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

Melidis, L.; Hill, H. J.; Coltman, N. J.; Davies, S. P.; Winczura, K.; Chauhan, T.; Craig, J. S.; Garai, A.; Hooper, C. A. J.; Egan, R. T.; McKeating, J. A.; Hodges, N. J.; Stamataki, Z.; Grzechnik, P.; Hannon, M. J.

doi:10.1101/2021.03.30.437757

bioRxiv · 10.1101/2021.03.30.437757

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

Melidis, L.·Hill, H. J.·Coltman, N. J.·Davies, S. P.·Winczura, K.·Chauhan, T.·Craig, J. S.·Garai, A.·Hooper, C. A. J.·Egan, R. T.·McKeating, J. A.·Hodges, N. J.·Stamataki, Z.·Grzechnik, P.·Hannon, M. J.

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Abstract

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.

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Melidis, L., Hill, H. J., Coltman, N. J., Davies, S. P., Winczura, K., Chauhan, T., Craig, J. S., Garai, A., Hooper, C. A. J., Egan, R. T., McKeating, J. A., Hodges, N. J., Stamataki, Z., Grzechnik, P., Hannon, M. J.. 2021-03-31. Supramolecular cylinders target bulge structures in the 5-prime UTR of the RNA genome of SARS-CoV-2 and inhibit viral replication. https://doi.org/10.1101/2021.03.30.437757

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