Andreozzi, Giorgia (2026) Design and synthesis of small molecules as modulators of microRNA function in neurodegenerative diseases. [Tesi di dottorato]

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Abstract

This research aims to explore the therapeutic potential of microRNAs by developing small molecules capable of modulating their expression and functions. This project focuses on the design and synthesis of a series of compounds, building on previous studies in the literature on the structure-activity relationship (SAR) of RNA structure binders. Some of the synthesised compounds were tested in vitro by analysing their toxicity and evaluating their effects under condition of oxygen and glucose deprivation in order to explain the role in neurodegenerative diseases. In addition, for some of these compounds, miRNA expression was evaluated following their administration. The microRNAs examined were: miR-150, miR-181, miR-218, and miR-223, whose 3D structures were subsequently predicted in order to conduct molecular docking studies to examine their interactions with the synthesised small molecules. The intriguing aspect that emerged from this work is undoubtedly its application to the treatment of ischaemic stroke, but potentially also to a series of neurodegenerative diseases involving microRNAs, given their countless targets. Therefore, the synthesised compounds not only represent modulators to be further investigated but are also starting points for expanding knowledge on RNA binders, both for the further design of molecules that share the same scaffolds and for refining the mechanism of action through which miRNA modulation is essential in conditions of ischaemia.

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