Marzano, Simona (2024) Exploring noncanonical nucleic acid structures: Biophysical characterization and interaction with proteins and potential drugs. [Tesi di dottorato]

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Abstract

Besides the canonical nucleic acid conformations, noncanonical secondary structures, such as G-quadruplexes (G4s) and i-motifs (iMs), are found in crit- ical areas of the human genome such as telomeres and gene promoters. G4 structures play a significant role in several biological processes, including te- lomere maintenance, malignant transformation, and cancer development. De- spite recent discussions and reviews on the structural aspects and potential bi- ological functions of iM structures, there is still much to learn about this unique nucleic acid conformation. In this PhD thesis, several studies have been carried out with the aim of char- acterizing these noncanonical secondary structures, as well as investigating their interaction with various molecules (proteins, small molecules, peptides). CHAPTER 1 provides a general description of nucleic acids and noncanonical oligonucleotide conformations, focusing on their structural properties and bi- ological roles. CHAPTER 2 discusses the main biophysical methodologies employed in the studies presented in the following chapters. CHAPTER 3 reports the study of four different DNA G4 structures as protein targets by employing a chemoproteomic approach. CHAPTER 4 describes the identification of new G4-targeting small molecules and peptides and the characterization of their interactions by means of a com- bination of physicochemical, mostly spectroscopic, techniques. Particularly, Paragraph 4.2 deals with an in-depth NMR characterization of the interaction between G4s and a new hit compound, conducted as a visiting PhD student in the laboratory of prof. Janez Plavec at Slovenian NMR Center in Ljubljana (SLO). CHAPTER 5 focuses on the investigation of the thermodynamics of folding of an iM-forming sequence, carried out with the aim of elucidating the unique features of these structures. The last section of this PhD thesis collects the GENERAL CONCLUSIONS. Finally, the APPENDIX reports the scientific articles published and cited throughout the thesis. PAPERS VI and VII are not included in the APPENDIX as they are still in preparation.

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