Abstract
Recurrent 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.
Highlights
The 21st century has seen a series of public health emergencies caused by zoonotic coronavirus (CoV) diseases: the SARS epidemic in 2002–2003, periodic MERS outbreaks since 2012, and the ongoing COVID-19 pandemic [1]
It is urgent to identify anti-viral therapeutics that are effective against a broad spectrum of CoVs, especially CoVs derived from bats, which are thought to have been the source of the previous 21st-century CoV zoonoses and are one of the most likely sources for future novel CoVs [2,3]
One possible target for developing broad-spectrum CoV therapeutics is a process that plays a key role in gene expression in all CoVs: −1 programmed ribosomal frameshifting
Summary
The 21st century has seen a series of public health emergencies caused by zoonotic coronavirus (CoV) diseases: the SARS epidemic in 2002–2003, periodic MERS outbreaks since 2012, and the ongoing COVID-19 pandemic [1]. The proteins needed for transcription and replication of the viral RNA in CoVs are encoded in ORF1b, which is out of frame with respect to ORF1a, and they are only expressed when the ribosome shifts into the −1 reading frame at a specific location in the viral genome [4] This programmed frameshift is directed by a tripartite signal in the mRNA that consists (from 50 to 30 ) of (i) a heptameric ‘slippery sequence’ where the readingframe shift occurs, (ii) a ~5–7-nucleotide (nt) spacer, and (iii) a structure in the mRNA that stimulates the frameshift [5,6,7]. An additional benefit of −1 PRF as a drug target is that it is orthogonal and complementary to more standard strategies of targeting viral proteins such as the RNA-dependent RNA polymerase (RdRP) or viral proteases, holding out the promise for combination therapies that could be effective when combining suppression of RdRP expression by −1 PRF inhibition with suppression of RdRP activity
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