Supramolecular cylinders target bulge structures in the 5’ UTR of the RNA genome of SARS-CoV-2 and inhibit viral replication

Melidis, Lazaros; Hill, Harriet J.; Coltman, Nicholas J.; Davies, Scott P.; Winczura, Kinga; Chauhan, Tasha; Craig, James S.; Garai, Aditya; Hooper, Catherine A..J.; Egan, Ross T.; McKeating, Jane A.; Hodges, Nikolas J.; Stamataki, Zania; Grzechnik, Pawel; Hannon, Michael J.

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with Molecular Dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5’ UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in the stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel antiviral agents.