Diakogiannaki, Isidora (2026) Biocomputing for the Discovery of RNA-based Therapeutics and Targeting Agents to Challenge Human Diseases. [Tesi di dottorato]

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Abstract

RNA plays a central role in molecular biology, participating in a wide range of cellular functions. Owing to its structural versatility, RNA can adopt diverse motifs, enabling specific molecular recognition and interactions with proteins, DNA, small molecules, and ions. As a large fraction of the human genome is transcribed into non-coding RNAs, RNA represents a promising target for therapeutic intervention. In this thesis, RNA-based therapeutics were investigated from three complementary perspectives, highlighting the potential of RNA in drug discovery. First, RNA was studied as a ligand for the EphA2 receptor, a target implicated in glioblastoma multiforme stem cells. The structure of the A40s RNA aptamer and its interaction with EphA2 were characterized, and the resulting model provides key insights for the rational optimization of A40s variants targeting EphA2-positive glioblastoma. In the second project, we evaluated the state-of-the-art force fields OL3, OL3 cP-ghbfix21, Shaw, and DES-AMBER for Molecular Dynamics simulations across a diverse set of RNA motifs. This analysis revealed strengths and limitations in their ability to accurately capture RNA structure and dynamics, providing guidance for the development of improved RNA force fields. Finally, the tau RNA exon 10–intron hairpin was targeted with small molecules to restore its structural stability and modulate alternative splicing. Through AI-based virtual screening, NMR spectroscopy, and biological assays, a small molecule was identified that binds tau RNA and modulates the 3R:4R tau isoform ratio. Overall, this work demonstrates the potential of RNA-focused drug discovery through the synergistic integration of computational and experimental approaches.

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