Helical aromatic oligoamide foldamers for peptide macrocycle and protein surface recognition

Wang, Lingfei (2025): Helical aromatic oligoamide foldamers for peptide macrocycle and protein surface recognition. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Proteins and peptides are essential biomolecules that regulate human homeostasis and maintain normal cellular functions. As key targets in disease research, understanding their interactions with various molecules is crucial for guiding drug design and development. However, most established principles/rules in drug design focus primarily on small molecules, there is a blank area in guiding the development of middle-size molecules like peptides. With the rapid advancements in peptide-based and antibody-drug therapeutics, expanding drug research into mid-sized molecular systems is increasingly important. Many types of aromatic oligoamides as structurally constrained oligomers, serve as valuable model systems due to their stable conformations in both aqueous and organic solutions. For a group of molecules with confined, folded structures, the term "foldamer" is used to describe them. In recent years, growing attention has been directed toward their interactions with biological targets. Moreover, the focus has gradually shifted from fundamental model systems to practical applications, highlighting their potential in drug discovery and development. In this work, helical aromatic oligoamide foldamers, based on quinoline (Q), benzene (B), and pyridine (P) rings as building blocks, are synthesized and studied in the field of recognition of peptide macrocycles as well as proteins. We first explore the potential of our foldamers with different side-chain presentations on the surface to randomly recognize a library of proteins (cell lysate). Submicromolar binding was observed, but P- and M-conformers did not differentiate from each other concerning binding affinities. Thanks to the stable helical structure of the foldamer, the interface, which is constituted by side chains of building blocks, can be precisely designed and has the potential to interact with other molecules. We then designed two series of foldamers with the same chemical formula but with different interfaces consisting of five biogenic side chains. The peptide macrocycle library built by the RaPID system (Random non-standard Peptide Integrated Discovery) was then selected against target foldamers. The selected peptide macrocycles showed high selectivity for a specific arrangement of foldamer side chains. This specificity was further proven by the fact that the selected peptides could exclusively bind one handedness of the helical foldamer, strongly suggesting that recognition might take place on the foldamer surface. Furthermore, we targeted a protein surface (HCA II) by tethering the foldamer with a nanomolar-binding protein ligand. Several new monomers were designed under the guidance of computational tools and synthesized to interact with the protein surface via their biogenic side chains. With four crystal structures of the complex between the foldamer and protein, we could prove that main chains are interchangeable in the context of the foldamer–protein complex. Side chains could be inserted into the foldamer structure without affecting the overall complex structures, which is different from peptide structure design. In conclusion, the development of side chains on Q and B monomers enables the design of various foldamer surfaces. The robustness of the foldamer helical structure could be further applied to structure-based design for covering large protein surface areas. The automatic synthesis of foldamers (on solid state) also brings the possibility of providing sequence libraries within a relatively short time compared with manual synthesis. These results present the high potential of aromatic oligoamide foldamers in recognizing peptide macrocycles and proteins

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Foldamer, Peptide macrocycle, Protein
• 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: 22. April 2025
• 1. Bericht­erstatter:in: Huc, Ivan