Targeting RNA G‐Quadruplex in SARS‐CoV‐2: A Promising Therapeutic Target for COVID‐19?

Abstract The COVID‐19 pandemic caused by SARS‐CoV‐2 has become a global threat. Understanding the underlying mechanisms and developing innovative treatments are extremely urgent. G‐quadruplexes (G4s) are important noncanonical nucleic acid structures with distinct biofunctions. Four putative G4‐forming sequences (PQSs) in the SARS‐CoV‐2 genome were studied. One of them (RG‐1), which locates in the coding sequence region of SARS‐CoV‐2 nucleocapsid phosphoprotein (N), has been verified to form a stable RNA G4 structure in live cells. G4‐specific compounds, such as PDP (pyridostatin derivative), can stabilize RG‐1 G4 and significantly reduce the protein levels of SARS‐CoV‐2 N by inhibiting its translation both in vitro and in vivo. This result is the first evidence that PQSs in SARS‐CoV‐2 can form G4 structures in live cells, and that their biofunctions can be regulated by a G4‐specific stabilizer. This finding will provide new insights into developing novel antiviral drugs against COVID‐19.