Versatile use of advanced NMR techniques for the identification of compounds able to interfere with ELAV protein−mRNA complexes

Abstract

The ultimate goal of the project in which this thesis took part is to develop a new series of small, drug like organic molecules able to modulate the stability of protein−RNA complexes involved in several diseases, thus regulating gene expression with an unprecedented mode of action and opening the way to a new class of therapeutic agents. I focused my research on ELAV protein HuR due to its involvement in several pathologies (i.e., cancer, retinopathy, etc.) in which the protein is overexpressed/hyper activated with consequences on target RNAs and their activity (i.e., transcription). In this context, the main aim would be to develop small molecules able to bind HuR and interfere with the formation and/or the stability of its complexes with target RNAs. Given the early stage of this research topic, the work was articulated in three main blocks: 1. Implementation of a systematic biophysical and in silico approach exploiting complementary and informative methods; 2. Design and synthesis of new ligands according to both a structure-based (in silico) and fragment-based (based on experimental fragment screening) approach; 3. Biophysical assessment of the interaction between compounds and target protein (HuR).