DNA mimic foldamers to interfere in DNA-protein interactions

Loos, Manuel (2026): DNA mimic foldamers to interfere in DNA-protein interactions. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Foldamers are abiotic oligomers that fold into defined three-dimensional structures, similarly to the biomolecules that inspired their design. Among them, aromatic oligoamide foldamers bearing negatively charged side chains can reproduce the double-helical array of negative charges characteristic of B-form DNA. They have been shown to inhibit several enzymes, including topoisomerase I and HIV-1 integrase in the presence of their canonical DNA ligand and outcompete DNA in binding affinity against other DNA binding proteins. These properties make them a versatile platform to interfere with protein-DNA interactions. This thesis focuses on the design, synthesis, structural and functional characterization of these foldamers. Central to this work is the development of an expanded library of monomeric building blocks for a peptide-like solid-phase synthesis of oligomers. This includes novel dimeric macromonomers, which have enabled the efficient production of foldamers of sufficient length to engage in complex biomolecular interactions. By using a combination of spectroscopic methods and computational techniques, the structural dynamics of these foldamers were investigated. The simulations revealed that the global flexibility parameters for twisting and bending of the foldamer helices are of similar magnitude to those of B-DNA, though distinct kinking events and motions are involved. We demonstrate that they are stable over a wide range of pH values, temperatures and salt concentrations. An assay was developed to quantitatively assess foldamer helix stability through measurement of the rate of interconversion between right-handed and left-handed diastereomeric conformers. Unexpectedly, suppressing some negatively charged side chains had a destabilizing effect on the helix, suggesting a more complex role of the side chains than electrostatic repulsions. Through collaboration, we characterized the binding of a DNA mimic foldamer to a multiprotein complex that senses extranucleosomal DNA. Using cryogenic electron microscopy, we were able to visualize the foldamer both as aggregated clusters in vitreous ice and in complex with the A-module of the INO80 chromatin remodeling complex. To target sequence selective DNA-binding proteins, we designed and synthesized a linker unit that interfaces DNA and DNA mimic foldamers. It serves both as a hairpin turn and as an anchor for ligating a foldamer, keeping their rims and grooves in register. These chimeric molecules may mutually benefit from the high affinities of DNA mimic foldamers and the sequence information provided by the DNA component. As such, they pave the way toward competitive inhibitors of protein-DNA interactions involving sequence-selective DNA-binding proteins as a new generation of DNA decoys.

• 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: 13. Februar 2026
• 1. Bericht­erstatter:in: Huc, Ivan