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Peptidomimetics have gained great attention for their function as protein-protein interaction (PPI) inhibitors. Herein, we report the design and investigation of a series of right-handed helical heterogeneous 1:1 α/Sulfono-γ-AA peptides as unprecedented inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous 1:1 α/Sulfono-γ-AA peptides were shown to bind tightly to MDM2 and MDMX, with K of 19.3 and 66.8 nM, respectively. Circular dichroism spectra, 2D-NMR spectroscopy, and the computational simulations suggested that these helical sulfono-γ-AA peptides could mimic the critical side chains of p53 and disrupt p53/MDM2 PPI effectively. It was noted that these 1:1 α/Sulfono-γ-AA peptides were completely resistant to proteolytic degradation, boosting their potential for biomedical applications. Furthermore, effective cellular activity is achieved by the stapled 1:1 α/Sulfono-γ-AA peptides, evidenced by significantly enhanced p53 transcriptional activity and much more induced level of MDM2 and p21. The 1:1 α/Sulfono-γ-AA peptides could be an alternative strategy to antagonize a myriad of PPIs.d of 19.3 and 66.8 nM, respectively. Circular dichroism spectra, 2D-NMR spectroscopy, and the computational simulations suggested that these helical sulfono-γ-AA peptides could mimic the critical side chains of p53 and disrupt p53/MDM2 PPI effectively. It was noted that these 1:1 α/Sulfono-γ-AA peptides were completely resistant to proteolytic degradation, boosting their potential for biomedical applications. Furthermore, effective cellular activity is achieved by the stapled 1:1 α/Sulfono-γ-AA peptides, evidenced by significantly enhanced p53 transcriptional activity and much more induced level of MDM2 and p21. The 1:1 α/Sulfono-γ-AA peptides could be an alternative strategy to antagonize a myriad of PPIs.

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.

Though antibiotics have been used for decades to treat bacterial infections, there is a great need for new treatment methods. Bacteria are becoming resistant to conventional antibiotics, as is the case with Methicillin resistant Staphylococcus aureus (MRSA). Herein we report the design of a series of lipidated α/Sulfono-α-AA heterogeneous peptides as mimics for Host Defense Peptides (HDPs). Utilizing fluorescence microscopy and depolarization techniques, our compounds demonstrate the ability to kill Gram-positive bacteria through cell membrane disruption. This mechanism of action makes it difficult for bacteria to develop resistance. Further time kill studies and hemolytic assays have also proven these compounds to be efficient in their ability to eradicate bacteria cells while remaining non-toxic to human red blood cells. This new class of peptidomimetics shows promise for the future antibiotic treatment of MRSA., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We show that submicron-sized patterns can be imprinted into soft, recombinant-engineered protein hydrogels (here elastin-like proteins, ELP) by transferring wavy patterns from polydimethylsiloxane (PDMS) molds. The high-precision topographical tunability of the relatively stiff PDMS is translated to a bio-responsive, soft material, enabling topographical cell response studies at elastic moduli matching those of tissues. Aligned and unaligned wavy patterns with mold periodicities of 0.24-4.54 μm were imprinted and characterized by coherent anti-Stokes Raman scattering and atomic force microscopy. The pattern was successfully transferred down to 0.37 μm periodicity (width in ELP: 250 ± 50 nm, height: 70 ± 40 nm). The limit was set by inherent protein assemblies (diameter: 124-180 nm) that formed due to lower critical solution temperature behavior of the ELP during molding. The width/height of the ELP ridges depended on the degree of hydration; from complete dehydration to full hydration, ELP ridge width ranged from 79 ± 9% to 150 ± 40% of the mold width. The surface of the ridged ELP featured densely packed protein aggregates that were larger in size than those observed in bulk/flat ELP. Adipose-derived stem cells (ADSCs) oriented along hydrated aligned patterns with periodicities ≥0.60 μm (height ≥170 ± 100 nm), while random orientation was observed for smaller distances/amplitudes, as well as flat and unaligned wavy ELP surfaces. Hence, micro-molding of ELP is a promising approach to create tissue-mimicking, hierarchical architectures composed of tunable micron-sized structures with nano-sized protein aggregates, which opens the way for orthogonal screening of cell responses to topography and cell-adhesion ligands at relevant elastic moduli.

New types of foldamer scaffolds are formidably challenging to design and synthesize, yet highly desirable as structural mimics of peptides/proteins with a wide repertoire of functions. In particular, the development of peptidomimetic helical foldamers holds promise for new biomaterials, catalysts, and drug molecules. Unnatural l-sulfono-γ-AApeptides were recently developed and shown to have potential applications in both biomedical and material sciences. However, d-sulfono-γ-AApeptides, the enantiomers of l-sulfono-γ-AApeptides, have never been studied due to the lack of high-resolution three-dimensional structures to guide structure-based design. Herein, we report the first synthesis and X-ray crystal structures of a series of 2:1 l-amino acid/d-sulfono-γ-AApeptide hybrid foldamers, and elucidate their folded conformation at the atomic level. Single-crystal X-ray crystallography indicates that this class of oligomers folds into well-defined right-handed helices with unique helical parameters. The helical structures were consistent with data obtained from solution 2D NMR, CD studies, and molecular dynamics simulations. Our findings are expected to inspire the structure-based design of this type of unique folding biopolymers for biomaterials and biomedical applications.