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

Abstract

Conspectus Foldamers have defined and predictable structures, improved resistance to proteolytic degradation, enhanced chemical diversity, and are versatile in their mimicry of biological molecules, making them promising candidates in biomedical and material applications. However, as natural macromolecules exhibit endless folding structures and functions, the exploration of the applications of foldamers remains crucial. As such, it is imperative to continue to discover unnatural foldameric architectures with new frameworks and molecular scaffolds. To this end, we recently developed a new class of peptidomimetics termed ″γ-AApeptides”, oligomers of γ-substituted-N-acylated-N-aminoethyl amino acids, which are inspired by the chiral peptide nucleic acid backbone. To date γ-AApeptides have been shown to be resistant to proteolytic degradation and possess limitless potential to introduce chemically diverse functional groups, demonstrating promise in biomedical and material sciences. However, the structures of γ-AApeptides were initially unknown, rendering their rational design for the mimicry of a protein helical domain impossible in the beginning, which limited their potential development. To our delight, in the past few years, we have obtained a series of crystal structures of helical sulfono-γ-AApeptides, a subclass of γ-AApeptides. The single-crystal X-ray crystallography indicates that sulfono-γ-AApeptides fold into unprecedented and well-defined helices with unique helical parameters. On the basis of the well-established size, shape, and folding conformation, the design of sulfono-γ-AApeptide-based foldamers opens a new avenue for the development of alternative unnatural peptidomimetics for their potential applications in chemistry, biology, medicine, materials science, and so on. In this Account, we will outline our journey on sulfono-γ-AApeptides and their application as helical mimetics. We will first briefly introduce the design and synthetic strategy of sulfono-γ-AApeptides and then describe the crystal structures of helical sulfono-γ-AApeptides, including left-handed homogeneous sulfono-γ-AApeptides, right-handed 1:1 α/sulfono-γ-AA peptide hybrids, and right-handed 2:1 α/sulfono-γ-AA peptide hybrids. After that, we will illustrate the potential of helical sulfono-γ-AApeptides for biological applications such as the disruption of medicinally relevant protein–protein interactions (PPIs) of BCL9−β-catenin and p53-MDM2/MDMX as well as the mimicry of glucagon-like peptide 1 (GLP-1). In addition, we also exemplify their potential application in material science. We expect that this Account will shed light on the structure-based design and function of helical sulfono-γ-AApeptides, which can provide a new and alternative way to explore and generate novel foldamers with distinctive structural and functional properties.

Synthesis of sulfonopeptides

“…Thus, it is reasonable to consider sulfonopeptides or peptides with certain sulfonamide moiety as potential medicinal candidates. Recently, N-sulfonylated peptides 106 and the modification of the sulfonamidecontaining peptides 107,108 have been paid more and more attention.…”

Geared Toward Applications: A Perspective on Functional Sequence-Controlled Polymers

“…Besides inhibiting the p53–hDM2 interactions, β 3 -peptide has also been developed to serve as HIV fusion inhibitors. They further developed a β 3 -decapeptide with a non-natural trifluoromethylbenzene side chain that inhibited the HIV gp41-mediated fusion with a CC 50 /EC 50 ratio of 8, a major improvement compared to previous works. , Cai et al developed an impressive class of sulfono-γ-AApeptides that can reproducibly fold into well-defined helical structures. − They demonstrated that these sulfono-γ-AApeptide helices were excellent mimicries of α-helices in several therapeutically relevant protein–protein interactions and could serve as inhibitors or agonists to these interactions, such as BCL9-β-catenin, p53-MDM2/MDMX, and glucagon peptide-GLP-1R. − …”

Morphology Transformation of Foldamer Assemblies Triggered by Single Oxygen Atom on Critical Residue Switch

“…Over the last few decades, conformationally well‐defined short peptides have been intensively studied to design peptide‐based drugs [ 1–2 ] and organic functional materials. [ 3–4 ] In particular, the helical peptide foldamers composed of nonproteinogenic amino acids have attracted enormous attention because they possess a strong tendency to adopt a robust helix with a relatively small number of residues (6–8 residues) in solution. [ 5–9 ] Since the foldamer's helical types that originate from intramolecular hydrogen‐bonding patterns are predictable and controllable at the molecular level, more sophisticated structures that are not found in nature can be designed with foldamers from scratch.…”