Christopher C. Williams's research while affiliated with The Scripps Research Institute and other places

SARS-CoV-2 has exploded throughout the human population. To facilitate efforts to gain insights into SARS-CoV-2 biology and to target the virus therapeutically, it is essential to have a roadmap of likely functional regions embedded in its RNA genome. In this report, we used a bioinformatics approach, ScanFold, to deduce the local RNA structural landscape of the SARS-CoV-2 genome with the highest likelihood of being functional. We recapitulate previously-known elements of RNA structure and provide a model for the folding of an essential frameshift signal. Our results find that SARS-CoV-2 is greatly enriched in unusually stable and likely evolutionarily ordered RNA structure, which provides a large reservoir of potential drug targets for RNA-binding small molecules. Results are enhanced via the re-analyses of publicly-available genome-wide biochemical structure probing datasets that are broadly in agreement with our models. Additionally, ScanFold was updated to incorporate experimental data as constraints in the analysis to facilitate comparisons between ScanFold and other RNA modelling approaches. Ultimately, ScanFold was able to identify eight highly structured/conserved motifs in SARS-CoV-2 that agree with experimental data, without explicitly using these data. All results are made available via a public database (the RNAStructuromeDB: https://structurome.bb.iastate.edu/sars-cov-2) and model comparisons are readily viewable at https://structurome.bb.iastate.edu/sars-cov-2-global-model-comparisons.

Targeting RNAs with small molecules represents a new frontier in drug discovery and development. The rich structural diversity of folded RNAs offers a nearly unlimited reservoir of targets for small molecules to bind, similar to small molecule occupancy of protein binding pockets, thus creating the potential to modulate human biology. Although the bacterial ribosome has historically been the most well exploited RNA target, advances in RNA sequencing technologies and a growing understanding of RNA structure have led to an explosion of interest in the direct targeting of human pathological RNAs. This review highlights recent advances in this area, with a focus on the design of small molecule probes that selectively engage structures within disease-causing RNAs, with micromolar to nanomolar affinity. Additionally, we explore emerging RNA-target strategies, such as bleomycin A5 conjugates and ribonuclease targeting chimeras (RIBOTACs), that allow for the targeted degradation of RNAs with impressive potency and selectivity. The compounds discussed in this review have proven efficacious in human cell lines, patient-derived cells, and pre-clinical animal models, with one compound currently undergoing a Phase II clinical trial and another that recently garnerd FDA-approval, indicating a bright future for targeted small molecule therapeutics that affect RNA function.