Designing Peptide-Derived Ligands that Target RNA

The design of RNA-binding molecules represents an outstanding challenge in drug discovery and chemical biology. Currently, oligonucleotide-based scaffolds represent the state-of-the-art, targeting RNA in a sequence-specific manner. Given the reduced cellular permeability of oligonucleotides however, alternative strategies have also been explored, particularly the development of ligands which recognize specific RNA structures. In this regard, RNA’s intrinsic flexibility and highly polar character often hampers the application of traditional, small molecules and has led researchers to explore diverse groups of intermediate- and larger-sized ligands. In recent years, interest has particularly grown in the use of peptides to bind discrete RNA structural motifs. Offering modular scaffolds which can be tuned to enhance both their functional and biological properties, a number of structure-based design strategies have yielded peptide-based ligands to target a variety “undruggable” targets. Inspired by such advances, in this thesis, structure-based design principles were used to generate a number of peptide-derived, RNA-binding ligands.