Aromatic foldamers: mimicking the DNA surface to target DNA-binding proteins

Wu, Jiaojiao (2025): Aromatic foldamers: mimicking the DNA surface to target DNA-binding proteins. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Protein-nucleic acid interactions are fundamental in various biological processes and thus represent attractive targets for therapeutic intervention. Consequently, numerous molecules mimicking the feature of DNA have been developed and interfere with pharmacologically relevant protein-DNA interactions. Among these strategies, aromatic foldamers stand out as a new class of molecules that give access to functions beyond natural DNA. Specifically, aromatic oligoamides that mimic the charge surface of B-DNA have shown the potential in inhibiting the activity of several non-sequence selective DNA-binding proteins. Despite these advances, a major challenge remains: designing DNA mimics that can outcompete DNA for binding to sequence-selective DNA-binding proteins. In this thesis, we attempted to address this challenge by feature-driven design of DNA mimic foldamers. We introduced stereo genic centre, C2-symmetry and sticky ends to enhance foldamer's similarity to double-stranded B-DNA. These new designs lead to the quantitative control of helical handedness, the construction of a foldamer mimicking palindromic DNA, and, significantly, the first crystal structure of a DNA mimic foldamer bearing anionic phosphonic side chains. Based on the optimization of DNA mimic foldamers, we attempted to investigate their interactions with the chromosomal protein Sac7d, a non-selective DNA-binding protein. Using a comprehensive set of techniques (including SPR, ITC, NMR, AFM and single-crystal X-ray crystallography), we demonstrated that DNA mimic foldamers bind to the DNA binding site of Sac7d but though a different mode, and that the binding affinity is orders of magnitude better than natural DNA. However the interactions between Sac7d and DNA mimic foldamers remain non sequenceselective. To advance toward sequence-selective protein recognition, we further modulated the foldamer's groove features by introducing new building blocks. Solution and solid-state studies confirm the new monomers' conformations and show their incorporation significantly changes helix flexibility and enhances groove characteristics, which is crucial to recognize specific DNA-binding proteins in the future. Overall, the work presented here validates the concept of using DNA surface mimicry as a potent DNA competitor to target DNA-binding proteins. Importantly, we obtained the first crystal structure of a protein-foldamer complex, providing the solid foundation for structural-based design to improve the binding affinity and specificity. These results, combined with improvements to the groove features of our DNA mimics, represent a major step toward optimizing DNA mimic foldamers for highly specific protein recognition.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 8. Dezember 2025
• 1. Bericht­erstatter:in: Huc, Ivan