Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses

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dc.contributor.authorMunshi, Sneha
dc.contributor.authorNeupane, Krishna
dc.contributor.authorIleperuma, Sandaru M.
dc.contributor.authorHalma, Matthew T. J.
dc.contributor.authorKelly, Jamie A.
dc.contributor.authorHalpern, Clarissa F.
dc.contributor.authorDinman, Jonathan D.
dc.contributor.authorLoerch, Sarah
dc.contributor.authorWoodside, Michael T.
dc.date.accessioned2023-10-26T19:04:54Z
dc.date.available2023-10-26T19:04:54Z
dc.date.issued2022-01-18
dc.description.abstractRecurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use −1 programmed ribosomal frameshifting (−1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates −1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored whether small-molecule inhibitors of −1 PRF in SARS-CoV-2 also inhibited −1 PRF in a range of bat CoVs—the most likely source of future zoonoses. Six inhibitors identified in new and previous screens against SARS-CoV-2 were evaluated against the frameshift signals from a panel of representative bat CoVs as well as MERS-CoV. Some drugs had strong activity against subsets of these CoV-derived frameshift signals, while having limited to no effect on −1 PRF caused by frameshift signals from other viruses used as negative controls. Notably, the serine protease inhibitor nafamostat suppressed −1 PRF significantly for multiple CoV-derived frameshift signals. These results suggest it is possible to find small-molecule ligands that inhibit −1 PRF specifically in a broad spectrum of CoVs, establishing frameshift signals as a viable target for developing pan-coronaviral therapeutics.
dc.description.urihttps://doi.org/10.3390/v14020177
dc.identifierhttps://doi.org/10.13016/dspace/wnqf-opxl
dc.identifier.citationMunshi, S.; Neupane, K.; Ileperuma, S.M.; Halma, M.T.J.; Kelly, J.A.; Halpern, C.F.; Dinman, J.D.; Loerch, S.; Woodside, M.T. Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses. Viruses 2022, 14, 177.
dc.identifier.urihttp://hdl.handle.net/1903/31155
dc.language.isoen_US
dc.publisherMDPI
dc.relation.isAvailableAtCell Biology & Molecular Geneticsen_us
dc.relation.isAvailableAtDigital Repository at the University of Marylanden_us
dc.relation.isAvailableAtCollege of Computer, Mathematical & Natural Sciencesen_us
dc.relation.isAvailableAtUniversity of Maryland (College Park, MD)en_us
dc.subjectcoronavirus
dc.subjectSARS-CoV-2
dc.subjectprogrammed ribosomal frameshifting
dc.subjecttranslation
dc.subjecttherapeutics
dc.titleIdentifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses
dc.typeArticle
local.equitableAccessSubmissionNo

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