Development of helical aromatic oligoamide foldamers for protein recognition

Sanchez, Florian (2025): Development of helical aromatic oligoamide foldamers for protein recognition. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Protein-protein interactions (PPIs) are key regulators of cellular signaling and represent promising yet complex therapeutic targets. Advances in chemical biology and structural computational tools now enable the design of molecules to modulate these interfaces. Inspired by natural biopolymer folding, aromatic oligoamide foldamers (AOFs) offer synthetically accessible, stable helical frameworks with predictable side-chain orientation, making them attractive candidates for functional design and drug discovery. This thesis presents the design and synthesis of novel building blocks for AOFs, enhancing the chemical diversity of the quinoline (Q) scaffold through targeted substitutions at positions 4, 5, 6, and 4,6. New methodologies enabled the incorporation of diverse biogenic side chains: cationic, anionic, polar, and hydrophobic. These new building blocks broaden the capabilities of AOFs for biomolecular recognition. Mechanistic studies of solid phase foldamer synthesis (SPFS) led to optimised protocols for automated synthesiser, allowing efficient parallel production of up to three AOF sequences. Making use of the newly established protocols and biogenic side chains, an AOF was designed and synthesised to randomly recognise a library of protein (affitin and affibody), clones were identified and submicromolar binding was observed for the racemic Q12 AOF candidate. We discovered an AOF capable of binding two structurally distinct protein scaffolds: β-sheet-based (affitin) and α-helical (affibody) selected via mRNA and phage display, respectively. Solution studies enabled truncation of the AOF to its minimal binding epitope. Notably, the AOF exhibits enantioselective recognition of both targets, driven by its intrinsic P-handedness. In an attempt to target the bio-relevant interaction between linear di-ubiquitin and the coiled-coil domain of NEMO, AOFs candidates were designed to mimic the interaction of the coiled-coil on the surface of the ubiquitin. Each AOF incorporated covalent linkers via triphosgene activation and an activated disulphide for site-specific ligation. Solution-state NMR confirmed local environmental perturbations upon ligation, although initial crystallisation attempts were unsuccessful. Modifications to linker length and side-chain composition enabled reproducible crystal formation, yet structural resolution remained limited due to poor diffraction and asymmetric unit complexity. In conclusion, this work highlights the synthetic versatility and functional potential of aromatic oligoamide foldamers (AOFs). The integration of diverse biogenic side chains and streamlined automated protocols enabled the generation of AOFs with submicromolar affinities for distinct protein targets. These findings underscore the promise of AOFs as adaptable molecular tools for protein recognition and interface mimicry in biologically relevant contexts.

• 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: 12. Dezember 2025
• 1. Bericht­erstatter:in: Huc, Ivan