Graziano, Raffaele (2024) Biophysical characterization and selective targeting of G-quadruplex nucleic acids for the development of potential anticancer agents. [Tesi di dottorato]

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Abstract

In addition to canonical nucleic acid conformations, noncanonical secondary structures such as G-quadruplexes (G4s) are present in key regions of the human genome, including telomeres and gene promoters. G4 structures play critical roles in biological processes such as telomere maintenance, malignant transformation, and cancer progression. This PhD thesis is divided into two main sections: the first focuses on the characterization of G4 structures, while the second explores strategies for targeting these structures for therapeutic purposes. CHAPTER 1 offers an overview of nucleic acids and noncanonical oligonucleotide conformations, emphasizing their structural features and biological relevance. CHAPTER 2 details the primary biophysical methodologies utilized in the studies presented in subsequent chapters. CHAPTER 3 reports a study on cytosine epigenetic modifications and conformational changes in G4-forming sequences from the promoters of the WNT1 and c-KIT genes, performed mainly by of UV resonance Raman (UVRR) spectroscopy. CHAPTER 4 describes the identification of the long non-coding RNA RP11-350G8.5 as a therapeutic target in multiple myeloma. Five G-rich sequences from this lncRNA were investigated to evaluate their ability to form G4 structures in solution, thus providing a promising avenue for therapeutic intervention. CHAPTER 5 reports the study of the interaction of a peptide containing an RG-rich motif (NIQI) with biologically relevant G4s of different topologies, contributing to paving the way for the design and application of a novel class of peptide-based G4 ligands. CHAPTER 6 examines the selective targeting of G4s within the c-KIT oncogene promoter using peptide nucleic acid (PNA) sequences. This research was conducted under the supervision of Dr. Enrico Cadoni and Prof. Annemieke Madder at Ghent University (Ghent, BE), where I spent one year as a visiting PhD student. The study evaluates the effect of ligand-conjugated PNAs on G4 structures, offering a promising approach for regulating oncogene expression. The thesis concludes with a summary of the GENERAL CONCLUSIONS and includes an APPENDIX of published scientific articles, except for PAPER IV, which is still in preparation.

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