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

Qu, Xiaogang; Zhao, Chuanqi; Qin, Geng; Niu, Jingsheng; Wang, Zhao; Wang, Chunyu; Ren, Jinsong

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 non-canonical nucleic acids structures with distinct biofunctions. Here, we studied four putative G4-forming sequences (PQSs) in SARS-CoV-2 genome. One of them (namely RG-1), which locates in the coding sequence (CDS) region of SARS-CoV-2 nucleocapsid phosphoprotein (N), has been verified to form stable RNA G4 structure in live cells. G4-specific compounds, such as PDP, can stabilize RG-1 G4 and significantly reduce the protein levels of SARS-CoV-2 N by inhibiting its translation bothin vitro andin vivo. To our knowledge, this is the first evidence that PQSs in SARS-CoV-2 can form G4 structures in live cells, and their biofunctions can be regulated by G4-specific stabilizer. We expect this finding will provide new insights into developing novel antiviral drugs against COVID-19.