Event

Title: Sequence-based design of small molecules targeting RNA structure
Speaker: Matthew Disney
Affiliation: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology
When? 9 February, 2 - 3 pm
Where? CeMM, Large and Small Seminar Rooms
Hosts: Georg Winter, Stefan Kubicek, SCP3 Organizers

Abstract:
One major scientific challenge is to understand biological pathways and to exploit the targets within them for therapeutic development.  Coding and non-coding RNAs both directly cause disease, whether by mutation or aberrant expression.  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 targeting disease relevant RNA structures to perturb and study their function.  In this talk, I will describe using 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.  Recently, we have devised a strategy to imbue biologically silent RNA-small molecule interactions with cellular activity.  In particular, chimeras comprising an inactive small molecule and ribonuclease recruiter trigger targeted 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.

About the speaker:
Dr. Matthew Disney’s laboratory focuses on deciphering how small molecules recognize RNA, a challenging but crucial area in chemical biology. He has pioneered a “bottom‑up” strategy that identifies RNA structural motifs with a natural affinity for small molecules, catalogs them, and uses this information to design highly selective, multivalent ligands that target disease‑causing RNAs - an approach that earned him the Eli Lilly Award in Biological Chemistry. His team developed Two‑Dimensional Combinatorial Screening and the StARTS analytical method to map RNA–small molecule interactions and predict affinity and selectivity, alongside computational tools that enable transcriptome‑wide design of bioactive RNA‑targeting compounds. These efforts have yielded some of the most selective RNA‑binding small molecules known, including agents that modulate microRNAs implicated in cancer, neurological disorders, addiction, and viral infections. His group has also developed strategies that enable small molecules to cleave or react with target RNAs in cells and has determined the structures of disease‑related RNAs using NMR and X‑ray crystallography.