Sulfono-γ-AApeptides as Helical Mimetics: Crystal Structures and Applications

Area of Science:

• * Chemical Biology
• * Materials Science
• * Supramolecular Chemistry

Background:

• * Foldamers offer predictable structures, proteolytic resistance, and chemical diversity for biomedical and material applications.
• * Natural macromolecules have diverse structures and functions, necessitating exploration of novel unnatural foldameric architectures.
• * γ-AApeptides, inspired by chiral peptide nucleic acid backbones, are a new class of peptidomimetics with proteolytic resistance and functional group versatility.

Purpose of the Study:

• * To introduce sulfono-γ-AApeptides, a subclass of γ-AApeptides, and elucidate their helical structures.
• * To explore the structure-based design and potential applications of these novel helical foldamers.
• * To highlight the development of unnatural peptidomimetics for advanced applications in chemistry, biology, and medicine.

Main Methods:

• * Single-crystal X-ray crystallography to determine the structures of helical sulfono-γ-AApeptides.
• * Design and synthesis of various sulfono-γ-AApeptide architectures, including homogeneous and hybrid peptides.
• * Investigation of biological applications, including disruption of protein-protein interactions and biomimicry.

Main Results:

• * Crystal structures reveal that sulfono-γ-AApeptides fold into unique, well-defined helices with distinct helical parameters.
• * Demonstrated potential for disrupting key protein-protein interactions, such as BCL9-β-catenin and p53-MDM2/MDMX.
• * Showcased mimicry of biologically relevant peptides like glucagon-like peptide 1 (GLP-1) and potential in material science.

Conclusions:

• * The established structure of helical sulfono-γ-AApeptides enables rational design for mimicking protein helical domains.
• * Sulfono-γ-AApeptide-based foldamers represent a new class of unnatural peptidomimetics with significant potential in diverse scientific fields.
• * This work opens new avenues for developing novel foldamers with unique structural and functional properties for various applications.