Chemical Biology Seminar
THIS WILL BE A HYBRID EVENT, limited in-person attendees must be vaccinated. Zoom is available.
A major scientific challenge is to understand biological pathways and to exploit the targets within them for therapeutic development. Coding and non-coding RNAs directly cause disease in varied ways. Akin to proteins, RNA structure often dictates its function in health or dysfunction in disease. RNA, however, is generally not considered a target for small molecule chemical probes and lead medicines, despite its immense potential. The focus of our research program is to uncover fundamental principles that govern the molecular recognition of RNA structures by small molecules to enable design of chemical probes that target disease relevant RNA structures to perturb and study their function.
In this talk, I will describe our efforts to use evolutionary principles to identify molecular recognition patterns between small molecules and RNA structures by studying the binding of RNA fold libraries to small molecule libraries. The resultant, privileged interactions are computationally mined across the human transcriptome to define cellular RNAs with targetable structure. Such an approach has afforded bioactive interactions that have uncovered new biology, where the small molecules bind to functional structures within a target RNA to inhibit or activation function. Recently, we have devised a strategy to imbue biologically silent RNA-small molecule interactions with cellular activity. Designed chimeras comprising an inactive RNA-binding small molecule and ribonuclease recruiting small molecule can affect RNA degradation of disease-causing RNAs. These degraders affect the biology of RNA in specific ways in cells and in mouse models of various diseases and can rationally reprogram protein-targeted medicines for RNA. There is much to learn about RNA structure-function relationships and one way to do it is to perturb RNA structures by using small molecules.