Abstracts
Short talk 5
Targeting Pathogenic Repeat Expansion RNAs with Small Synthetic Molecules: Structural Rearrangements and Therapeutic Implications
Presenting Author: Agnieszka Kiliszek
Institute of Bioorganic Chemistry Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, PL, kiliszek@ibch.poznan.pl
Author(s)
Prof. Agnieszka Kiliszek1, Dr. Leszek Błaszczyk
The presented work is part of our crystallographic studies focused on the structural analysis of interactions between disease-related RNAs and synthetic molecules. Recent progress in high-throughput screening of small-molecule libraries has led to the discovery of numerous drug-like compounds. However, their further optimization requires the determination of three-dimensional structures revealing the molecular details of RNA–ligand interactions.
The abnormal expansion of repetitive sequences within specific genes gives rise to mutant RNAs that acquire pathogenic properties. Specific binding of small molecules to these mutant RNAs can interfere with pathological pathways and potentially prevent disease progression.
Using X-ray crystallography and biophysical methods, we analysed a series of small molecules that recognize unique patterns of nucleobases engaged in non-canonical base pairing or exposed within single-stranded regions of repeat expansion RNAs. The structures of the complexes enabled a detailed characterization of RNA–ligand interactions and revealed how small molecules can induce structural rearrangements of RNA molecules. Moreover, these structural insights lay the foundation for the rational design of therapeutics targeting pathogenic repeat expansion RNAs and for improving computational predictions of RNA–ligand recognition.
Acknowledgment: NCN UMO-2022/45/B/NZ7/03543 and UMO-2017/26/E/NZ1/00950; PLGrid PLG/2025/018816 and PLG/2026/019240.