Potent broad-spectrum anti-coronaviral frameshift inhibitors from virtual screen of RNA binding

Neupane, K.; Sekar, R. V.; Ileperuma, S. M.; Reklow, E.; Munshi, S.; Omar, S. I.; Arbabimoghadam, S.; Peterson, J. A.; Tuszynski, J. A.; Hobman, T. C.; Woodside, M. T.

doi:10.1101/2025.09.17.676934

bioRxiv · 10.1101/2025.09.17.676934

Potent broad-spectrum anti-coronaviral frameshift inhibitors from virtual screen of RNA binding

Neupane, K.·Sekar, R. V.·Ileperuma, S. M.·Reklow, E.·Munshi, S.·Omar, S. I.·Arbabimoghadam, S.·Peterson, J. A.·Tuszynski, J. A.·Hobman, T. C.·Woodside, M. T.

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Abstract

Coronavirus genomes contain an RNA pseudoknot that directs -1 programmed ribosomal frame-shifting (-1 PRF) to control expression of viral proteins crucial for replication. Ligands that inhibit -1 PRF can thus attenuate viral propagation and have potential as drugs for limiting corona-virus infections. To search for novel small-molecule frameshift inhibitors with anticoronaviral activity, we computationally screened over 14 million compounds for binding to the SARS-CoV-2 pseudoknot, followed by experimental validation of the top hits for inhibition of -1 PRF and viral replication. We identified multiple potent -1 PRF inhibitors, effective at nM concentrations, some of which significantly suppressed SARS-CoV-2 replication in cell culture. Several compounds also inhibited -1 PRF in multiple representative bat coronaviruses, indicating broad-spectrum activity. These results showcase the promise of viral RNA structures like frameshift-stimulatory pseudoknots as targets for broad-spectrum antiviral drugs.

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Neupane, K., Sekar, R. V., Ileperuma, S. M., Reklow, E., Munshi, S., Omar, S. I., Arbabimoghadam, S., Peterson, J. A., Tuszynski, J. A., Hobman, T. C., Woodside, M. T.. 2025-09-18. Potent broad-spectrum anti-coronaviral frameshift inhibitors from virtual screen of RNA binding. https://doi.org/10.1101/2025.09.17.676934

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