by the presence of potassium. G4s in the ORF1ab and S genes repressed RNA synthesis and gene expression with a differentiated response to G4 ligands. Four classic G4 ligands bound to the G4s in vitro, among which NMM and TMPyP4 exhibited efficient antiviral activity against SARS-CoV-2 in host cells. This demonstrates the potential of G4 ligands to inhibit the replication of SARS-CoV-2 in cells, suggesting that G4s hold promise as potential antiviral therapeutic targets.